# NDR2 kinase: A review of its physiological role and involvement in carcinogenesis

Tiphaine Biojout, Emmanuel Bergot, Benoit Bernay, Guénaëlle Levallet, Jérôme Levallet

► To cite this version:

Tiphaine Biojout, Emmanuel Bergot, Benoit Bernay, Guénaëlle Levallet, Jérôme Levallet. NDR2 kinase: A review of its physiological role and involvement in carcinogenesis. International Journal of Biological Macromolecules, 2025, 311, pp.143656. 10.1016/j.ijbiomac.2025.143656. hal-05057193

HAL Id: hal-05057193

https://normandie-univ.hal.science/hal-05057193v1

Submitted on 27 May 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

Review

# NDR2 kinase: A review of its physiological role and involvement in carcinogenesis

<figure><img src="image_3.png" /></figure>

Tiphaine Biojout<sup>a</sup>, Emmanuel Bergot<sup>a,b</sup>, Benoit Bernay<sup>c</sup>, Guénaëlle Levallet<sup>a,d,*</sup>,
Jérôme Levallet<sup>a</sup>

ARTICLE INFO

Keywords:

NDR2
cancer

Therapeutic target

Lung cancer

Hippo pathway

A B S T R A C T

The Hippo kinase, NDR2, plays a key role in the natural history of several human cancers, particularly lung cancer, by regulating processes such as proliferation, apoptosis, migration, invasion, vesicular trafficking, autophagy, ciliogenesis and immune response. To examine the specificity of NDR2's action, interaction and function in physiological or tumoral contexts, we first focus on the structural differences in the amino-acid sequence between NDR1 and NDR2. We then establish a correlation between these NDR1/2 differences and specific post-translational regulation, as well as the distinct action, interactions, and functions of NDR2 in physiological or tumoral paradigms, such as lung cancer. Furthermore, the full set of NDR2 partners and/or substrates remains to be identified. Given that it is hypothesized that NDR2 and its partners may offer new perspectives for anticancer therapies, we emphasize potential clustering or functional enrichment networks among the NDR2-specific interactants. Additionally, we provide an unpublished proteomic comparison of the NDR1 versus NDR2 interactome, focusing on human bronchial epithelial cells (HBEC-3), lung adenocarcinoma cells (H2030), and their brain metastasis-derived counterparts (H2030-BrM3). In conclusion, this study underscores the pivotal role of NDR2 in cancer progression, particularly lung cancer, and helps to better understand their specific functions and interactions in both normal and tumor contexts. The identification of NDR2 partners and substrates remains essential, with the potential to open new avenues for anticancer therapies.

# 1. Introductory overview

The serine/threonine kinase NDR was initially identified in the budding yeast *Saccharomyces cerevisiae* [1]. It was later described in *Neurospora crassa* [2], in Drosophila homolog [3], and in human cells and designated NDR1/2 kinases [4].

In mammals, the NDR/LATS kinase family consists of four members: NDR1 (STK38), NDR2 (STK38L), LATS1 and LATS2. These proteins belongs to the subclass of serine/threonine protein kinases A, G and C (AGC) in the Hippo signaling pathway, a tumor suppressor pathway [5]. Members of the NDR/LATS kinase family are involved in a wide range of biological processes, including cell division and morphology, regulation of infection and inflammation as well as apoptosis and tumor suppression [6,7]. Comprehensive and details reviews outline the functions and roles of NDR1/2 kinases in the Hippo signaling pathway [6] and in

various aspects of human physiology and pathology, including cancer [8–10]. Due to their structural similarity [11], NDR1/2 kinases are often treated as interchangeable; however, NDR1 and NDR2 actually play distinct or even opposing roles in cancer. For instance, NDR1 has been shown to suppress the epithelial-mesenchymal transition (EMT) and subsequent metastasis of prostate cancer cells [12,13], while NDR2 has been implicated in the invasion and cytokinesis defects of lung cancer cells [14] and the brain metastasis of non-small cell lung cancer (NSCLC) [15]. The current lack of knowledge regarding NDR2 compared to other NDR kinases is addressed in this review, which focuses on the differences in action, interaction and functions of NDR2 kinase.

<footnote><sup>a</sup> Université de Caen Normandie, CNRS, Normandie Université, ISTCT UMR6030, GIP CYCERON, F-14000 Caen, France</footnote>

<footnote><sup>b</sup> Centre Hospitalier Universitaire de Caen Normandie, Département de Pneumologie et d'Oncologie thoracique, F-14000 Caen, France</footnote>

<footnote><sup>c</sup> Université de Caen Normandie - Plateforme PROTEOGEN, US EMerode, 14032 Caen, cedex 5, France</footnote>

<footnote><sup>d</sup> Centre Hospitalier Universitaire de Caen Normandie, Département de Pathologie, F-14000 Caen, France</footnote>

<footnote>* Corresponding author at: ISTCT-UMR6030, OncoCARE group, Avenue H.Becquerel, 14074 Caen, France.</footnote>

<footnote>E-mail address: guenaelle.levallet@unicaen.fr (G. Levallet).</footnote>
## 2. Structure and regulation of NDR1/2 kinases: Similarities and differences

### 2.1. Regulation of NDR1/2 activity

#### 2.1.1. The Canonical signaling pathway

The activation of NDR1/2 is a multistep process involving binding of MOB1 (Mps-One-Binder 1 protein), an allosteric co-activator, auto-phosphorylation of S281/282 which is necessary for full activation of NDR1/2 and phosphorylation of the hydrophobic motif site T444/442 by upstream MST kinases [16–19]. The adaptor protein MOB1 is phos-phorylated by MST1/2 to form the MOB1/NDR1/2 complex [5,8]. MST1/2 and MST3, another member of the MST kinase family, can phosphorylate and activate NDR1/2 on the hydrophobic motif phos-phorylation site T444/442 [5,20,21]. The binding of co-activators, MOB1A/B or MOB2, to the NTR domain of NDR1/2 releases the auto-inhibition exerted in the catalytic domain by the basic residue-rich insert (autoinhibitory sequence (AIS), residues 244–276 in NDR1). This release allows for efficient autophosphorylation of S281/282, located in the activation segment, thereby enhancing NDR1/2 activity [11,22]. However, MOB2 also acts as a competitive antagonist of MOB1A, pre-venting the autophosphorylation of NDR1/2 and consequently blocking

their activity [19,23]. Conversely, both S281/282 and T444/442 can be dephosphorylated by protein phosphatase type 2 A (PP2A) [24]. Furry (FRY) is a critical regulator of NDR1 activation, functioning as a scaffold that binds to both NDR1 and MOB2, thereby synergistically activating NDR1 with MOB2 [25]. In the FRY- Knock-out (KO) cells, the activities of NDR1 and NDR2 responsible for the phosphorylation of YAP-1 were suppressed, suggesting that NDR2 may also be regulated by Fry binding [26]. However, depletion of FRY did not affect LATS1/2 kinase activities [25].

#### 2.1.2. Additional actors of the NDR1/2 regulation

NDR1/2 kinases are also controlled by a calcium-dependent mech-anism. This process involves the binding of the S100B activator to the NTR domain of NDR1/2 which releases the autoinhibitory motif and promotes the autophosphorylation of S281/282 [20,27,28]. Other ki-nases can control NDR1/2 by adding a phosphate group to T444/442 on the hydrophobic motif. For example, MAP4K-type kinases [10,29] or PDK1 can activate NDR2 during insulin-like growth factor 1 (IGF-1) signaling, promoting cell survival and invasion [30].

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** 2D/3D sequence comparison between NDR1 and NDR2 kinases. A. 2D sequence alignment of NDR1 and NDR2. The functional domains: N-terminal MOB coactivator binding domain (BD), S100B binding domain (BD), Basic-residue-rich insert, Activation segment, Hydrophobic domain and PTS1-like sequence were boxed. Phosphorylation, SUMOylation (SUMO.), Acetylation (Acet.) and Ubiquitination (Ubi) sites are numbered and located by arrowhead. (For more details, see Supplemental Fig. 1) B. 3D predictive sequence NDR1 and NDR2. Functional domains and posttranscriptional modification site are localized. The same caption is used for panel A and B.</figcaption></figure>
## 2.2. NDR1/2 kinases: Sequence and structure

The NDR2 kinase exhibits a domain organization analogous to that of NDR1, with an 87 % similarity [11], and an 66 % to LATS1/2 kinases [27,28].

### 2.2.1. Key residues involved in NDR1/2 activity conserved between NDR1 and NDR2

In the catalytic kinase domain, the highly conserved domain (93 % similarity) between NDR1 and NDR2, includes (Fig. 1 and Supplemental Fig. 1): i) K118, which is involved in ATP binding [31], ii) two key regulatory phosphorylation sites [32], S282 (S281 in NDR1) in the activation segment and T442 (T444 in NDR1) in the hydrophobic motif at the C-terminal, iii) T74 and S91, which are involved in NDR1 binding to S100B activator [27] and stability [33], respectively. The phosphorylation of S91 by the MAPKK kinase (MAP3K) MEKK2 prevents the cleavage of NDR1 by heat and calpain. This demonstrate that S91 is important for the stability of NDR1 [20] and potentially for NDR2 as this phosphorylation site (S92) is conserved in the NDR2 sequence.

### 2.2.2. Potential site of regulation not conserved between NDR1 and NDR2

Amino acid (AA) variations have been identified at other sites of phosphorylation, which may consequently impact the structure, function and regulation of these two kinases in a distinct way.

In the N-terminal regulatory domain (NTR) of NDR1, the glycogen synthase kinase 3 (GSK-3) phosphorylates S6 and T7, thereby inhibiting NDR1 full activation [31]. This process is largely dependent on a PKA-mediated priming phosphorylation at residues S10 and S11, respectively [34]. However, this mechanism may be specific to NDR1, as, with the exception for T8, these phosphorylation sites are absent in the NTR of NDR2.

### 2.2.3. Posttranscriptional modification of NDR1/2 kinases

In addition to the phosphorylation sites, other amino acids have been shown to play a role in post-transcriptional modification (PTM) such as ubiquitination, SUMOylation or acetylation resulting to differential regulation of NDR kinases activities. SUMOylation, a highly dynamic and rapidly reversible PTM process with a similar enzymatic machinery to ubiquitination, inhibits the S282/T444 phosphorylation and subsequent activation of NDR2 [35]. The SENP2 (Sentrin/small ubiquitin-like modifier (SUMO)-specific proteases (SENPs)) targets NDR2 for de-SUMOylation at K432, enhancing NDR2 kinase activity and leading to p21 inhibition and cell cycle progression, which contributes to lung cancer cell growth [35]. NDR1 is also a target for SUMOylation, but at K465, the last AA residue of the NDR1 protein. However, this PTM has a minimal effect on NDR1 kinase activity and subcellular localization [36].

Lysine at position 463 (K463) in NDR2, analogous to K465 in NDR1, is not a SUMOylation site [36] but instead an acetylated site in NDR2. Acetylation of K463 is regulated by p300/CBP acetyltransferases and SIRT1 deacetylase [37], but consequences of acetylation on NDR2 activity and function remain unknown [35,37].

Cell starvation induced TRIM27-dependent ubiquitination of NDR2 at K73 and K119, resulting in its activation rather than its ubiquitin-mediated proteasomal degradation. This process forms a molecular complex that regulates autophagy and tumorigenesis [38]. Ubiquitination appears to be a common process regulatory mechanism for NDR/LATS kinases, potentially involving multiple E3 ligases. However, its impact on protein stability and subsequent kinase activity and function is isoform-specific for each Hippo kinase [39]. In response to hypoxia, the E3 ubiquitin ligase SIAH2 stimulates YAP-1 by destabilizing LATS2 in a human breast cancer cell line [40]. The protein sequence alignment between LATS2 and NDR2 reveals that the target sequence of SIAH2 is partially conserved in NDR2, suggesting that NDR2 could be a potential substrate of SIAH2 and thus regulated by hypoxia, in line with our recently published results in lung cancer and brain metastasis from

NSCLC [15].

## 2.3. Tissue specificity and subcellular localization

Although NDR1/2 share a high degree of similarity, each kinase exhibits distinct cellular expression and subcellular localization, suggesting that each kinase may have non-redundant functions. NDR2 is predominantly expressed in the brain [41–43], heart, thymus [11], small intestine, stomach and testis [31]. While both NDR1/2 share a nuclear localization signal (NLS)-like sequence located in the auto-inhibitory sequence (AIS) [31,32], the subcellular localization of NDR2 is mainly cytoplasmic, close to cytoskeletal elements or to the plasma membrane [11] or in centrosomes [16].

# 3. Specific functions of NDR2 kinase and its role in cancer

## 3.1. Functional activity of NDR1/2

In the Hippo pathway, activated NDR1/2 regulate the activity of their main downstream effectors YAP-1 and TAZ [8]. Phosphorylation of YAP-1/TAZ on multiple serine/threonine residues including S127 induces their cytoplasmic retention and 14-3-3-mediated proteasomal degradation [6,29]. YAP-1/TAZ proteins lack a DNA-binding domain and exert their effects mainly through association with DNA-binding proteins, with the TEAD proteins being their major partners. These interactions regulate the expression of target genes and have diverse physiological and pathological effects [44]. Indeed, YAP-1/TAZ proteins are closely associated with enzyme activity, cell proliferation, differentiation, tissue and organ growth and the production of proinflammatory factors [6].

Whether NDR1/2 functions are mainly mediated through the phosphorylation of the YAP-1/TAZ co-activator, the consensus phosphorylation motif, HXRXXpS/T [6], can also be found in other target substrates of NDR1/2 kinase. Some of these additional targets have already been identified for NDR1 and/or NDR2 such as Rabin8, p21, Par3 or CDC25A, illustrating the multiple roles of NDR1/2 [6].

The following section will focus on the specific role of NDR2 in different tissues and organs even in cases where no NDR2 substrate has yet been identified (Fig. 2). Deregulation of NDR2 functions contributes to tumor initiation and progression by promoting proliferation through support of cell cycle progression as well as migration and metastasis [45–47]. In addition, NDR2 mediates the transformation of healthy cells into malignant cells by inducing defects in cytokinesis [14,16]. However, NDR2 also plays context-dependent and tissue-specific roles in both oncogenesis and tumor suppression, which will be discussed in the next part and summarized in Fig. 3 (Fig. 3).

## 3.2. NDR2 in organogenesis and brain development

Concomitant KO models for NDR1/2 are not viable. Indeed, simultaneous loss of NDR1 and NDR2 in mice results in embryonic death, presumably due to cardiac malformation. However, this phenotype is not found in NDR1 or NDR2 single KO, suggesting a compensation between the two kinases and demonstrating their critical role in development [48]. This is further illustrated in mouse brain development, where loss of NDR2 disrupts neuronal polarization, preventing proper differentiation [46] and dendritic branching in the hippocampus [41]. For neuronal polarity, both NDR1/2 kinases can phosphorylate Par3 at S383 in a non-consensus sequence SPGRFpS. Phosphorylation at S383 inhibits the interaction of Par3 with dynein, thereby polarizing Par3 distribution and strengthening axon specification [49]. However, the regulation of integrin-dependent dendritic and axonal growth in mouse hippocampal neurons has only been demonstrated for NDR2 [41,50]. NDR2 induces phosphorylation at the T788/789 site of β1-integrin, a critical site for activity and trafficking, to stimulate PKC and CaMKII-dependent activation of β1-integrins and their exocytosis [41]. The
<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Roles of NDR2 in Physiological Processes.</figcaption></figure>

NDR2 is an essential protein involved in several biological processes. It plays a key role in organogenesis, particularly in the embryonic development of the brain and lungs. NDR2 promotes cell proliferation by being activated by MST3 and cyclin D1, which inhibits p21 and activates c-Myc. In apoptotic processes, NDR2 is activated by FASL/FAS signaling, which stimulates caspase-3 activity. Regarding autophagy, NDR2 has a dual role: it inhibits autophagy via Rabin8/mTORC while promoting it through Raph/Lpd, facilitating the transport of ATG9 A to endosomes for autophagosome formation. NDR2 is also involved in ciliogenesis by activating Rabin8, which aids in the transport of vesicles necessary for their assembly. Finally, NDR2 contributes to the immune response and inflammation by facilitating the migration of T cells and activating LFA-1 during antigen recognition.

NDR2: Nuclear Dbf2-related kinase 2 Cell Proliferation. MST1: Mammalian STE20-like protein kinase 1. Myc: Myelocytomatosis oncogene. p21: Cyclin-dependent kinase inhibitor 1 A (CDKN1A). FASL: Fas Ligand. FAS: Fas (CD95, APO-1). ATG9 A: Autophagy-related protein 9A. mTORC: Mammalian Target of Rapamycin Complex Raph/Lpd: Ras-associated and pleckstrin homology domains-containing protein 1 (RAPH1), also known as Lamellipodin. ULK1: Unc-51 Like Autophagy Activating Kinase 1. Rabin8: Ras-related protein Rab-8B effector protein. Rab: RAS related GTP-binding protein. ICAM-1: Intercellular Adhesion Molecule 1. LFA-1: Lymphocyte Function Associated antigen-1. TCR: T cell receptor. MHC: major histocompatibility complex.

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Role of the NDR2 kinase in variety of cancer.</figcaption></figure>

NDR2 plays varying roles in cancer. In breast cancer, NDR2 is activated by TRIM27 under starvation, leading to autophagy inhibition and tumor development. In lung cancer, NDR2 promotes cell proliferation and survival by inhibiting p21 and activating transcription factors like YAP-1, c-Jun, and HIF-1, facilitating tumor progression and metastasis (See Fig. 4 for more details). In colorectal cancer, NDR2 is activated by PDK1 through IGF-1 signaling, enhancing tumor cell survival and proliferation via ARK5 activation. In ovarian cancer, NDR2 activates RAF1, triggering the ERK1/2 pathway to promote tumor cell survival, although miR-493-3p can inhibit this pathway. In pancreatic cancer, elevated NDR2 levels correlate with increased KRAS expression and mutations, supporting tumor cell proliferation by inhibiting p21 and suppressing LATS2. NDR2 expression is also upregulated in gliomas. Conversely, in T-cell lymphomas and urothelial/renal cancer, NDR2 is thought to act as a tumor suppressor, where its inhibition promotes proliferation.

TRIM27: Tripartite motif-containing protein 27. DR2: Nuclear Dbf2-related kinase 2. ULK1: Unc-51 Like Autophagy Activating Kinase 1. p21: Cyclin-dependent kinase inhibitor 1 A (CDKN1A). YAP-1: Yes-associated protein 1. HIF-1: Hypoxia-inducible factor 1. IGF-1: Insulin-like growth factor 1. IGF-1R: Insulin-like growth factor 1 receptor. PI3K: Phosphoinositide 3-kinase. AKT: Protein kinase B (PKB). PDK-1: 3-Phosphoinositide-dependent kinase 1. LATS2: Large tumor suppressor homolog 2.

ARK5: AMPK-related kinase 5. KRAS: Kirsten Rat sarcoma virus protein. RAF1: Proto-oncogene serine/threonine-protein kinase. MEK1/2: Mitogen-activated protein kinase kinase 1/2. ERK1/2: Extracellular signal-regulated kinases 1/2.
authors also suggest that NDR2 may regulate α-integrin trafficking via Rab-dependent transport mechanisms, as NDR2 can associate with Rab5 and Rab11 in positive integrin recycling vesicles [41]. Additionally, the Rab-8 guanine exchange factor, Rabin8, is a substrate for NDR1/2 kinases [51]. In addition to β1 integrin subunit activation, NDR2 regulates α1 integrin trafficking, thereby controlling neurite growth [50]. NDR2 also interacts with actin cytoskeleton, regulating structural processes in differentiating and mature neuronal cells [42], During neurite outgrowth, the RhoA GTPase signaling pathway and SAX-1, the NDR kinase orthologue in *C. elegans*, share a common function [52], confirming that NDR2 may be involved in neuronal functions [42].

By controlling neuronal polarity, NDR2 prevents the formation of supernumerary axons in the hippocampus. Excessive expression of NDR2 in the mouse brain, particularly in the granular cells of the gyrus dente, disrupts the activity of the hippocampal network [53]. Such overexpression of NDR2, due to gene amplification, induces the development of intellectual disability in mouse [54].

### 3.3. NDR2 in cell proliferation and cytokinesis

The cellular functions of NDR kinases in cell cycle progression and tissue growth are well established [6,7,43,55]. The NDR1/2 kinases control progression to the G1 phase by promoting the stabilization and activity of c-myc and p21/Cip1 [7,56]. This occurs through the binding of NDR1/2 to c-myc, independent of NDR kinase activity [56], and phosphorylation of p21 in S146 (KRRQTpS) [7]. NDR1/2 activity peaks in G1 phase and remains at a certain level in S phase. In this phase, NDR1/2 phosphorylates/inhibits the cell cycle inhibitor p21 and thus controls the G1/S cell cycle transition [7,56]. As mentioned in section 2.3, NDR2 possess a SUMOylation site at position K432 in an inverted consensus motif DYK, a residue absent in the NDR1 sequence. DeSUMOylation of K432 by (SUMO)-specific proteases (SENPs) leads to NDR2 activation, increases instability of the downstream target p21, and accelerates G1/S cell cycle progression [35]. Inhibition of SENP2 in lung cancer cells has been shown to increase the half-life of p21 [35].

Cyclin D1/Cdk4 are other critical protein kinases regulating cell cycle progression, particularly in the G1 phase. Cyclin D1 promotes cell cycle progression by enhancing NDR2 kinase activity through phosphorylation of S282, but independently of Cdk4 [57]. NDR2 interacts with cyclin D1, enhancing NDR2 phosphorylation, stimulated by MOB1A or MST1. However, overexpression of Cdk4 inhibits the interaction between NDR2 and MST1, without affecting the association of NDR2 with MOB1A [57]. Although Cyclin D1 and NDR2 do not phosphorylate each other, Cyclin D1 promotes NDR2 autophosphorylation by releasing its self-inhibition motif. Activated NDR2 can then phosphorylate p21, promoting its degradation and thus supporting the cell cycle progression [57]. Indeed, NDR2 depletion increases expression of the kinase LATS2 and the cell cycle regulator p21, which together promote the loss of cell viability in a subset of KRAS-dependent pancreatic cancer cell lines [58].

Another critical step in cell cycle progression is proper cytokinesis, which requires centriole formation and centrosome duplication. Human NDR directly contributes to centrosome duplication through a mechanism that requires Cdk2 activity. However, the direct substrates of NDR kinase on centrosomes remain unidentified [16,17]. These experiments focus on NDR1, but overexpression of functional NDR2 causes centrosome amplification and the formation of subsequent polynucleated cells [17].

A defect in cytokinesis is observed in the HBEC-3 cell line (bronchial origin) with the loss of the tumor suppressor RASSF1A, which promotes NDR2 activity. NDR2 interacts directly with GEF-H1, a RhoB GDP-GTP exchange factor containing the NDR phosphorylation consensus motif HXRXXS/T, resulting in its inhibition and downregulation of RhoB [14]. In *Saccharomyces cerevisiae*, the kinase Cbk1, an Ndr/LATS-related protein, regulates mitotic exit and daughter cell separation after cytokinesis [59]. Centrosome abnormalities (increased size and number) due to

cytokinesis defects create chromosomal instability, which promotes tumor development and progression [16,60].

Genome-wide association studies in glioma have identified a novel locus associated with glioma risk corresponding to the NDR2 gene [61,62]. NDR2 is expressed 1.8-fold more highly in glioma samples than in healthy samples. However, according to the Human atlas protein (HAP) database (Supplemental Fig. 2), NDR2 expression does not appear to correlate with overall survival (OS) in glioma patients.

### 3.4. NDR2 in apoptosis

NDR1/2 are proapoptotic kinases and their knockdown results in resistance to apoptosis [63]. Stimulation of death receptors Fas and TNFα receptor, indirectly stimulates NDR1/2 kinases by promoting phosphorylation through MST1 on their hydrophobic motif (T444/442). Both NDR1 and NDR2 isoforms mediate Fas-induced apoptosis, as evidenced by the significant reduction in cell death observed upon NDR1/2 KO. Furthermore, overexpression of NDR1 kinase enhances apoptosis in MCF7 cells [64].

MICAL-1 (molecule interacting with CasL) is atypical multidomain flavoenzyme that negatively regulates the activation of NDR1/2 kinases by competing with MST1 for NDR1/2 binding. By doing so, MICAL-1 inhibits the MST1-NDR2 signaling and apoptotic pathway [65]. The authors demonstrated that the KO of NDR1/2 resulted in the inhibition of caspase-3 cleavage induced by etoposide. Conversely, the KO of MICAL-1 increases signals for cleaved caspase-3 [65].

NDR2 also plays a role in regulating ARK5 (a member of the AMP-activated protein kinase (AMPK)2 catalytic subunit family), which is closely implicated in tumor progression, particularly during insulin-like growth factor (IGF)-1 signaling. NDR2 promotes cell survival and invasion of colorectal cancer (CRC) cell lines by phosphorylating and activating ARK5 [30]. During IGF-1 signaling, NDR2 is activated by phosphorylation of three residues: T75 (required for interaction with S100B), S282 (MOB-mediated autophosphorylation) and T442 (in a PDK-1-dependent manner). Notably, PDK-1 is not involved in the phosphorylation of the C-terminal threonine in NDR1 [24]. Activated NDR2 then phosphorylates the conserved threonine T211 in a non-consensus NDR kinase site (DKFLQT) on the active T-loop of ARK5, promoting cell survival and invasion of colorectal cancer cells [30].

However, the role of NDR2 in CRC is unclear. The *STK38L* gene, which encodes NDR2, can be mutated and is involved in CRC tumorigenesis [30,66]. Nevertheless, NDR2 protein expression is progressively silenced during chemically-induced colon carcinogenesis in mice models [67]. In the majority of colon cancer tissue microarray samples, NDR2 and YAP-1 protein levels exhibited an inverse correlation, suggesting that NDR2 may play a tumor-suppressive role in human CRC [67]. In the HAP database (Supplemental Fig. 2), NDR2 expression is not association with OS in CRC patients.

In ovarian cancer cells, NDR2 phosphorylates the proto-oncogene RAF1 at S621, promoting its binding to 14-3-3 proteins and preventing its proteasomal degradation [68]. The oncogenic action of NDR2 is inhibited by miR493-3p, which downregulates NDR2 mRNA and protein levels. This interaction enhances apoptosis in ovarian tumor cells. In the HAP, NDR2 expression correlates with significantly poorer patient OS ($p = 0.031, n = 349$)(Supplemental Fig. 2).

In pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignancy associated with poor clinical prognosis, high expression of NDR2 correlates with worse OS [58]. In KRAS-dependent pancreatic cancer cell lines, RNAi-mediated depletion of NDR2 inhibits cellular proliferation and induces apoptosis. Concomitantly, NDR2 depletion resulted in increased expression of the cell cycle regulator p21 and LATS2 kinase, but had no effect on NDR1 or LATS1 mRNA transcript levels [58]. The authors concluded that the cytotoxicity associated with NDR2 depletion in KRAS-dependent PDAC cells is mediated, at least in part, by the induction of LATS2 expression. Furthermore, NDR2 and KRAS may function in parallel pathways to promote tumor cell survival.
However, this appears to be tumor context dependent, as NDR2 knockdown fails to induce apoptosis in a KRAS-mutant lung cancer cell line (H358) [58].

The involvement of NDR2 in urothelial and renal cancer has not been extensively studied. However, significant alterations in RASSF1A Hippo pathway molecules (YAP-1, CTGF, and CYR61) have been correlated with disease severity in bladder cancer patients [69,70]. Overexpression of YAP-1 contributes to the progressive features and poor prognosis observed in human urothelial carcinoma of the bladder [71]. In the urothelial cancers database, higher expression of NDR2 is associated with better survival (p = 0.011). In contrast, in renal cancer, high expression of NDR2 correlates with worse patient survival (p = 0.034) (HAP database (Supplemental Fig. 2)).

### 3.5. NDR2 in migration and invasion

The depletion of NDR2 reverses the migratory and metastatic phenotypes induced by RASSF1A loss in human bronchial epithelial cells (HBEC) [14]. NDR2 affects cytoskeletal conformation by interacting with RhoGTPases, leading to cytoskeletal remodeling, epithelial-mesenchymal transition (EMT), and enhanced cell migration [14]. In addition, NDR2 activates YAP-1 through a non-canonical Hippo pathway, thereby promoting EMT [14]. The findings are consistent with the role of the NDR2 kinase in regulating cell movement via modulation of YAP-1 activity [72]. In NSCLC cells, NDR2 acquires pro-metastatic properties. In a mouse metastasis model, loss of NDR2 reduces the size and number of brain metastases whereas NDR1 knockdown had the opposite effect, promoting metastasis [15]. Higher expression levels of NDR2 are measured in metastatic NSCLC compared to localized NSCLC

[15]. The hypoxic environment typically found in NSCLC [15], along with epigenetic deregulation [73] stabilizes and activates NDR2, enhancing its activities and contributing to tumor progression and metastasis [72] (Fig. 4).

Integrins plays a crucial role in cancer cells migration and metastasis formation [74]. Since NDR2 regulates integrin trafficking and activation during neuronal development [41,50], it is plausible that NDR2 may also facilitate migration/invasion in tumors by regulating the integrin signaling pathway.

In lung cancer adenocarcinoma, NDR2 expression correlates with poorer patient survival (p = 0.0033, n = 497, HPA) [75](Supplemental Fig. 2). This correlation highlights NDR2's critical role in tumor progression and metastatic spread in lung cancer. A study demonstrated that the miR-135b enhances the invasive and migratory capabilities of cancer cells in vitro and promotes lung cancer metastasis in vivo [76]. MiR-135b regulates several targets within the Hippo pathway, including LATS2 and NDR2. Conversely, TAZ effector was upregulated in the miR-135b-overexpressing cells. The authors found a link between miR-135b expression, downregulation of LATS2, and the nuclear localization of TAZ, suggesting that these factors could serve as a useful prognostic signature for NSCLC. However, the specific role of NDR2 in this process remains unaddressed.

### 3.6. NDR2 in vesicular traffic

The relationship between NDR2 and vesicular trafficking has not been thoroughly documented. However, some proteins involved in intracellular vesicle trafficking, such as AAK1 (AP-2 associated kinase) and Rabin8, which are known to be substrates of NDR1/2 kinases,

<figure><img src="image_7.png" /><figcaption>**Fig. 4.** Implications of NDR2 Kinase in NSCLC Tumor Progression.</figcaption></figure>

NDR2 plays a significant role in enhancing the invasive capabilities and proliferation of non-small cell lung cancer (NSCLC) cells by inhibiting RhoB and promoting YAP-1 activation, which leads to cytokinesis defects. It also activates SUMOylation through SENP2, resulting in the inhibition of p21. In a hypoxic microenvironment, NDR2 is activated, inducing oncogenes c-Jun and YAP-1, as well as the hypoxia response via HIF-1, which drives tumor cell survival, proliferation, epithelial-to-mesenchymal transition (EMT), and invasion. In brain metastases, NDR2 similarly promotes tumor cell survival and proliferation. Additionally, NDR2 may regulate autophagy, supporting cell survival under stress conditions like hypoxia and extracellular matrix detachment. It may also interact with key players in migration and invasion, such as FAM20C, the Golgi apparatus, and EGFR signaling. Through its interactions with the actin cytoskeleton or integrins, NDR2 could facilitate tissue colonization by promoting rolling and extravasation. For the abbreviation, see the legends in Figs. 2 and 3.
contain the consensus sequence for phosphorylation by these kinases [51,77,78]. Biosynthetic membrane trafficking from the Golgi complex to the plasma membrane requires the functional association of PI4KB and Rab11fip5 [79,80]. PI4KB promotes membrane trafficking at the post-Golgi and recycling [77], and Rab11fip5 is involved in endosome recycling [78]. Although not yet confirmed as direct substrates and lacking a clear consensus sequence, both PI4KB and Rab11fip5 are phosphorylated at S277 and S307, respectively, and may potential be regulated by NDR1/2 substrates in mammalian cells. In mouse brains, PI4KB, Rab11fip5 and AAK1 have been identified as direct substrates of NDR1/2 [6,51].

Moreover, NDR2 has been shown to interact with the actin cytoskeleton, suggesting that NDR2 may play a role in vesicle or protein trafficking and/or a role in cytoskeletal reorganization or cell polarization by controlling actin phosphorylation and actin filament dynamics [42].

More recently, Roșianu and colleagues report that the NDR1/2 depletion impairs endomembrane trafficking and autophagy through regulation of clathrin-mediated endocytosis and ATG9A trafficking in mouse models [81]. These findings highlight the potential involvement of NDR2 in the regulation of vesicular trafficking and cellular processes dependent on endomembrane dynamics.

### 3.7. NDR2 in autophagy

The cross-talk between the Hippo and autophagy pathways and its implications in physiology and cancer has been well documented [43,82–86]. However, these pathways exhibit complex and reciprocal interactions [82] which align with the dual roles of autophagy in cancer progression [87]. Initially, autophagy inhibits the tumor’s development, by promoting cancer cell death. As cancer progresses, autophagy can support tumor invasion and dissemination [87].

In breast cancer, NDR2 inhibits autophagy, thereby promoting tumor development [38]. On the other hand, NDR2 may activate autophagy in neurodegenerative diseases [81] as well as in tumor cells where it contributes to invasion and metastasis. The involvement of the NDR/LATS kinases in autophagy regulation further complicates the picture [84,86]. While, LAST1/2 kinases have been shown to repress autophagy by suppressing mTORC1 activity in mouse models [88], Tang et al. observed that LATS1, but not LATS2, represses autophagy in hepatocellular carcinoma (HCC) cells [89]. This highlights a non-classical, LATS1-mediated interaction between the Hippo signaling pathway and autophagy that may influence therapeutic response and carcinogenesis [90].

The roles of NDR1/2 in autophagy regulation are equally ambiguous and sometimes contradictory. Several studies have highlighted the role of NDR1’s involvement in Beclin-1-induced autophagy in both human cells and in Drosophila. NDR1 is activated by the serine/threonine kinase ULK1, facilitating the formation of the Beclin-Exo84-VPS34 complex [81,91,92]. Additionally, NDR1 interacts with XPO1 to modulate the subcellular localization of Beclin-1, thereby regulating the nuclear export of autophagy proteins and other cargoes [93,94]. In contrast, NDR2 inhibits autophagy, particularly by blocking autophagosome formation. This inhibition is facilitated by the phosphorylation of Rabin 8 at S272 by NDR2, which in turn promotes TORC1 activity [95]. Consequently, TORC1 suppresses ULK1, a key initiator of autophagy, and this regulation results in decreased autophagic activity [96]. NDR2 also negatively regulates starvation-induced autophagy by promoting the TRIM27/ULK1 complex [38]. NDR2 serves as a scaffold protein, enabling the binding of TRIM27 (tripartite motif-containing 27), an E3 ubiquitin ligase to ULK1. The subsequent destruction of ULK1 by NDR2 abolishes ULK1-induced autophagy, which in turn promotes tumorigenesis in human breast cancer [38]. TRIM27 also catalyzes NDR2 ubiquitination at K73 and K119, leading to its subsequent activation [38]. Despite this, NDR2 expression does not correlate with OS in breast cancer patients according to the HAP database (Supplemental Fig. 2).

In neurons, NDR2 maintains homeostasis by regulating the trafficking of ATG9A-positive vesicles, which are essential for autophagy. ATG9A is located in the trans-golgi network and endosomes [81]. During autophagy, ATG9A-positive vesicles interact with phagophores, promoting their expansion [97,98]. While the precise role of NDR2 and ATG9A in autophagosome formation remains unclear, there is a possibility of a direct interaction between the two, as ATG9A contains a consensus motif for phosphorylation by NDR2 (¹⁹⁹^HKRELPT²⁰⁴) that can be phosphorylated by NDR2. Thus, NDR2 could either activate ATG9A through phosphorylation or facilitate the transport of ATG9A-positive vesicles along the cytoskeleton to fuse with phagophores. This mechanism is currently under investigation.

In neurons lacking NDR1/2, the formation of autophagosomes is reduced, leading to reduced autophagy efficiency, which in turn leads to p62 accumulation and subsequent neurotoxicity [81]. AS-IV (astragaloside IV, an active ingredient of Jinfukang Oral Liquid, a clinical combination anticancer drug approved by the National Food and Drug Administration (FDA) of China), potentiates the anti-proliferative and pro-apoptotic effects of bevacizumab on NSCLC. The mechanism underlying these effects involves inhibition of the autophagy pathway via the targeting de-SUMOylation of NDR2, thereby increasing its activity [35,99].

### 3.8. NDR2 in ciliogenesis

NDR2 participates in vesicles trafficking necessary for ciliogenesis. NDR2 phosphorylates Rabin 8 [100], a key player in the early stages of ciliogenesis [101,102]. This phosphorylation activates the exocyst complex, which is essential for the attachment and docking of vesicles to the plasma membrane at the centrosome [103,104]. This process is vital for the attachment and fusion of vesicles during cilium formation [100]. Notably, NDR2 is present on the surface of peroxisomes at the centrosome, which is required for the formation of primary cilia [105]. Interestingly, NDR2, but not NDR1, is involved in this primary cilium formation, likely due to their distinct subcellular localizations [100,105]. This difference can be attributed to the presence of a peroxisome-targeting signal type-1 (PTS1), a typical motif (Gly-Lys-Leu, or GKL) at the C-terminal end of NDR2 [106]. In contrast, NDR1 carries an Ala-Lys sequence at the same position (Supplemental Fig. 1) which likely contributes to their different roles in ciliogenesis.

NDR2 is also identified as the causal gene for canine early retinal degeneration, the genetic disorder corresponding to the human ciliopathy [107–109]. A mutation removes exon 4 from the canine STK38L/NDR2 gene, resulting in the loss of most of the N terminus of the translated protein. This results in the loss of binding sites for S100B and Mob proteins, part of the protein kinase domain, and a T75 residue critical for autophosphorylation [107].

### 3.9. NDR2 in immune response - inflammation

Like MST1/2 (other Hippo kinases) and NDR1 (its counterpart), NDR2 regulates immunity [110–113]. Additionally, unregulated genes in NDR2 KO retinas highlight its potential involvement in oxidative, mitochondrial stress and inflammation [109]. Both NDR2 and NDR1 prevent the excessive production of inflammatory cytokines by inhibiting the TLR9-mediated innate immune response [111,112]. In the absence of NDR2, the expression of IL-17 induced cytokines (IL-6, CXLC20, CCL20), highlighting NDR2’s role in cytokine regulation [40].

During infection with a RIG-I-sensitive RNA virus, NDR2 controls the production of interferons (IFNs) and pro-inflammatory cytokines. NDR2 also enables full activation of RIG-I by serving as a scaffold protein between RIG-I and TRIM25, a polyubiquitin [111,114]. This complex is crucial for proper polyubiquitination of RIG-I, which is necessary for its activation and antiviral immune response [114,115]. In HIV-1 infection, NDR2 is cleaved at the C-terminal position (F438) by the HIV protease, producing a truncated NDR2 that translocate to the nucleus. However,
truncation of NDR2 (or NDR1 at F440) does not interfere with its as-
sociation with Mob2 or its autophosphorylation activity, but alters its
enzymatic activity or substrate specificity [116]. If HIV protease-
mediated truncation also affects NDR1, the functional consequences
may be different because NDR1 is mainly nuclear whereas NDR2 is
typically cytoplasmic [11] (see section 2.3). Thus, a change in the NDR2
localization could provide it with new substrates and new functions
[116].

NDR1/2 are required for thymic immunity, particularly in the exit
and migration of naive T lymphocytes from the thymus following
maturation. In mice with T-cell-specific NDR1/2 KO, a 60 % reduction in
peripheral T cells occurs [117]. Upon T-cell receptor (TCR) stimulation,
NDR2 is activated and phosphorylates filamin A (FLNa), leading to
activation of the integrin LFA-1. This activation is necessary for the
proper T lymphocyte response. NDR2 enables LFA-1 to undergo a
conformational change, increasing its affinity for its ligand [118]. Spe-
cifically, NDR2 phosphorylates FLNa at serine 2152 (in a non-consensus
phosphorylation site RxxS instead of the usual HxxS), promoting
the dissociation of FLNa from LFA-1 and stabilizing the open confor-
mation of LFA-1 in T Cells [118].

In T-cells, loss of NDR1/2 is linked to lymphoma development [61,114,115]. Reduced NDR1 levels lead to a defective response to pro-apoptotic signals, promoting cancer cell survival and facilitating tumor development in mice. In this scenario, NDR1 acts as tumor suppressors [61]. Furthermore, in mice with Dalton's lymphoma, decreased NDR2 protein levels in the spleen are associated with enhanced tumor cell proliferation [115].

4. Contribution of Proteomics to Identifying Specific NDR2 Partners and Substrates

The aim of this study was to identify common interaction partners for
NDR2 and NDR1 in healthy, non-metastatic, and metastatic human lung
cancer cells, as well as to identify NDR2-specific interactors and their

potential cellular functions. To achieve this, a co-immunoprecipitation
approach was utilized, employing IgG, NDR1-coupled IgG, or NDR2-
coupled IgG on three distinct whole cell extracts. These included one
from non-tumoral human lung epithelial cells (HBEC-3) and two from
lung adenocarcinoma cells, one from primitive (H2030) and the other
from brain metastasis (H2030-BrM3). LC-MS quantitative DIA Label-
Free analysis was performed using biological triplicates for each con-
dition. Differential proteins were identified through enrichment analysis
based on linear models and empirical Bayes statistics. The statistical
criteria used for this analysis included a 1.2-fold change threshold and a
p-value cut-off of >0.05. The STRING database was employed to explore
the direct and indirect correlations between known and predicted pro-
tein-protein interactions. The NDR2 interactome was clustered based on
enrichment in the Reactome, pathway, and molecular function data-
bases, as well as the Kyoto Encyclopedia of Genes and Genomes (KEGG,
https://www.genome.jp/kegg/) (Supplemental Fig. 3).

4.1. *Interactome of NDR2 from HBEC-3 cell extract* (Fig. 5)

In the HBEC-3 extract, which is derived from an hTERT-
immortalized epithelial cell isolated from the bronchus of a 65-year-
old female patient, 40 proteins were specifically co-
immunoprecipitated by the anti-NDR1 antibody, while 73 proteins
were co-immunoprecipitated by the anti-NDR2 antibody. Among these
proteins, 11 interact with both NDR1 and NDR2 (Fig. 5A, Supplemental
Table 1). Notable examples include the regulator of CDKN1A expression
(NLE1), the transmembrane protein 150C (a non-selective cation
channel with high permeability to Ca2+) or the cytoplasmic Malate
dehydrogenase (MDH1). A total of 62 proteins has physical interactions
exclusively with the NDR2 kinase. Using natural MCL clustering (infla-
tion parameter = 3), distinct clusters were identified based on biological
processes, as classified by Gene Ontology (Fig. 5B and C).

<figure><img src="image_8.png" /><figcaption>**Fig. 5.** Interactome of NDR2 from HBEC cell extract. A. A Venn diagram illustrating the number of proteins specifically co-immunoprecipitated by the anti-NDR1 antibody, the anti-NDR2 antibody, or both. B. The NDR2-specific interactome generated using the STRING website (https://string-db.org/), displaying functional protein association networks. C. Clustering of the NDR2 interactome was performed using natural MCL clustering (inflation parameter = 3), resulting in distinct clusters based on biological processes (Gene Ontology), as well as enrichment from reactome, pathway, and molecular function databases.</figcaption></figure>
### 4.1.1. Glycolysis, gluconeogenesis and Ca2+ homeostasis

One cluster consists of enzymes involved in glycolysis and gluconeogenesis, including Phosphoglycerate kinase 1 (PGK1), Alpha-enolase (ENO1), Glucose-6-phosphate isomerase (GPI), and Aspartate aminotransferase (GOT2) [119-122]. Metabolic reprogramming (MR), a hallmark of cancer, supports the survival and proliferation of malignant cells and is linked to the Hippo pathway, including the onco-suppressive kinase cascade and YAP-1/TAZ effectors [123-126]. This cluster also includes two S100A proteins (S100A4 and S100A7), which regulate calcium homeostasis and influence energy metabolism, motility, angiogenesis, differentiation, apoptosis, and autophagy [127-130]. Overexpression of S100A4 or S100A7 is associated with poor prognosis and metastasis in cancers, including NSCLC [131-134]. In breast cancer, S100A7 enhances aggressiveness by interacting with c-Jun activation domain-binding protein 1 and HIF-1 transcription factors [135]. Hypoxia-induced NDR2 overactivation contributes to brain metastasis in NSCLC through a c-Jun-dependent mechanism [15], suggesting S100A proteins may play a role in NDR2-driven metastasis.

### 4.1.2. Thioredoxin-disulfide reductase system

Thioredoxin (TXN), thioredoxin reductase 1 (TXNRD1), and aldoketo reductase (AKR1C3) are part of the thioredoxin disulfide reductase (TRX) system, a key antioxidant defense against oxidative stress. This system regulates cell proliferation, angiogenesis, apoptosis, and senescence [120,136,137]. The Hippo pathway [138,139] and hypoxia [140] are sensitive to the redox environment. For example, the TRX system is required for the antiapoptotic effect of YAP-1 in insulin-producing β-cells [141]. In human melanoma cells, LATS1, another NDR kinase, regulates ROS, with increased oxidative stress observed after LATS1 KO [142]. In addition, exposure to H2O2 can induce phosphorylation of MST1/2, Mob, and LATS1 [143]. As the TRX system emerges as a potential cancer therapy target [137], core Hippo kinases like NDR2 may also be considered.

Ubiquitin-like protein 5 (UBL5) is an atypical ubiquitin-like protein that regulates stress responses and protein targeting to mitochondria or pre-mRNA splicing but lacks the carboxy-terminal motif needed for degradation [144,145]. Knockdown of UBL5 induces severe apoptosis in culture and suppresses tumorigenicity of cancer cells in vivo [145]. The involvement of UBL5 in the mechanisms of carcinogenesis [146] and its cellular localization in both in cytoplasm and nucleus [145] suggest UBL5 as a potential partner for NDR2.

### 4.1.3. Actin cytoskeleton and cell junction system

This cluster contains protein regulating cell morphology and cytoskeletal organization Cofilin-1 (CFL1) or Zyxin (ZYX) and two adapters protein DLG5 and YWHAZ (Fig. 5C). Cofilin, is an actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits polymerization of monomeric G-actin [147]. LIM kinase and Ca/calmodulin-dependent protein kinases II (CaMKII) phosphorylate and inactivate cofilin at S3 [148,149], while PKCα at S23 and/or S24 [150]. Phosphorylated cofilin failed to manipulate F-actin polymerization and lamellipodium formation, impairing migration [151]. LATS1 can directly interact with LIMK1 to inactivate cofilin, independent of LATS1 kinase activity. This negative regulation of LATS1 on LIMK1 controls F-actin level specifically at the contractile ring and the periphery of cells for the proper progression of cytokinesis [152]. In mouse fibroblasts, the Hpo orthologs MST1 and MST2 colocalize with F-actin structures and are activated upon F-actin depolymerization. The authors suggest, that by tethering components of the Hippo pathway, F-actin dynamics modulate their activity [153]. Indeed, Cofilin is the terminal effector of Rho GTPase signaling, which is a major pathway of the actin cytoskeleton dynamics and can promote the cancer metastasis by regulating EMT. Mechanism which is can by reverted in HBEC cells by NDR2 depletion [14,15,72]. Cofilin is significantly increased in various tumors [154], including NSCLC [155].

Zyxin is a member of the cell-cell adhesion complex and controls cell

cytoskeleton and motility and thus linked with a number of cancers such as melanoma, hepatocellular carcinoma, oral squamous-cell carcinoma [156]. Zyxin is phosphorylated by CDK1 during mitosis, then activated Zyxin regulates YAP activity and promotes cell growth [157]. In response to hypoxia and TGF-β stimuli, Zyxin via its LIM domain, can act as a scaffold protein to forms a ternary complex with LATS2 and SIAH2. This interaction facilitates LATS2 ubiquitination and degradation, YAP dephosphorylation and subsequent activation. Thus Zyxin may function as a negative regulator of Hippo signaling through controlling LATS2 stability and YAP activity in human breast cancer [158]. However, a decreased expression of Zyxin has been shown in NSCLC which may indicate a suppressor role of this protein in NSCLC [159]. Thus, by regulating Hippo kinase Zyxin may play an important role in tumorigenesis.

The membrane-associated guanylate kinase (MAGUK) protein discs large homolog 5 (DLG5) is a multifunctional adaptor and scaffolding protein containing four PDZ domains [160]. DLG5 is involved in both epithelial cell structuring, adherens junction formation, and intracellular signaling [161] and can connect cell polarity and Hippo signaling protein networks [162]. DLG5 inhibits MST1/2-mediated phosphorylation of LATS1 by promoting recruitment of the Par-1 polarity proteins microtubule affinity-regulating kinases 3 (MARK3) to MST1/2 [162,163]. Thus, loss of DLG5 promotes breast cancer malignancy by inhibiting the Hippo pathway [163]. In NSCLC, resistance to chemotherapy is associated with increased DLG5 expression [164]. In squamous cell lung cancer, DLG5 expression is downregulated in patient tissue samples and is associated with EMT biomarkers [165]. Thus, DLG5 controls cell proliferation, EMT, cell migration and invasion, epithelial cell polarity and acts as a regulator of the Hippo signaling pathway [162], a set of roles that DLG5 shares with NDR2. Whether, DLG5 binds directly to MST1/2 through its third PDZ domain, DLG5 sequence also contains three consensus phosphorylation sites for NDR kinases (HxRxxS/T) at start positions 235-HSRLLS, 1442-HSRSSS and 1695-HKRSGS and thus emerge as a potential substrate of NDR1/2 kinases. In hepatocellular carcinoma cell models, DLG5 undergoes continuous ubiquitination and proteasome degradation in a phospho-S730-dependent manner [161]. This suggests that, as already proposed in Drosophila, the Hippo pathway may reciprocally modulate the scaffolding function of DLG5 in the control of growth, cell polarity and cell adhesion [166].

This cluster also includes the YWHAZ protein (14-3-3 protein zeta/delta), an adaptor protein able to bind to number of enzymes, signaling proteins, and transcription factors. YWHAZ regulates a broad spectrum of signaling pathways by binding to the phosphorylated transcription factor TFEB and promoting its cytosolic retention and inactivation [167]. TFEB acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response by regulating the expression of multiple genes in the Coordinated Lysosomal Expression and Regulation (CLEAR) network [168]. YAP-1 interacted with TFEB [169] which is consistent with importance of the Hippo pathway in the regulation of cellular trafficking and autophagy [84]. A mechanism similar to LATS/NDR phosphorylation of YAP-1/TAZ, whereby YAP-1 is recruited by 14-3-3, to the cytoplasm, resulting in the termination of TEAD-dependent gene transcription [5].

### 4.1.4. Hippo pathway

Only the Hippo pathway protein, MOB2A, is found in NDR2 actome, suggesting a specific association between MOB2 and NDR2 in HBEC cells, whose inhibitory role on NDR kinases is described by competes with MOB1A for NDR binding and activation [11,23,170].

### 4.1.5. Cellular macromolecule metabolic process

A cluster of 11 proteins annotated in cellular macromolecule metabolism process is identified. These proteins are chromatin regulators (PHF1, DNMT3A, RBBP5 and WDR5), involved in prevention of
phagosomal-lysosomal fusion (RPS27A, HGS) or in protein biosynthesis (Eukaryotic peptide chain release factor subunit 1 (ETF1), Alanine-tRNA ligase (AARS1) or Isoleucine-tRNA ligase (IARS1). Nine of these are post-translationally modified by the attachment of at least one ubiquitin-like modifier protein, a mechanism known to enhance NDR2 kinase activity [35]. Additionally, AARS1 functions as a lactate sensor that mediates global lysine acylation (called lactylation) of protein such as p53 in tumor cells [171,172]. AARS1 uses lactate and ATP to catalyze protein lactylation on TEAD and YAP-1 which promotes expression of Hippo pathway target genes in gastric cancer [173].

Although not included in a specific cluster, the Receptor-mediated endocytosis 8 (RME-8)/DNAJC13 protein (DNAJC13) is retained by beads coupled to the anti-NDR2 antibody. RME-8 is a positive modulator of autophagy that stabilizes cellular protein homeostasis by interfering with ATG9A trafficking [174]. RME-8 is involved in membrane trafficking through early endosomes, early endosome-to-recycling endosome or early endosome-to-late endosome transport. It has also been implicated in transferrin recycling and epidermal growth factor (EGF) and EGF receptor (EGFR) degradation [175,176].

## 4.2. Interactome of NDR2 from H2030 cell extract

H2030 cells (CRL-5914™, ATCC) were isolated in 1988 from the lungs of a non-smoking man with NSCLC and exhibited epithelial morphology. In H2030 cell lysate, 41 proteins were retained by the anti-

NDR2 antibody, but 19 of these were also retained by the anti-NDR1 antibody (Fig. 6A, Supplemental Table 1). Among them, only ABLIM3 has a consensus NDR kinase phosphorylation site (HxRxxS/T) at position 47-HIRCFT and 337-HSRYMS respectively. ABLIM3, is a member of the actin-binding LIM (abLIM) protein family, a component of the junctional complex. ABLIM3 plays a role in embryonic development, cell lineage determination and cancer progression [177] and neuroblastoma metastasis via regulating of the cell adhesion molecule pathway [178]. The small number of proteins identified in the NDR2 interactome limits the identification of functional clustering. Only 3 enrichments based on reactome pathways were found (Fig. 6B).

### 4.2.1. p53 signaling pathway

Cytochrome c (CYCS) is a central figure in the activation of the intrinsic apoptotic pathway, mediating the allosteric activation of apoptosis-protease activating factor 1 (Apaf-1), which is required for the proteolytic maturation of caspase-9 and caspase-3 [179]. Hippo pathway is an inducers of apoptosis in response to wide range of stimuli [180]. The tumor suppressor RASSF1 gene is an important determinant in mediating YAP-1 pro-apoptotic activities and the inactivation of RASSF1A in lung cancer cells induced NDR2 hyperactivation [14,72]. Furthermore, the LATS1/2 kinases and YAP-1 function in a complex network with p53 to regulate apoptosis [181].

Thrombospondin-1 (TSP1) is a multifunctional protein, involved in apoptosis, angiogenesis, senescence, metabolic homeostasis [182] and

<figure><img src="image_9.png" /><figcaption>**Fig. 6.** Interactome of NDR2 from H2030 cell and H2030-BrM3 extracts. A and C. Venn diagram showing numbers of proteins specifically co-immunoprecipitated by the anti-NDR1 antibody, anti-NDR2 antibody or both from H2030 and H2030-BrM3 extracts respectively. B and D. NDR2 specific interactome generated by STRING's website (https://string-db.org/) showing functional protein association networks for in H2030 and H2030-BrM3 respectively. Clustering of the NDR2 interactome using natural MCL clustering (inflation parameter = 3), different clusters, based on biological process (Gene Ontology), enrichment of reactome, pathway, and molecular function databases.</figcaption></figure>
in autophagy upon inhibition of the Rho-Associated Protein Kinase (ROCK) inhibitor [183]. TSP1 dysregulates YAP-1 nuclear translocation during the initial phase of infection of cardiac endothelial cells by the parasite, *Trypanosoma cruzi* [184]. This nuclear translocation is dependent on YAP-1 phosphorylation by upstream LATS/NDR kinases [29]. In turn, YAP-1 transcriptionally activates TSP1/FAK signaling which promotes focal adhesion and tumor aggressiveness in breast cancer [185]. These findings suggest a potential crosstalk between Hippo pathway kinases, such as NDR2, and TSP1 in the context of invasiveness.

### 4.2.2. Mitochondrial protein import

This cluster includes only the COX assembly mitochondrial protein 2 homolog (CMC2) and cytochrome c oxidase assembly factor 6 (COA6), which are involved in cytochrome c oxidase biogenesis and mitochondrial respiratory chain complex IV maturation, respectively [186]. COA6 regulates cell proliferation, apoptosis, migration, and invasion through modulation of oxidative phosphorylation in both breast cancer [187] and lung adenocarcinoma [188,189].

### 4.2.3. 16p11.2 proximal deletion syndrome

Major vault protein (MVP), encoded by a gene located on chromosome 16 (16p11.2), is the major component of a ribonucleoprotein particle with a hollow barrel-like structure called the vaults complex. MVP plays a role in the inflammatory process [190] and in the chemo-[191] and radio-resistance [192] cancer cells. MVP is a nucleocytoplasmic transporter involved in major cytoplasmic signal transduction cascades through binding to various kinases (Erk, src) and phosphatases (PTEN, SH2-domain-containing tyrosine phosphatase SHP-2) [192]. The role of MVPs in human cancer remains unclear. In glioblastoma, vaults proteins have a tumor-promoting potential by stabilizing EGFR/PI3K-mediated migration and survival pathways [193]. In renal adenocarcinoma cells, a complex formation of vaults with HIF-1α, PHDs and pVHL is reported, suggesting that MVP/vault may act as scaffold protein for ubiquitination and degradation of HIF1α, thereby affecting hypoxia-regulated expression of HIF-1α-dependent genes [194]. In lung adenocarcinoma, the increased expression of MVP is associated with a better prognosis and thus, by inhibiting STAT3 pathway, MVP may act as a lung tumor suppressor [195] and is called lung resistance-related protein (LRP) [196]. Surprisingly, no published work other than the present review establishes a potential link between the Hippo pathway via NDR2 and MVP. However, MVP is regulated at the level of tyrosyl phosphorylation, in EGF-stimulated cells, tyrosine phosphorylation is required for MVP to reveal its scaffolding or direct regulatory function [197].

T-complex protein 1 subunit theta (TCP-1-theta) (CCT8 on chromosome 21q21.3)) is highly expressed in most cancers with a poor prognosis [198], including lung adenocarcinoma [199]. TCP-1-theta is a component of chaperonin-containing T-complex (CCT), a molecular chaperone complex that controls the folding of a variety of proteins associated with cell cycle regulation, chromatin remodeling, secretory pathways, phosphatase activity, and cytoskeletal function [200]. For example, CCT8 promotes the migration and invasion of esophageal squamous cell carcinoma (ESCC) by regulating the expression of α-actin and β-tubulin [201].

### 4.2.4. Potential NDR2 interactors not included in MCL clustering

The FAM83B protein, which possesses a consensus NDR kinase site (537-HSRLRS) appears specifically in NDR2 interactome. FAM83B is a putative proto-oncogene that functions in the EGFR signaling pathway. It activates EGFR itself as well as the downstream RAS/MAPK and PI3K/AKT/TOR signaling cascades to promote epithelial cell transformation and resistance to TKI therapies [202-205]. Additionally, variations in the expression levels of FAM83B influence the progression of autophagy in breast cancer cell lines [206]. In lung adenocarcinoma, FAM83B regulates mitochondrial metabolism and anti-apoptotic activity [207]. Indeed, a group of NSCLCs characterized by short disease-free survival

(DFS) is enriched for FAM83B mutations [208]. FAM83A, another member of the FAMily with sequence similarity 83 (FAM83) protein family, regulates the Wnt and Hippo signaling pathways, which in turn promote lung cancer progression and a poor prognosis [209]. Consequently, both FAM83B and FAM83A are prognostic biomarkers and potential therapeutic targets in NSCLC [210,211].

Autophagy-related protein 13 (ATG13), a protein identified in the NDR2 interactome, plays a critical role in the initiation of autophagy. ATG13 participates in the phagophore assembly site, where autophagosomes are formed [212].

## 4.3. Interactome of NDR2 from H2030-BrM3 cell extract

H2030-BrM3 (generously provided by Dr. Joan Massagué (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY) were isolated from brain metastases of H2030 lung adenocarcinoma cells harboring a *KRAS*<sup>G12C</sup> mutation. In H2030-BrM3 cell lysate, only 17 proteins were specifically retained by the Anti-NDR2 antibody and 9 by anti-NDR2 and anti-NDR1 antibodies (Supplemental Table 1). One enrichment was found based on subcellular localization in the Golgi membrane and one in the KEGG pathway related to protein processing in the endoplasmic reticulum, including MBTPS1 and HSP90B1 proteins (Fig. 6C and D).

### 4.3.1. Golgi membrane localization

The AP-1 complex subunit sigma-1 A (Sigma1A-adaptin) (AP1S1) is a key component of Adaptor protein complex-1 (AP-1), which is crucial for intracellular protein trafficking. Its involved in the intracellular vesicle trafficking of membrane proteins, including receptors, from the trans-Golgi network (TGN) to endosomes, lysosomes or the plasma membrane [213,214]. Downregulation of AP1S1 causes the lysosomal degradation of EGFR in NSCLC by recycling ligand-stimulated EGFR back to the plasma membrane via RAB11-positive endosomes [215].

Membrane-bound transcription factor site-1 protease (MBTPS1) cleaves the pro-peptide from FAM20C, which is required for its release from the Golgi membrane and for the enhancement of FAM20C kinase activity [216]. FAM20C is a secretory kinase involved in the phosphorylation of numerous ECM-related secreted proteins. Increased secretion of FAM20C leads to extracellular matrix degradation and loss of vascular basement membrane integrity, thereby promoting tumor metastatic dissemination [217]. In the gingival fibrosis cells, FAM20C depletion activates the TGFβ-YAP-1/TAZ signaling pathway [218]. High expression or hypomethylation of FAM20C correlates with poor prognosis in hypoxia-associated lung adenocarcinoma [219]. Consistently, a decreased mRNA expression level of MBTPS1 has also been shown in NSCLC [220]. Collectively, these data suggest that MBTPS1 and FAM20C may contribute to bronchial carcinogenesis and its metastatic progression in hypoxic tumors through the modulation of Hippo signaling, a hypothesis consistent with the observations reported for NDR2 in NSCLC [15].

Tapasin (TAPBP) belongs to the immunoglobulin superfamily and is found in the Golgi membrane protein cluster of the NDR2-specific interactome. TAPBP mediates the interaction between newly assembled major histocompatibility complex class 1 (MHC class I) and antigen processing-associated transporter (TAP). In NSCLC, increased TAPBP gene expression in peripheral blood is associated with improved disease-free survival and tapasin expression in tumor samples is positively correlated with improved OS [221,222]. Hippo pathway, via YAP-1/TEAD complex controls antitumor immunity by regulating the expression of MHC class I-mediated tumor antigen processing and presentation (APP) pathway genes, providing a rationale for inhibiting YAP activity in immunotherapy for cancer [223].

PITPNB, the phosphatidylinositol transfer protein beta isoform (PITPβ), is required for retrograde transport from the Golgi to the endoplasmic reticulum [224]. PITPα/β can affect the Hippo pathway by regulating LATS and YAP-1 via plasma membrane phosphatidylinositol-
4-phosphate [225]. The signaling connection between the Hippo and
phosphoinositide pathways controls the transcriptional activation of
YAP-1 [226]. PITPα/β are highly expressed in tumor tissues and are
associated with a poor prognosis in gastric cancer [227]. Microcolin H, a
naturally occurring marine lipopeptide, directly binds PITPα/β and
shows antiproliferative activity on several types of tumor cell lines.
Guan et al. reported microcolin as an inhibitor targeting PITPα/β to
activate the Hippo/YAP pathway and suppress the proliferation of YAP-
dependent tumor cells [225]. Additionally, treatment with microcolin H
increases the conversion of LC3I to LC3II, accompanied by a reduction in
p62 levels in cancer cells, leading to autophagic cell death [227]. These
data provide further evidence that NDR2 may be involved in the overall
mechanism for the regulation of autophagy.

5. NDR2 as a therapeutic target: Current status and future perspectives

Researchers are continually exploring methods to advance person-
alized and precision medicine, notably by deploying conventional
pharmacological approaches as well as innovative strategies such as
RNAi therapy and gene editing [228,229]. These strategies are sum-
marized in many comprehensive reviews [228,230–237]. In the
following sections, we will focus on Hippo kinases including NDR2-
based strategies.

5.1. *Hippo pathway core kinases in cancer treatment*

Numerous preclinical and clinical (phase 1) trials targeting Hippo
pathways have been conducted, but no drug has been developed for
clinical use [238,239]. These preclinical and clinical trials mainly target
YAP-1/TAZ expression/activity (such as EZH2 inhibitors or Fingolimod
for the treatment of hepatocellular carcinoma [240]) or the YAP-TEAD
interaction. Another therapeutic strategy is to inhibit Hippo core ki-
nase, such as MSTs kinase [241] or LATSs [242], to control YAP-1/TAZ
nuclear or cytoplasmic location and subsequently their co-
transcriptional capabilities [238]. In a recent study, an MST1/2 inhibi-
tor, utilizing a neratinib backbone, which is a clinically approved,
epidermal growth factor receptor (EGFR)/EGFR2 inhibitor identified to
have also high MST1 inhibitory activity, was applied in preclinical
models of murine partial hepatectomy and demonstrated an accelerated
liver regeneration with improved survival in models of steatohepatitis
[243]. Even with prolonged dosing, no adverse effects on liver function
or evidence of carcinogenesis were observed [243]. Liver regeneration is
also induced by siRNA-mediated knockdown of MST1/2 in partial
hepatectomy mouse models [244]. However, to our knowledge, these
strategies have not yet led to drug development.

5.2. NDR2 as target in cancer therapy

5.2.1. Targeting the NDR2 kinase or its substrates through conventional pharmaceutical inhibitors

No drug has been developed for clinical use that specifically targets the NDR2 kinase. The main reason for this absence may be its potential off-target activity. NDR2 kinase shares up to 90 % sequence similarity with NDR1 and the LATS1/2 kinases, particularly in its active and ATP-binding sites [20]. Therefore, developing a pharmacological inhibitor that can selectively target NDR2 activity without affecting other related kinases is challenging but vital since NDR2 has oncogenic properties, while NDR1, LATS1, and LATS2 are tumor suppressors in lung cancer cells [15,245].

Comparing the NDR1 and NDR2 interactome revealed new partners potentially able to modulate NDR2 activity and/or bioavailability, as well as new specific substrates of NDR2. Many of these proteins participate in well-characterized cellular processes. The consequences of disrupting these potential NDR2 interactors have already been studied, particularly on the progression and metastasis of several types of cancer.

Potential therapeutic targets may emerge from the NDR2 interactome
however, to date, no pharmaceutical molecule can stop the deregulation
of an NDR2 substrate that supports carcinogenic processes. Studies
remain necessary to identify the key substrates and then to develop in-
hibitors of these candidates.

5.2.2. Targeting the NDR2 expression in cancer cells

We demonstrated using epigenetic approach, shRNA-transformed
cells or direct siRNA silencing, the pro-metastatic nature of NDR2 in
vitro in lung cancer cells and in vivo in mice models [14,15]. Due to
their requirement for 100 % complementarity to their target, necessary
for stable pairing and subsequent degradation, siRNAs exhibit a high
degree of specificity [246,247]. Therefore, NDR2 siRNA silences NDR2
expression but not NDR1 expression [15]. A therapeutic approach using
nanoparticle-encapsulated therapeutic RNA to target and silence NDR2
mRNA expression could therefore be expected. Although previous
technical limitations have hindered the use of therapeutic siRNAs,
recent advances in chemical modifications [248] have enhanced their
efficiency and stability [249], reducing the amount required to effec-
tively target a gene [250], and increasing their intracellular persistence
[251]. Delivery remains a critical challenge in gene silencing, but
nanoparticles (NPs) have emerged as promising candidates. Conven-
tional lipid nanoparticles, such as liposomes, emulsions, and micelles,
are commonly used to deliver pharmaceutical agents and nucleic acids
(e.g., mRNA) into tumor tissues. However, these NPs have low loading
capacities (<5 % by weight), limiting their broader clinical use
[252,253]. Zeolite nanoparticles, in contrast, efficiently transport siR-
NAs, protect them from degradation, and enable effective drug delivery
to target cells, offering better safety than viral vector-based systems
[254]. Additionally, zeolites are highly stable [255,256] and their
composition can be modulated as needed [257], making them NPs to be
considered in future developments aimed at delivering therapeutic
RNAs.

6. Conclusion

This review highlights the structural differences between NDR1 and
NDR2, correlating them with the specific post-translational regulation of
NDR2, to provide an overview of the biological processes and functions
uniquely associated with NDR2. While the exact mechanisms remain
incompletely understood, substantial evidence suggests that NDR2 plays
a role in key biological processes, including proliferation, apoptosis,
migration, invasion, vesicular trafficking, and autophagy. Additionally,
specific NDR2 substrates, protein interactions, and functions have been
identified in cellular models representing various stages of cancer, both
before and after oncogenic transformation. Although functional in-
teractions between NDR2 and these substrates/partners need further
validation, they present new avenues for exploration to better under-
stand the kinase's role. Identifying the partners, mechanisms, and
cellular processes dependent on NDR2 in both physiological and path-
ological contexts, including cancer, is critical. Targeting of NDR2 by
therapeutic RNA may prevent cancer spread and improve patient
prognosis in cancers with NDR2 overexpression. Thus, NDR2 and its
partners offer promising prospects for cancer therapy.

CRediT authorship contribution statement

**Tiphaine Biojout:** Writing – review & editing, Writing – original draft, Validation, Methodology, Formal analysis, Conceptualization.
**Emmanuel Bergot:** Writing – review & editing, Funding acquisition.
**Benoît Bernay:** Validation, Formal analysis, Data curation.
**Guénaëlle Levallet:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.
**Jérôme Levallet:** Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration,
Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

## Patient consent for publication

Not applicable.

## Ethics approval and consent to participate

Not applicable.

## Funding sources

Tiphaine Biojout benefits from a doctoral grant from the Région Normandie (RIN 100 % PhD student, 2022). Research grants were provided from the Association des Insuffisants respiratoires (AIR partenaires Santé) to G. Levallet (2020). This research was also funded by the Association pour le Développement de la Pneumologie (ADP, Pr Bergot), the Université Caen-Normandie (UNICAEN) and the Centre Hospitalier Universitaire de Caen Normandie.

## Declaration of competing interest

The authors declare no competing interests.

## Acknowledgements

The authors thank the University Hospital of Caen for its support. The authors are also grateful to the Proteogen facilities, US EMerode, University of Caen Normandie, Caen, France. We would also like to thank Dr. Laurent Chatre (CNRS, ISTCT) for his helpful discussions and guidance on the transcriptomic approach.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijbiomac.2025.143656.

## Data availability

For all original proteomic data, please contact Dr. Jérôme Levallet (jerome.levallet@unicaen.fr).

## References

[1] L.H. Johnston, S.L. Eberly, J.W. Chapman, H. Araki, A. Sugino, The product of the Saccharomyces cerevisiae cell cycle gene DBF2 has homology with protein kinases and is periodically expressed in the cell cycle, Mol. Cell. Biol. 10 (1990) 1358-1366, https://doi.org/10.1128/MCB.10.4.1358.

[2] O. Yarden, M. Plamann, D.J. Ebbole, C. Yanofsky, Cot-1, a gene required for hyphal elongation in Neurospora crassa, encodes a protein kinase, EMBO J. 11 (1992) 2159-2166, https://doi.org/10.1002/j.1460-2075.1992.tb05275.x.

[3] W. Geng, B. He, M. Wang, P.N. Adler, The tricornered gene, which is required for the integrity of epidermal cell extensions, encodes the Drosophila nuclear DBF2-related kinase, Genetics 156 (2000) 1817-1828, https://doi.org/10.1093/genetics/156.4.1817.

[4] T. Millward, P. Cron, B.A. Hemmings, Molecular cloning and characterization of a conserved nuclear serine(threonine) protein kinase, Proc. Natl. Acad. Sci. USA 92 (1995) 5022-5026, https://doi.org/10.1073/pnas.92.11.5022.

[5] A. Hergovich, Regulation and functions of mammalian LATS/NDR kinases: looking beyond canonical hippo signalling, Cell Biosci. 3 (2013) 32, https://doi.org/10.1186/2045-3701-3-32.

[6] A. Hergovich, The roles of NDR protein kinases in hippo Signalling, Genes 7 (2016) 21, https://doi.org/10.3390/genes7050021.

[7] H. Cornils, R.S. Kohler, A. Hergovich, B.A. Hemmings, Downstream of human NDR kinases: impacting on c-myc and p21 protein stability to control cell cycle progression, Cell Cycle 10 (2011) 1897-1904, https://doi.org/10.4161/cc.10.12.15826.

[8] A. Hergovich, B.A. Hemmings, Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling, BioFactors 35 (2009) 338-345, https://doi.org/10.1002/biof.47.

[9] P.F. Santos, B. Fazendeiro, F.C. Luca, A.F. Ambrósio, H. Léger, The NDR/LATS protein kinases in neurobiology: key regulators of cell proliferation, differentiation and migration in the ocular and central nervous system, Eur. J. Cell Biol. 102 (2023) 151333, https://doi.org/10.1016/j.ejcb.2023.151333.

[10] A.A.D. Sharif, A. Hergovich, The NDR/LATS protein kinases in immunology and cancer biology, Semin. Cancer Biol. 48 (2018) 104-114, https://doi.org/10.1016/j.semcancer.2017.04.010.

[11] E. Devroe, H. Erdjument-Bromage, P. Tempst, P.A. Silver, Human mob proteins regulate the NDR1 and NDR2 serine-threonine kinases, J. Biol. Chem. 279 (2004) 24444-24451, https://doi.org/10.1074/jbc.M401999200.

[12] J. Yue, H. Sun, S. Liu, F. Yu, S. Wang, F. Wang, R. Shen, F. Zhu, L. Zhang, C. Shao, Downregulation of NDR 1 contributes to metastasis of prostate cancer cells via activating epithelial-mesenchymal transition, Cancer Med. 7 (2018) 3200-3212, https://doi.org/10.1002/cam4.1532.

[13] Y. Bai, X. Sui, Z. Xuan, Y. Du, M. Fu, Z. Zheng, K. Yang, C. Xu, Y. Liu, B. Liu, M. Zhong, Z. Zhang, J. Zheng, X. Hu, L. Zhang, H. Sun, C. Shao, Discovery of a small-molecule NDR1 agonist for prostate cancer therapy, Front. Pharmacol. 15 (2024) 1367358, https://doi.org/10.3389/fphar.2024.1367358.

[14] M. Keller, F. Dubois, S. Teulier, A.P.J. Martin, J. Levallet, E. Maille, S. Brosseau, N. Elie, A. Hergovich, E. Bergot, J. Camonis, G. Zalcman, G. Levallet, NDR2 kinase contributes to cell invasion and cytokinesis defects induced by the inactivation of RASSF1A tumor-suppressor gene in lung cancer cells, J. Exp. Clin. Cancer Res. 38 (2019) 158, https://doi.org/10.1186/s13046-019-1145-8.

[15] J. Levallet, T. Biojout, C. Bazille, M. Douyère, F. Dubois, D.L. Ferreira, J. Taylor, S. Teulier, J. Toutain, N. Elie, M. Bernaudin, S. Valable, E. Bergot, G. Levallet, Hypoxia-induced activation of NDR2 underlies brain metastases from non-small cell lung Cancer, Cell Death Dis. 14 (2023) 823, https://doi.org/10.1038/s41419-023-06345-3.

[16] A. Hergovich, S. Lamla, E.A. Nigg, B.A. Hemmings, Centrosome-associated NDR kinase regulates centrosome duplication, Mol. Cell 25 (2007) 625-634, https://doi.org/10.1016/j.molcel.2007.01.020.

[17] A. Hergovich, R.S. Kohler, D. Schmitz, A. Vichalkovski, H. Cornils, B. A. Hemmings, The MST1 and hMOB1 tumor suppressors control human centrosome duplication by regulating NDR kinase phosphorylation, Curr. Biol. 19 (2009) 1692-1702, https://doi.org/10.1016/j.cub.2009.09.020.

[18] A. Hergovich, S.J. Bichsel, B.A. Hemmings, Human NDR kinases are rapidly activated by MOB proteins through recruitment to the plasma membrane and phosphorylation, Mol. Cell. Biol. 25 (2005) 8259-8272, https://doi.org/10.1128/MCB.25.18.8259-8272.2005.

[19] J.C. Duhart, L.A. Raftery, Mob family proteins: regulatory partners in hippo and hippo-like intracellular signaling pathways, Front. Cell Dev. Biol. 8 (2020) 161, https://doi.org/10.3389/fcell.2020.00161.

[20] M.R. Stegert, R. Tamaskovic, S.J. Bichsel, A. Hergovich, B.A. Hemmings, Regulation of NDR2 protein kinase by multi-site phosphorylation and the S100B calcium-binding protein, J. Biol. Chem. 279 (2004) 23806-23812, https://doi.org/10.1074/jbc.M402472200.

[21] P. Ling, T.-J. Lu, C.-J. Yuan, M.-D. Lai, Biosignaling of mammalian Ste20-related kinases, Cell. Signal. 20 (2008) 1237-1247, https://doi.org/10.1016/j.cellsig.2007.12.019.

[22] S.J. Bichsel, R. Tamaskovic, M.R. Stegert, B.A. Hemmings, Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by the hMOB1 protein, J. Biol. Chem. 279 (2004) 35228-35235, https://doi.org/10.1074/jbc.M404542200.

[23] R.S. Kohler, D. Schmitz, H. Cornils, B.A. Hemmings, A. Hergovich, Differential NDR/LATS interactions with the human MOB family reveal a negative role for human MOB2 in the regulation of human NDR kinases, Mol. Cell. Biol. 30 (2010) 4507-4520, https://doi.org/10.1128/MCB.00150-10.

[24] T.A. Millward, D. Hess, B.A. Hemmings, Ndr protein kinase is regulated by phosphorylation on two conserved sequence motifs, J. Biol. Chem. 274 (1999) 33847-33850, https://doi.org/10.1074/jbc.274.48.33847.

[25] S. Chiba, M. Ikeda, K. Katsunuma, K. Ohashi, K. Mizuno, MST2- and furry-mediated activation of NDR1 kinase is critical for precise alignment of mitotic chromosomes, Curr. Biol. 19 (2009) 675-681, https://doi.org/10.1016/j.cub.2009.02.054.

[26] K. Irie, T. Nagai, K. Mizuno, Furry protein suppresses nuclear localization of yes-associated protein (YAP) by activating NDR kinase and binding to YAP, J. Biol. Chem. 295 (2020) 3017-3028, https://doi.org/10.1074/jbc.RA119.010783.

[27] R. Tamaskovic, S.J. Bichsel, B.A. Hemmings, NDR family of AGC kinases – essential regulators of the cell cycle and morphogenesis, FEBS Lett. 546 (2003) 73-80, https://doi.org/10.1016/S0014-5793(03)00474-5.

[28] R. Tamaskovic, S.J. Bichsel, H. Rogniaux, M.R. Stegert, B.A. Hemmings, Mechanism of Ca2+-mediated regulation of NDR protein kinase through autophosphorylation and phosphorylation by an upstream kinase, J. Biol. Chem. 278 (2003) 6710-6718, https://doi.org/10.1074/jbc.M210590200.

[29] Z. Meng, T. Moroishi, K.-L. Guan, Mechanisms of hippo pathway regulation, Genes Dev. 30 (2016) 1-17, https://doi.org/10.1101/gad.274027.115.

[30] A. Suzuki, T. Ogura, H. Esumi, NDR2 acts as the upstream kinase of ARK5 during insulin-like growth Factor-1 signaling, J. Biol. Chem. 281 (2006) 13915-13921, https://doi.org/10.1074/jbc.M511354200.

[31] T. Fukasawa, A. Enomoto, A. Yoshizaki-Ogawa, S. Sato, K. Miyagawa, A. Yoshizaki, The role of mammalian STK38 in DNA damage response and targeting for radio-sensitization, Cancers 15 (2023) 2054, https://doi.org/10.3390/cancers15072054.

[32] T.A. Millward, Calcium regulation of Ndr protein kinase mediated by S100 calcium-binding proteins, EMBO J. 17 (1998) 5913-5922, https://doi.org/10.1093/emboj/17.20.5913.
[33] A. Enomoto, T. Fukasawa, H. Tsumoto, M. Karube, K. Nakagawa, A. Yoshizaki, S. Sato, Y. Miura, K. Miyagawa, Prevention of calpain-dependent degradation of STK38 by MEKK2-mediated phosphorylation, Sci. Rep. 9 (2019) 16010, https://doi.org/10.1038/s41598-019-52435-8.

[34] A. Enomoto, N. Kido, M. Ito, N. Takamatsu, K. Miyagawa, Serine-threonine kinase 38 is regulated by glycogen synthase Kinase-3 and modulates oxidative stress-induced cell death, Free Radic. Biol. Med. 52 (2012) 507-515, https://doi.org/10.1016/j.freeradiomed.2011.11.006.

[35] Y. Cheng, W. Hou, H. Fang, Y. Yan, Y. Lu, T. Meng, C. Ma, Q. Liu, Z. Zhou, H. Li, H. Li, N. Xiao, SENP2-NDR2-p21 axis modulates lung cancer cell growth, Eur. J. Pharmacol. 978 (2024) 176761, https://doi.org/10.1016/j.ejphar.2024.176761.

[36] N. Xiao, H. Li, W. Yu, C. Gu, H. Fang, Y. Peng, H. Mao, Y. Fang, W. Ni, M. Yao, SUMO-specific protease 2 (SENP2) suppresses keratinocyte migration by targeting NDR1 for de-SUMOylation, FASEB J. 33 (2019) 163-174, https://doi.org/10.1096/fj.201800353R.

[37] Y. Tang, W. Yu, SIRT1 and p300/CBP regulate the reversible acetylation of serine-threonine kinase NDR2, Biochem. Biophys. Res. Commun. 518 (2019) 396-401, https://doi.org/10.1016/j.bbcrr.2019.08.069.

[38] Y. Yang, Y. Zhu, S. Zhou, P. Tang, R. Xu, Y. Zhang, D. Wei, J. Wen, R.F. Thorne, X. D. Zhang, J. Guan, L. Liu, M. Wu, S. Chen, TRIM27 cooperates with STK38L to inhibit ULK1-mediated autophagy and promote tumorigenesis, EMBO J. 41 (2022) e109777, https://doi.org/10.15252/embj.2021109777.

[39] N. Furth, Y. Aylon, The LATS1 and LATS2 tumor suppressors: beyond the hippo pathway, Cell Death Differ. 24 (2017) 1488-1501, https://doi.org/10.1038/cdd.2017.99.

[40] X. Ma, D. Wang, N. Li, P. Gao, M. Zhang, Y. Zhang, Hippo kinase NDR2 inhibits IL-17 signaling by promoting Smurf1-mediated MEKK2 ubiquitination and degradation, Mol. Immunol. 105 (2019) 131-136, https://doi.org/10.1016/j.molimm.2018.10.005.

[41] K. Rehberg, S. Kliche, D.A. Madencioglu, M. Thiere, B. Müller, B.M. Meineke, C. Freund, E. Budinger, O. Stork, The serine/threonine kinase Ndr2 controls integrin trafficking and integrin-dependent neurite growth, J. Neurosci. 34 (2014) 5342-5354, https://doi.org/10.1523/JNEUROSCI.2728-13.2014.

[42] O. Stork, A. Zhdanov, A. Kudersky, T. Yoshikawa, K. Obata, H.-C. Pape, Neuronal functions of the novel serine/threonine kinase Ndr2, J. Biol. Chem. 279 (2004) 45773-45781, https://doi.org/10.1074/jbc.M403552200.

[43] K. Jonischkies, M. Del Angel, Y.E. Demiray, A. Lozaiz Zambrano, O. Stork, The NDR family of kinases: essential regulators of aging, Front. Mol. Neurosci. 17 (2024) 1371086, https://doi.org/10.3389/fnmol.2024.1371086.

[44] Y. Wei, V.L.Z. Hui, Y. Chen, R. Han, X. Han, Y. Guo, YAP/TAZ: molecular pathway and disease therapy, MedComm 4 (2023) e340, https://doi.org/10.1002/mco2.340.

[45] S. Qie, J.A. Diehl, Cyclin D1, cancer progression, and opportunities in cancer treatment, J. Mol. Med. 94 (2016) 1313-1326, https://doi.org/10.1007/s00109-016-1475-3.

[46] M.C. Casimiro, M. Velasco-Velázquez, C. Aguirre-Alvarado, R.G. Pestell, Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present, Expert Opin. Investig. Drugs 23 (2014) 295-304, https://doi.org/10.1517/13543784.2014.867017.

[47] P. Ramos-García, J. Gil-Montoya, C. Scully, A. Ayén, L. González-Ruiz, F. Navarro-Triviño, M. González-Moles, An update on the implications of cyclin D1 in oral carcinogenesis, Oral Dis. 23 (2017) 897-912, https://doi.org/10.1111/odi.12620.

[48] D. Schmitz-Rohmer, S. Probst, Z.-Z. Nang, F. Laurent, M.B. Stadler, A. Zuniga, R. Zeller, D. Hynx, B.A. Hemmings, A. Hergovich, NDR kinases are essential for somitogenesis and cardiac looping during mouse embryonic development, PLoS One 10 (2015) e0136566, https://doi.org/10.1371/journal.pone.0136566.

[49] R. Yang, E. Kong, J. Jin, A. Hergovich, A.W. Püscher, Rassf5 and Ndr kinases act in a novel pathway regulating neuronal polarity through Par3 phosphorylation, J. Cell Sci. (2014) jcs.146696, https://doi.org/10.1242/jcs.146696.

[50] Y.E. Demiray, K. Rehberg, S. Kliche, O. Stork, Ndr2 kinase controls neurite outgrowth and dendritic branching through α1 integrin expression, Front. Mol. Neurosci. 11 (2018) 66, https://doi.org/10.3389/fmol.2018.00066.

[51] S.K. Ulanter, N.T. Hertz, G. Li, W.-P. Ge, A.L. Burlingame, S.J. Pleasure, K. M. Shokat, L.Y. Jan, Y.-N. Jan, Chemical genetic identification of NDR1/2 kinase substrates AAK1 and Rabin8 uncovers their roles in dendrite Arborization and spine development, Neuron 73 (2012) 1127-1142, https://doi.org/10.1016/j.neuron.2012.01.019.

[52] J.A. Zallen, E.L. Peckol, D.M. Tobin, C.I. Bargmann, Neuronal cell shape and neurite initiation are regulated by the Ndr kinase SAX-1, a member of the Orb6/COT-1/warts serine/threonine kinase family, MBoC 11 (2000) 3177-3190, https://doi.org/10.1091/mbc.11.9.3177.

[53] C. Zhang, Z. He, Z. Tan, F. Tian, Silencing of dentate gyrus inhibits mossy fiber sprouting and prevents epileptogenesis through NDR2 kinase in pentylenetetrazole kindling rat model of TLE, PLoS One 18 (2023) e0284359, https://doi.org/10.1371/journal.pone.0284359.

[54] D.A. Madencioglu, G. Çalışkan, P. Yuanxiang, K. Rehberg, Y.E. Demiray, E. Kul, A. Engler, H. Hayani, J.R. Bergado-Acosta, A. Kummer, I. Müller, I. Song, A. Dityatev, T. Kähne, M.R. Kreutz, O. Stork, Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function, iScience 24 (2021) 102868, https://doi.org/10.1016/j.isci.2021.102868.

[55] C. Chen, M. Rodriguez Pino, P.R. Haller, F. Verde, Conserved NDR/LATS kinase controls RAS GTPase activity to regulate cell growth and chronological lifespan, MBoC 30 (2019) 2598-2616, https://doi.org/10.1091/mbc.E19-03-0172.

[56] H. Cornils, R.S. Kohler, A. Hergovich, B.A. Hemmings, Human NDR kinases control G1/S cell cycle transition by directly regulating p21 stability, Mol. Cell. Biol. 31 (2011) 1382-1395, https://doi.org/10.1128/MCB.01216-10.

[57] Z. Du, X. Tong, X. Ye, Cyclin D1 promotes cell cycle progression through enhancing NDR1/2 kinase activity independent of cyclin-dependent kinase 4, J. Biol. Chem. 288 (2013) 26678-26687, https://doi.org/10.1074/jbc.M113.466433.

[58] T.J. Grant, A.K. Mehta, A. Gupta, A.A.D. Sharif, K.S. Arora, V. Deshpande, D. T. Ting, N. Bardeesy, N.J. Ganem, A. Hergovich, A. Singh, STK38L kinase ablation promotes loss of cell viability in a subset of KRAS-dependent pancreatic cancer cell lines, Oncotarget 8 (2017) 78556-78572, https://doi.org/10.18632/oncotarget.20833.

[59] J. Brace, J. Hsu, E.L. Weiss, Mitotic exit control of the Saccharomyces cerevisiae Ndr/LATS kinase Cbk1 regulates daughter cell separation after cytokinesis, Mol. Cell. Biol. 31 (2011) 721-735, https://doi.org/10.1128/MCB.00403-10.

[60] A.P. Sagona, H. Stenmark, Cytokinesis and cancer, FEBS Lett. 584 (2010) 2652-2661, https://doi.org/10.1016/j.feb.2010.03.044.

[61] H. Chen, G. Chen, G. Li, S. Zhang, H. Chen, Y. Chen, D. Duggan, Z. Hu, J. Chen, Y. Zhao, Y. Zhao, H. Huang, S.L. Zheng, J.M. Trent, L. Yu, D. Jiang, Z. Mo, H. Wang, Y. Mou, T. Jiang, Y. Mao, J. Xu, D. Lu, Two novel genetic variants in the STK38L and RAB27A genes are associated with glioma susceptibility, Int J. Biol. of, Cancer 145 (2019) 2372-2382, https://doi.org/10.1002/ijc.3217.

[62] Q.T. Ostrom, S.S. Francis, J.S. Barnholtz-Sloan, Epidemiology of brain and other CNS tumors, Curr. Neurol. Neurosci. Rep. 21 (2021) 68, https://doi.org/10.1007/s11910-021-01152-9.

[63] H. Cornils, M.R. Stegert, A. Hergovich, D. Hynx, D. Schmitz, S. Dirnhofer, B. A. Hemmings, Ablation of the kinase NDR1 predisposes mice to the development of T cell lymphoma, Sci. Signal. 3 (2010), https://doi.org/10.1126/scisignal.2000681.

[64] A. Vichalkovski, E. Gresko, H. Cornils, A. Hergovich, D. Schmitz, B.A. Hemmings, NDR kinase is activated by RASSF1A/MST1 in response to Fas receptor stimulation and promotes apoptosis, Curr. Biol. 18 (2008) 1889-1895, https://doi.org/10.1016/j.cub.2008.10.060.

[65] Y. Zhou, Y. Adolfs, W.W.M.P. Pijnappel, S.J. Fuller, R.C. Van Der Schors, K.W. Li, P.H. Sugden, A.B. Smit, A. Hergovich, R.J. Pasterkamp, MICAL-1 is a negative regulator of MST-NDR kinase signaling and apoptosis, Mol. Cell. Biol. 31 (2011) 3603-3615, https://doi.org/10.1128/MCB.M03189-10.

[66] J. Kondelin, K. Salokas, L. Saarinen, K. Ovaska, H. Rauanheimo, R. Plaketti, J. Hamberg, X. Liu, L. Yadav, A.E. Gylfe, T. Cajuso, U.A. Hänninen, K. Palin, H. Ristolainen, R. Katainen, E. Kaasinen, T. Tanskanen, M. Aavikko, M. Taipale, J. Taipale, L. Renkonen-Sinisalo, A. Lepistö, S. Koskensalo, J. Böhm, J. Mecklin, H. Ongen, E.T. Dermitzakis, O. Kilpivaara, P. Vahteristo, M. Turunen, S. Hautaniemi, S. Tuupanen, A. Karhu, N. Välimäki, M. Varjosalo, E. Pitkänen, L. A. Altonen, Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer, EMBO Mol. Med. 10 (2018) e8552, https://doi.org/10.15252/emmm.201708552.

[67] L. Zhang, F. Tang, L. Terracciano, D. Hynx, R. Kohler, S. Bichet, D. Hess, P. Cron, B.A. Hemmings, A. Hergovich, D. Schmitz-Rohmer, NDR functions as a physiological YAP1 kinase in the intestinal epithelium, Curr. Biol. 25 (2015) 296-305, https://doi.org/10.1016/j.cub.2014.11.054.

[68] M. Kleemann, H. Schneider, K. Unger, B. Bereuther, S. Fischer, S. Sander, E. Marion Schneider, P. Fischer-Posovszky, C.U. Riedel, R. Handrick, K. Otte, Induction of apoptosis in ovarian cancer cells by miR-493-3p directly targeting AKT2, STK38L, HMGAA, ETS1 and E2F5, Cell. Mol. Life Sci. 76 (2019) 539-559, https://doi.org/10.1007/s00018-018-2958-x.

[69] M. Khandelwal, V. Anand, S. Appunni, A. Seth, P. Singh, S. Mathur, A. Sharma, RASSF1A-hippo pathway link in patients with urothelial carcinoma of bladder: plausible therapeutic target, Mol. Cell. Biochem. 464 (2020) 51-63, https://doi.org/10.1007/s11010-010-01964-y.

[70] B. Cinar, E. Alp, M. Al-Mathkour, A. Boston, A. Dwead, K. Khazaw, A. Gregory, The hippo pathway: an emerging role in urologic cancers, Am J Clin Exp Urol 9 (2021) 301-317.

[71] J.-Y. Liu, Y.-H. Li, H.-X. Lin, Y.-J. Liao, S.-J. Mai, Z.-W. Liu, Z.-L. Zhang, L.-J. Jiang, J.-X. Zhang, H.-F. Kung, Y.-X. Zeng, F.-J. Zhou, D. Xie, Overexpression of YAP 1 contributes to progressive features and poor prognosis of human urothelial carcinoma of the bladder, BMC Cancer 13 (2013) 349, https://doi.org/10.1186/1471-2407-13-349.

[72] F. Dubois, M. Keller, O. Calvayrac, F. Soncin, L. Hoa, A. Hergovich, M.-C. Parrini, J. Mazières, M. Vaisse-Lesteven, J. Camonis, G. Levallet, G. Zalcman, RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non-Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway, Cancer Res. 76 (2016) 1627-1640, https://doi.org/10.1158/0008-5472.CAN-15-1008.

[73] F. De Fraipont, G. Levallet, C. Creveuil, E. Bergot, M. Beau-Faller, M. Mounawar, N. Richard, M. Antoine, I. Rouquette, M.-C. Favrot, D. Debieuvre, D. Braun, V. Westeel, E. Quoix, E. Brambilla, P. Hainaut, D. Moro-Sibilot, F. Morin, B. Milleron, G. Zalcman, An apoptosis methylation prognostic signature for early lung Cancer in the IFCT-0002 trial, Clin. Cancer Res. 18 (2012) 2976-2986, https://doi.org/10.1158/1078-0432.CCR-11-2797.

[74] P.T. Caswell, J.C. Norman, Integrin trafficking and the control of cell migration, Traffic 7 (2006) 14-21, https://doi.org/10.1111/j.1600-0854.2005.00362.x.

[75] M. Uhlen, L. Fagerberg, B.M. Hallström, C. Lindskog, P. Oskvold, A. Mardinoglu, Å. Sivertsson, C. Kampf, E. Sjöstedt, A. Asplund, I. Olson, K. Edlund, E. Lundberg, S. Navani, C.A.-K. Szigyarto, J. Odeberg, D. Djureinovic, J.O. Takanen, S. Hober, T. Alm, P.-H. Edqvist, H. Berling, H. Tegel, J. Mulder, J. Rockberg, P. Nilsson, J. M. Schwenk, M. Hamsten, K. Von Feilitzen, M. Forsberg, L. Persson, F. Johansson,
[76] M. Zwahlen, G. Von Heijne, J. Nielsen, F. Pontén, Tissue-based map of the human proteome, Science 347 (2015) 1260419, https://doi.org/10.1126/science.1260419.

[77] C.-W. Lin, Y.-L. Chang, Y.-C. Chang, J.-C. Lin, C.-C. Chen, S.-H. Pan, C.-T. Wu, H.-Y. Chen, S.-C. Yang, T.-M. Hong, P.-C. Yang, MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the hippo pathway and LZTS1, Nat. Commun. 4 (2013) 1877, https://doi.org/10.1038/ncomms2876.

[78] M. Antonietta De Matteis, A. Di Campli, A. Godi, The role of the phosphoinositides at the Golgi complex, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1744 (2005) 396-405, https://doi.org/10.1016/j.bbamcr.2005.04.013.

[79] R. Prekeris, J. Klumperman, R.H. Scheller, A Rab11/Rip1 protein complex regulates apical membrane trafficking via recycling endosomes, Mol. Cell 6 (2000) 1437-1448, https://doi.org/10.1016/S1097-2765(00)00140-4.

[80] P. De Graaf, W.T. Zwart, R.A.J. Van Dijken, M. Deneka, T.K.F. Schulz, N. Geijsen, P.J. Coffer, B.M. Gadella, A.J. Verkleij, P. Van Der Sluijs, P.M.P. Van Bergen En Henegouwen, Phosphatidylinositol 4-kinaseβ is critical for functional association of rab11 with the Golgi complex, MBOC 15 (2004) 2038-2047, https://doi.org/10.1091/mbc.e03-12-0862.

[81] J.E. Burke, A.J. Inglis, O. Perisic, G.R. Masson, S.H. McLaughlin, F. Rutaganira, K. M. Shokat, R.L. Williams, Structures of PI4KIIIβ complexes show simultaneous recruitment of Rab11 and its effectors, Science 344 (2014) 1035-1038, https://doi.org/10.1126/science.1253397.

[82] F. Rosjanu, S.R. Mihaylov, N. Eder, A. Martiniaci, S. Claxton, H.R. Flynn, S. Jalal, M.-C. Domart, L. Collinson, M. Skehel, A.P. Snijders, M. Krause, S.A. Tooze, S. K. Ulanir, Loss of NDR1/2 kinases impairs endomembrane trafficking and autophagy leading to neurodegeneration, Life Sci. Alliance 6 (2023) e202201712, https://doi.org/10.26508/lsa.202201712.

[83] D. Wang, J. He, B. Huang, S. Liu, H. Zhu, T. Xu, Emerging role of the hippo pathway in autophagy, Cell Death Dis. 11 (2020) 880, https://doi.org/10.1038/s41419-020-03069-6.

[84] M. Pavel, S.J. Park, R.A. Frake, S.M. Son, M.M. Manni, C.F. Bento, M. Renna, T. Ricketts, F.M. Menzies, R. Tanasa, D.C. Rubinsztein, A-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation, Nat. Commun. 12 (2021) 1703, https://doi.org/10.1038/s41467-021-21882-1.

[85] Y. Maejima, D. Zablocki, J. Nah, J. Sadoshima, The role of the hippo pathway in autophagy in the heart, Cardiovasc. Res. 118 (2023) 3320-3330, https://doi.org/10.1093/cvr/cvac014.

[86] Y. Xiang, P. Peng, X. Liu, X. Jin, J. Shen, T. Zhang, L. Zhang, F. Wan, Y. Ren, Q. Yu, H. Zhao, Y. Si, Y. Liu, Paris saponin VII, a hippo pathway activator, induces autophagy and exhibits therapeutic potential against human breast cancer cells, Acta Pharmacol. Sin. 43 (2022) 1568-1580, https://doi.org/10.1038/s41401-021-00755-9.

[87] F. Tang, G. Christofori, The cross-talk between the hippo signaling pathway and autophagy:implications on physiology and cancer, Cell Cycle 19 (2020) 2563-2572, https://doi.org/10.1080/15384101.2020.1806450.

[88] C.W. Yun, S.H. Lee, The roles of autophagy in Cancer, IJMS 19 (2018) 3466, https://doi.org/10.3390/ijms19113466.

[89] W. Gan, X. Dai, X. Dai, J. Xie, S. Yin, J. Zhu, C. Wang, Y. Liu, J. Guo, M. Wang, J. Liu, J. Hu, R.J. Quinton, N.J. Ganem, P. Liu, J.M. Asara, P.P. Pandolfi, Y. Yang, Z. He, G. Gao, W. Wei, LATS suppresses mTORC1 activity to directly coordinate hippo and mTORC1 pathways in growth control, Nat. Cell Biol. 22 (2020) 246-256, https://doi.org/10.1038/s41556-020-0463-6.

[90] F. Tang, R. Gao, B. Jeevan-Raj, C.B. Wyss, R.K.R. Kalathur, S. Piscuoglio, C.K. Y. Ng, S.K. Hindupur, S. Nuciforo, E. Dazert, T. Bock, S. Song, D. Buechel, M. F. Morini, A. Hergovich, P. Matthias, D.-S. Lim, L.M. Terraccucco, M.H. Heim, M. N. Hall, G. Christofori, LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function, Nat. Commun. 10 (2019) 7555, https://doi.org/10.1038/s41467-019-13591-7.

[91] F. Tang, G. Christofori, LATS1-Beclin1 mediates a non-canonical connection between the hippo pathway and autophagy, Mol. Cell. Oncol. 7 (2020) 1757378, https://doi.org/10.1080/23723556.2020.1757378.

[92] C. Joffre, N. Dupont, L. Hoa, V. Gomez, R. Pardo, C. Gonçalves-Pimentel, P. Achard, A. Bettoun, B. Meunier, C. Bauvy, I. Cascone, P. Codogno, M. Fanto, A. Hergovich, J. Camonis, The pro-apoptotic STK38 kinase is a new Beclin1 partner positively regulating autophagy, Curr. Biol. 25 (2015) 2479-2492, https://doi.org/10.1016/j.cub.2015.08.031.

[93] C. Joffre, P. Codogno, M. Fanto, A. Hergovich, J. Camonis, STK38 at the crossroad between autophagy and apoptosis, Autophagy 12 (2016) 594-595, https://doi.org/10.1080/15548627.2015.1135283.

[94] A.P. Martin, M. Jacquemyn, J. Lipecka, C. Chhuon, V.N. Aushev, B. Meunier, M. K. Singh, N. Carpi, M. Piel, P. Codogno, A. Hergovich, M.C. Parrini, G. Zalcman, I. C. Guerrera, D. Daelemans, J.H. Camonis, STK 38 kinase acts as XPO 1 gatekeeper regulating the nuclear export of autophagy proteins and other cargoes, EMBO Rep. 20 (2019) e48150, https://doi.org/10.15252/embr.201948150.

[95] A. Pj, V.N. Martin, G. Aushev, J.H. Camonis Zalcman, The STK38-XPO1 axis, a new actor in physiology and cancer, Cell. Mol. Life Sci. 78 (2021) 1943-1955, https://doi.org/10.1007/s00018-020-03690-w.

[96] Y. Amagai, T. Itoh, M. Fukuda, K. Mizuno, Rabin8 suppresses autophagosome formation independently of its guanine nucleotide-exchange activity towards Rabb, J. Biochem. 158 (2015) 139-153, https://doi.org/10.1093/jb/mvv032.

[97] Z. Wei, X. Hu, Y. Wu, L. Zhou, M. Zhao, Q. Lin, Molecular mechanisms underlying initiation and activation of autophagy, Biomolecules 14 (2024) 1517, https://doi.org/10.3390/biom14121517.

[98] M. Pavel, D.C. Rubinsztein, Mammalian autophagy and the plasma membrane, FEBS J. 284 (2017) 672-679, https://doi.org/10.1111/febs.13931.

[99] E. Zubkova, A. Kalinin, A. Bolotskaya, I. Beloglazova, M. Menshikov, Autophagy-dependent secretion: crosstalk between autophagy and exosome biogenesis, CIMB 46 (2024) 2209-2235, https://doi.org/10.3390/cimb46030142.

[100] L. Li, G. Li, M. Chen, R. Cai, Astragaloside IV enhances the sensibility of lung adenocarcinoma cells to bevacizumab by inhibiting autophagy, Drug Dev. Res. 83 (2022) 461-469, https://doi.org/10.1002/ddr.21878.

[101] S. Chiba, Y. Amagai, Y. Homma, M. Fukuda, K. Mizuno, NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidyserine to Sec15, EMBO J. 32 (2013) 874-885, https://doi.org/10.1038/emb0.2013.32.

[102] H. Zhao, Z. Khan, C.J. Westlake, Ciliogenesis membrane dynamics and organization, Semin. Cell Dev. Biol. 133 (2023) 20-31, https://doi.org/10.1016/j.semcdb.2022.03.021.

[103] C.-H. Sung, M.R. Leroux, The roles of evolutionarily conserved functional modules in cilia-related trafficking, Nat. Cell Biol. 15 (2013) 1387-1397, https://doi.org/10.1038/ncb2888.

[104] H. Hehnly, C.-T. Chen, C.M. Powers, H.-L. Liu, S. Doxsey, The centrosome regulates the Rab11- dependent recycling endosome pathway at appendages of the mother centriole, Curr. Biol. 22 (2012) 1944-1950, https://doi.org/10.1016/j.cub.2012.08.022.

[105] M.R. Heider, M. Munson, Exorcising the exocyst complex, Traffic 13 (2012) 898-907, https://doi.org/10.1111/j.1600-0854.2012.01353.x.

[106] S. Abe, T. Nagai, M. Masukawa, K. Okumoto, Y. Homma, Y. Fujiki, K. Mizuno, Localization of protein kinase NDR2 to peroxisomes and its role in Ciliogenesis, J. Biol. Chem. 292 (2017) 4089-4098, https://doi.org/10.1074/jbc.M117.775916.

[107] B.W. Swinkels, S.J. Gould, S. Subramani, Targeting efficiencies of various permutations of the consensus C-terminal tripeptide peroxisomal targeting signal, FEBS Lett. 305 (1992) 133-136, https://doi.org/10.1016/0014-5793(92)80880-P.

[108] O. Goldstein, A.V. Kukekova, G.D. Aguirre, G.M. Acland, Exonic SINE insertion in STK38L causes canine early retinal degeneration (erd), Genomics 96 (2010) 362-368, https://doi.org/10.1016/j.ygeno.2010.09.003.

[109] A.I. Berta, K. Boesze-Battaglia, S. Genini, O. Goldstein, P.J. O'Brien, Á. Szél, G. M. Acland, W.A. Beltran, G.D. Aguirre, Photoreceptor cell death, proliferation and formation of hybrid rod/S-cone photoreceptors in the degenerating STK38L mutant retina, PLoS One 6 (2011) e24074, https://doi.org/10.1371/journal.pone.0024074.

[110] H. Léger, E. Santana, N.A. Leu, E.T. Smith, W.A. Beltran, G.D. Aguirre, F.C. Luca, Ndr kinases regulate retinal interneuron proliferation and homeostasis, Sci. Rep. 8 (2018) 12544, https://doi.org/10.1038/s41598-018-30492-9.

[111] M. Wen, X. Ma, H. Cheng, W. Jiang, X. Xu, Y. Zhang, Y. Zhang, Z. Guo, Y. Yu, H. Xu, C. Qian, X. Cao, H. An, Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages, Nat. Commun. 6 (2015) 7167, https://doi.org/10.1038/ncomms8167.

[112] X. Ye, N. Ong, H. An, Y. Zheng, The emerging roles of NDR1/2 in infection and inflammation, Front. Immunol. 11 (2020) 534, https://doi.org/10.3389/fimmu.2020.00534.

[113] D. Tang, H. Xu, X. Du, The role of non-canonical hippo pathway in regulating immune homeostasis, Eur. J. Med. Res. 28 (2023) 498, https://doi.org/10.1186/s40001-023-01484-x.

[114] L. Hong, X. Li, D. Zhou, J. Geng, L. Chen, Role of hippo signaling in regulating immunity, Cell. Mol. Immunol. 15 (2018) 1003-1009, https://doi.org/10.1038/s41423-018-0007-1.

[115] Z. Liu, C. Wu, Y. Pan, H. Liu, X. Wang, Y. Yang, M. Gu, Y. Zhang, X. Wang, NDR2 promotes the antiviral immune response via facilitating TRIM25-mediated RIG-I activation in macrophages, Sci. Adv. 5 (2019) eaav0163, https://doi.org/10.1126/sciadv.eaav0163.

[116] W. Liu, J. Li, W. Zheng, Y. Shang, Z. Zhao, S. Wang, Y. Bi, S. Zhang, C. Xu, Z. Duan, L. Zhang, Y.L. Wang, Z. Jiang, W. Liu, L. Sun, Cyclophilin A-regulated ubiquitination is critical for RIG-I-mediated antiviral immune responses, eLife 6 (2017) e24425, https://doi.org/10.7554/eLife.24425.

[117] E. Devroe, P.A. Silver, A. Engelman, V.I. Golvin, A. Meissner, I. and proteolytically processes human NDR1 and NDR2 serine-threonine kinases, Virology 331 (2005) 181-189, https://doi.org/10.1016/j.viroi.2004.10.023.

[118] F. Tang, J. Gill, X. Ficht, T. Barthlott, H. Cornils, D. Schmitz-Rohmer, D. Hynx, D. Zhou, L. Zhang, G. Xue, M. Grzmil, Z. Yang, A. Hergovich, G.A. Hollaender, J. V. Stein, B.A. Hemmings, P. Matthias, The kinases NDR1/2 act downstream of the hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility, Sci. Signal. 8 (2015), https://doi.org/10.1126/scisignal.aab2425.

[119] N. Waldt, A. Seifert, Y.E. Demiray, E. Devroe, B.E. Turk, P. Reichardt, C. Mix, A. Reinhold, C. Freund, A.J. Müller, B. Schraven, O. Stork, S. Kliche, Filamin a phosphorylation at serine 2152 by the serine/threonine kinase Ndr2 controls TCR-induced LFA-1 activation in T cells, Front. Immunol. 9 (2018) 2852, https://doi.org/10.3389/fimmu.2018.02852.

[120] M.J. Bollong, G. Lee, J.S. Coukos, H. Yun, C. Zambaldo, J.W. Chang, E.N. Chin, I. Ahmad, A.K. Chatterjee, L.L. Lairson, P.G. Schultz, R.E. Moellering, A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling, Nature 562 (2018) 600-604, https://doi.org/10.1038/s41586-018-0622-0.

[121] Q. Huang, M. Peng, Y. Gu, J. Wu, Y. Zhan, Z. Deng, S. Chen, R. Yang, J. Chen, J. Xie, Metabolism-related gene TXNRD1 regulates inflammation and oxidative stress induced by cigarette smoke through the Nrf2/HO-1 pathway in the small
airway epithelium, Oxidative Med. Cell. Longev. 2022 (2022) 1–16, https://doi.org/10.1155/2022/7067623.

[121] R. Mojzikova, P. Koralkova, D. Holub, Z. Saxova, D. Pospisilova, D. Prochazkova, P. Dzubak, M. Horvathova, V. Divoky, Two novel mutations (p.(Ser160Pro) and p. (Arg472Cys)) causing glucose-6-phosphate isomerase deficiency are associated with erythroid dysplasia and inappropriately suppressed hepcidin, Blood Cell Mol. Dis. 69 (2018) 23–29, https://doi.org/10.1016/j.bcmd.2017.04.003.

[122] S.A. Kerk, J. Garcia-Bermudez, K. Birsoy, M.H. Sherman, Y.M. Shah, C.A. Lyssiotis, Spotlight on GOT2 in Cancer metabolism, OTT Volume 16 (2023) 695–702. doi: https://doi.org/10.2147/OTT.S382161.

[123] X. Zhang, H. Zhao, Y. Li, D. Xia, L. Yang, Y. Ma, H. Li, The role of YAP/TAZ activity in cancer metabolic reprogramming, Mol. Cancer 17 (2018) 134, https://doi.org/10.1186/s12943-018-0882-1.

[124] G. Di Benedetto, S. Parisi, T. Russo, F. Passaro, YAP and TAZ mediators at the crossroad between metabolic and cellular reprogramming, Metabolites 11 (2021) 154, https://doi.org/10.3390/metabo11030154.

[125] T. Kashihara, J. Sadoshima, Role of YAP/TAZ in energy metabolism in the heart, J. Cardiovasc. Pharmacol. 74 (2019) 483–490, https://doi.org/10.1097/FJC.0000000000000736.

[126] T. Gao, L. Yang, Y. Zhang, O. Bajinka, X. Yuan, Cancer metabolic reprogramming and precision medicine-current perspective, Front. Pharmacol. 15 (2024) 1450441, https://doi.org/10.3389/fphar.2024.1450441.

[127] S. Tarabykina, T.L. Griffiths, E. Tulchinsky, J. Mellon, I. Bronstein, M. Kriajevska, Metastasis-associated protein S100A4: spotlight on its role in cell migration, CCDT 7 (2007) 217–228, https://doi.org/10.2174/15680097780618329.

[128] F. Fei, J. Qu, M. Zhang, Y. Li, S. Zhang, S100A4 in cancer progression and metastasis: a systematic review, Oncotarget 8 (2017) 73219–73239, https://doi.org/10.18632/oncotarget.18016.

[129] T. Wang, G. Du, D. Wang, The S100 protein family in lung cancer, Clin. Chim. Acta 520 (2021) 67–70, https://doi.org/10.1016/j.cca.2021.05.028.

[130] J. Guo, Y. Bian, Y. Wang, L. Chen, A. Yu, X. Sun, FAM107B is regulated by S100A4 and mediates the effect of S100A4 on the proliferation and migration of MGC803 gastric cancer cells, Cell Biol. Int. 41 (2017) 1103–1109, https://doi.org/10.1002/cbin.10816.

[131] L. Padilla, S. Dakhel, J. Adan, M. Masa, J.M. Martinez, L. Roque, T. Coll, R. Hervas, C. Calvis, L. Llinas, S. Buenestado, J. Castellsague, R. Messeguer, F. Mitjans, J.L. Hernandez, S100A7: from mechanism to cancer therapy, Oncogene 36 (2017) 6749–6761, https://doi.org/10.1038/onc.2017.283.

[132] K. Boye, G.M. Maelandsmo, S100A4 and Metastasis, Am. J. Pathol. 176 (2010) 528–535, https://doi.org/10.2353/ajpath.2010.090526.

[133] Z. Lu, S. Zheng, C. Liu, X. Wang, G. Zhang, F. Wang, S. Wang, J. Huang, S. Mao, Y. Lei, Z. Wang, N. Sun, J. He, S100A7 as a potential diagnostic and prognostic biomarker of esophageal squamous cell carcinoma promotes M2 macrophage infiltration and angiogenesis, Clinical & Translational Med 11 (2021) e459, https://doi.org/10.1002/ctm.2459.

[134] J. Zhang, Y. Gu, X. Liu, X. Rao, G. Huang, Y. Ouyang, Clinicopathological and prognostic value of S100A4 expression in non-small cell lung cancer: a meta-analysis, Biosci. Rep. 40 (2020) BSR20201710, https://doi.org/10.1042/BSR20201710.

[135] E.D. Emberley, Y. Niu, L. Curtis, S. Troup, S.K. Mandal, J.N. Myers, S.B. Gibson, L. C. Murphy, P.H. Watson, The S100A7-c-Jun activation domain binding protein 1 pathway enhances Prosurvival pathways in breast Cancer, Cancer Res. 65 (2005) 5696–5702, https://doi.org/10.1158/0008-5472.CAN-04-3927.

[136] L.O. Xinstale-Castillo, A. Landa, Physiological and modulatory role of thioredoxins in the cellular function, Open Medicine 17 (2022) 2021–2035, https://doi.org/10.1515/med-2022-0596.

[137] R. Seitz, D. Tümen, C. Kunst, P. Heumann, S. Schmid, A. Kandulski, M. Müller, K. Gülow, Exploring the Thioredoxin system as a therapeutic target in Cancer: mechanisms and implications, Antioxidants 13 (2024) 1078, https://doi.org/10.3390/antiox13091078.

[138] R.K. Gandhirajan, M. Jain, B. Walla, M. Johnsen, M.P. Bartram, M. Huynh Anh, M.M. Rinschen, T. Benzing, B. Schermer, Cysteine S-Glutathionylation promotes stability and activation of the hippo downstream effector transcriptional co-activator with PDZ-binding motif (TAZ), J. Biol. Chem. 291 (2016) 11596–11607, https://doi.org/10.1074/jbc.M115.712539.

[139] P. Khanal, Z. Jia, X. Yang, Cysteine residues are essential for dimerization of hippo pathway components YAP2L and TAZ, Sci. Rep. 8 (2018) 3485, https://doi.org/10.1038/s41598-018-21828-6.

[140] T.C. Karlenius, K.F. Tonissen, Thioredoxin and Cancer: a role for Thioredoxin in all states of tumor oxygenation, Cancers 2 (2010) 209–232, https://doi.org/10.3390/cancers2020209.

[141] T. Yuan, S. Rafizadeh, Z. Azizi, B. Lupse, K.D.D. Gorrepati, S. Awal, J. Oberholzer, K. Maedler, A. Ardestani, Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells, JCI Insight 1 (2016), https://doi.org/10.1172/jci.insight.86326.

[142] U. Kazimierczak, E. Dondajewska, M. Zajaczowska, M. Karwacka, T. Kolenda, A. Mackiewicz, LATS1 is a mediator of Melanogenesis in response to oxidative stress and regulator of melanoma growth, IJMS 22 (2021) 3108, https://doi.org/10.3390/ijms22063108.

[143] M. Praskova, F. Xia, J. Avruch, MOBKL1A/MOBL1B phosphorylation by MST1 and MST2 inhibits cell proliferation, Curr. Biol. 18 (2008) 311–321, https://doi.org/10.1016/j.cub.2008.02.006.

[144] S. Chanarat, UBL5/Hub1: An atypical ubiquitin-like protein with a typical role as a stress-responsive regulator, IJMS 22 (2021) 9384, https://doi.org/10.3390/ijms22179384.

[145] W. Wang, A.M. Hawkridge, Y. Ma, B. Zhang, J.B. Mangrum, Z.H. Hassan, T. He, S. Blat, C. Guo, H. Zhou, J. Liu, X.-Y. Wang, X. Fang, Ubiquitin-like protein 5 is a novel player in the UPR-PERK arm and ER stress-induced cell death, J. Biol. Chem. 299 (2023) 104915, https://doi.org/10.1016/j.jbc.2023.104915.

[146] K.K.athur, P. Mallya, S. Barve, S.L. Bojia, M.M. Wagle, Moonlighting functions of the ubiquitin-like protein, Hub1/UBL-5, Int. J. Biochem. Cell Biol. 162 (2023) 106445, https://doi.org/10.1016/j.biocel.2023.106445.

[147] P. Hotulainen, E. Paunola, M.K. Vartiainen, P. Lappalainen, Actin-depolymerizing factor and Cofilin-1 play overlapping roles in promoting rapid F-actin Depolymerization in mammalian nonmuscle cells, MBoC 16 (2005) 649–664, https://doi.org/10.1091/mbc.e04-07-0555.

[148] A. Saito, K. Miyajima, J. Akatsuka, H. Kondo, T. Mashiko, T. Kiuchi, K. Ohashi, K. Mizuno, Ca MKII β-mediated LIM-kinase activation plays a crucial role in BDNF-induced neuritogenesis, Genes Cells 18 (2013) 533–543, https://doi.org/10.1111/gtc.12054.

[149] C. Prunier, R. Prudent, R. Kapur, K. Sadoul, L. Lafanechère, LIM kinases: cofilin and beyond, Oncotarget 8 (2017) 41749–41763, https://doi.org/10.18632/oncotarget.16978.

[150] M. Sakuma, Y. Shirai, K. Yoshino, M. Kuramasu, T. Nakamura, T. Yanagita, K. Mizuno, I. Hide, Y. Nakata, N. Saito, Novel PKCα-mediated phosphorylation site(s) on cofilin and their potential role in terminating histamine release, MBoC 23 (2012) 3707–3721, https://doi.org/10.1091/mbc.e12-01-0053.

[151] C. Shi, Y. Cai, Y. Li, Y. Li, N. Hu, S. Ma, S. Hu, P. Zhu, W. Wang, H. Zhou, Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways, Redox Biol. 14 (2018) 59–71, https://doi.org/10.1016/j.redox.2017.08.013.

[152] X. Yang, K. Yu, Y. Hao, D. Li, R. Stewart, K.L. Insogna, T. Xu, LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1, Nat. Cell Biol. 6 (2004) 609–617, https://doi.org/10.1038/ncb1140.

[153] R.M. Densham, E. O'Neill, J. Munro, I. König, K. Anderson, W. Kolch, M.F. Olson, MST kinases monitor actin cytoskeletal integrity and signal via c-Jun N-terminal kinase stress-activated kinase to regulate p21Waf1/cip1 stability, Mol. Cell. Biol. 29 (2009) 6380–6390, https://doi.org/10.1128/MCB.00116-09.

[154] J. Xu, Y. Huang, J. Zhao, L. Wu, Q. Qi, Y. Liu, G. Li, J. Li, H. Liu, H. Wu, Cofilin: a promising protein implicated in Cancer metastasis and apoptosis, Front. Cell Dev. Biol. 9 (2021) 599065, https://doi.org/10.3389/fcel.2021.599065.

[155] R. Wei, Y. Zhang, L. Shen, W. Jiang, C. Li, M. Zhong, Y. Xie, D. Yang, L. He, Q. Zhou, Comparative proteomic and radiobiological analyses in human lung adenocarcinoma cells, Mol. Cell. Biochem. 359 (2012) 151–159, https://doi.org/10.1007/s11010-011-1008-x.

[156] A. Kotb, M.E. Hyndman, T.R. Patel, The role of zyxin in regulation of malignancies, Heliyon 4 (2018) e00695, https://doi.org/10.1016/j.heliyon.2018.06.0095.

[157] J. Zhou, Y. Zeng, L. Cui, X. Chen, S. Stauffer, Z. Wang, F. Yu, S.M. Lele, G. A. Talmon, A.R. Black, Y. Chen, J. Dong, Zyxin promotes colon cancer tumorigenesis in a mitotic phosphorylation-dependent manner and through CDK8-mediated YAP activation, Proc. Natl. Acad. Sci. USA 115 (2018), https://doi.org/10.1073/pnas.1800621115.

[158] B. Ma, H. Cheng, R. Gao, C. Mu, L. Chen, S. Wu, Q. Chen, Y. Zhu, Zyxin-Siah2-Lats2 axis mediates cooperation between hippo and TGF-β signalling pathways, Nat. Commun. 7 (2016) 11123, https://doi.org/10.1038/ncomms11123.

[159] A. Partynska, A. Gomulkiewicz, A. Piotrowska, J. Grzegorzka, A. Rzехonek, K. Ratajczak-Wielgomas, M. Podhorska-Okolow, P. Dziegiel, Expression of Zyxin in non-small cell lung Cancer—a preliminary study, Biomolecules 12 (2022) 827, https://doi.org/10.3390/biomol2061287.

[160] X. Song, Q. Li, J. Zhang, A double-edged sword: DLG5 in diseases, Biomed. Pharmacother. 162 (2023) 114611, https://doi.org/10.1016/j.biopha.2023.114611.

[161] C. Andolfi, C. Tiribelli, D. Pascut, Recent hints on the dual role of discs large MAGUK scaffold protein 5 in cancers and in hepatocellular carcinoma, Front. Biosci. (Landmark Ed) 27 (2022) 164, https://doi.org/10.31083/j.fbl2705164.

[162] J. Kwan, A. Szczaniecka, E. Heidary Arash, L. Nguyen, C.-C. Chen, S. Ratkovic, O. Klezovitch, L. Attisano, H. McNeill, A. Emili, V. Vasioukhin, DLG5 connects cell polarity and hippo signaling protein networks by linking PAR-1 with MST1/2, Genes Dev. 30 (2016) 2696–2709, https://doi.org/10.1101/gad.284539.116.

[163] J. Liu, J. Li, P. Li, Y. Wang, Z. Liang, Y. Jiang, J. Li, C. Feng, R. Wang, H. Chen, C. Zhou, J. Zhang, J. Yang, P. Liu, Loss of DLG5 promotes breast cancer malignancy by inhibiting the hippo signaling pathway, Sci. Rep. 7 (2017) 42125, https://doi.org/10.1038/srep42125.

[164] D. Paul, V. Chanukuppa, P.J. Reddy, K. Taunk, R. Adhav, S. Srivastava, M. K. Santra, S. Rapole, Global proteomic profiling identifies etoposide chemoresistance markers in non-small cell lung carcinoma, J. Proteome 138 (2016) 95–105, https://doi.org/10.1016/j.jprot.2016.02.008.

[165] J. Che, J. Wang, H. Li, H. Zhen, K. Shang, Y. Yang, B. Cao, Decreased expression of Dlg5 is associated with a poor prognosis and epithelial–mesenchymal transition in squamous cell lung cancer, J. Thorac. Dis. 13 (2021) 3115–3125, https://doi.org/10.21037/jtd.21-752.

[166] P. Venugopal, H. Veysière, J.-L. Couderc, G. Richard, C. Vachias, V. Mirouse, Multiple functions of the scaffold protein discs large 5 in the control of growth, cell polarity and cell adhesion in Drosophila melanogaster, BMC Dev. Biol. 20 (2020) 10, https://doi.org/10.1186/s12861-020-00218-0.

[167] Z. Zhang, C. Chen, F. Yang, Y.-X. Zeng, P. Sun, P. Liu, X. Li, Itaconate is a lysosomal inducer that promotes antibacterial innate immunity, Mol. Cell 82 (2022) 2844–2857.e10, https://doi.org/10.1016/j.molcel.2022.05.009.
[168] H.-Y. Pan, M. Valapala, Role of TFEB in diseases associated with lysosomal dysfunction, in: J.D. Ash, E. Pierce, R.E. Anderson, C. Bowes Rickman, J. G. Hollyfield, C. Grimm (Eds.), Retinal Degenerative Diseases XIX, Springer International Publishing, Cham, 2023, pp. 319–325, https://doi.org/10.1007/978-3-031-27681-1-14.

[169] I. Rabinovich-Nikitin, L.A. Kirshenbaum, YAP/TFEB pathway promotes autophagic cell death and hypertrophic cardiomyopathy in lysosomal storage diseases, J. Clin. Invest. 131 (2021) e146821, https://doi.org/10.1172/JCI146821.

[170] W. Zhang, J. Shen, F. Gu, Y. Zhang, W. Wu, J. Weng, Y. Liao, Z. Deng, Q. Yuan, L. Zheng, Y. Zhang, W. Shen, Monopolar spindle-one-binder protein 2 regulates the activity of large tumor suppressor/yes-associated protein to inhibit the motility of SMMC-7721 hepatocellular carcinoma cells, Oncol. Lett. (2018), https://doi.org/10.3892/ol.2018.7952.

[171] Y. Yang, N. Luo, Z. Gong, W. Zhou, Y. Ku, Y. Chen, Lactate and lysine lactylation of histone regulate transcription in cancer, Heliyon 10 (2024) e38426, https://doi.org/10.1016/j.heliyon.2024.e38426.

[172] Z. Zong, F. Xie, S. Wang, X. Wu, Z. Zhang, B. Yang, F. Zhou, Alanyl-TRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis, Cell 187 (2024) 2375–2392.e33, https://doi.org/10.1016/j.cell.2024.04.002.

[173] J. Ju, H. Zhang, M. Lin, Z. Yan, L. An, Z. Cao, D. Geng, J. Yue, Y. Tang, L. Tian, F. Chen, Y. Han, W. Wang, S. Zhao, S. Jiao, Z. Zhou, The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer, J. Clin. Invest. 134 (2024) e174587, https://doi.org/10.1172/JCI174587.

[174] A.S. Besemer, J. Maus, M.D.A. Ax, A. Stein, S. Vo, C. Freese, K. Nalbach, C. Von Hilchen, I.F. Pfalzgraf, I. Koziellek-Drechsler, B. Silva, H. Huesmann, F. Boukhallouk, L. Florin, A. Kern, C. Behl, A.M. Clement, Receptor-mediated endocytosis 8 (RME-8)/DNAJC13 is a novel positive modulator of autophagy and stabilizes cellular protein homeostasis, Cell. Mol. Life Sci. 78 (2021) 645–660, https://doi.org/10.1007/s00018-020-03521-y.

[175] A. Fujibayashi, T. Taguchi, R. Misaki, M. Ohtani, N. Dohmae, K. Takio, M. Yamada, J. Gu, M. Yamakami, M. Fukuda, S. Waguri, Y. Uchiyama, T. Yoshimori, K. Sekiguchi, Human RME-8 is involved in membrane trafficking through early endosomes, Cell Struct. Funct. 33 (2008) 35–50, https://doi.org/10.1247/csf.07045.

[176] M. Girard, P.S. McPherson, RME-8 regulates trafficking of the epidermal growth factor receptor, FEBS Lett. 582 (2008) 961–966, https://doi.org/10.1016/j.feblets.2008.02.042.

[177] M. Krupp, A. Weinmann, P. Galle, A. Teufel, Actin binding LIM protein 3 (abLIM3), Int. J. Mol. Med. (2006), https://doi.org/10.3892/ijmm.17.1.129.

[178] B. Gong, T. Qu, J. Zhang, Y. Jia, Z. Song, C. Chen, J. Yang, C. Wang, Y. Liu, Y. Jin, W. Cao, Q. Zhao, Downregulation of ABLIM3 confers to the metastasis of neuroblastoma via regulating the cell adhesion molecules pathway, computational and structural, Biotechnol. J. 23 (2024) 1547–1561, https://doi.org/10.1016/j.csbj.2024.04.024.

[179] C. Garrido, L. Galluzzi, M. Brunet, P.E. Puig, C. Didelot, G. Kroemer, Mechanisms of cytochrome c release from mitochondria, Cell Death Differ. 13 (2006) 1423–1433, https://doi.org/10.1038/sj.cdd.4401950.

[180] S.W. Chan, C. Ong, W. Hong, The recent advances and implications in cancer therapy for the hipp pathway, Curr. Opin. Cell Biol. 93 (2025) 102476, https://doi.org/10.1016/j.iceb.2025.102476.

[181] N. Furth, Y. Aylon, M. Oren, p53 shades of hippo, Cell Death Differ. 25 (2018) 81–92, https://doi.org/10.1038/cdd.2017.163.

[182] L.S. Gutierrez, J. Gutierrez, Thrombospondin 1 in metabolic diseases, Front. Endocrinol. 12 (2021) 638536, https://doi.org/10.3389/fendo.2021.638536.

[183] K.P.C. Catalr, C.-Y. Tse, W.-Y. Yang, C.-Y. Ling, O.-L. Kwok, K.-Y. Choy, D.-Q. Lu, J.-F. Bian, T.C. Lam, D.Y.-Y. Tse, S.S.-W. Shan, Thrombospondin 1 mediates autophagy upon inhibition of the rho-associated protein kinase inhibitor, Cells 13 (2024) 1907, https://doi.org/10.3390/cells13221907.

[184] A. Arun, K.J. Rayford, A. Cooley, T. Rana, G. Rakhakonda, F. Villalta, S. Pratap, M.F. Lima, N. Sheibani, P.N. Nde, Thrombospondin-1 expression and modulation of Wnt and hippo signaling pathways during the early phase of Trypanosoma cruzi infection of heart endothelial cells, PLoS Negl. Trop. Dis. 16 (2022) e0010074, https://doi.org/10.1371/journal.pntd.00010074.

[185] J. Shen, B. Cao, Y. Wang, C. Ma, Z. Zeng, L. Liu, X. Li, D. Tao, J. Gong, D. Xie, Hippo component YAP promotes focal adhesion and tumour aggressiveness via transcriptionally activating THBS1/FAK signalling in breast cancer, J. Exp. Clin. Cancer Res. 37 (2018) 175, https://doi.org/10.1186/s13046-018-0850-z.

[186] S. Maghool, N.D.G. Cooray, D.A. Stroud, D. Aragão, M.T. Ryan, M.J. Maher, Structural and functional characterization of the mitochondrial complex IV assembly factor Coa6, Life Sci. Alliance 2 (2019) e201900458, https://doi.org/10.26508/lsa.201900458.

[187] X. Jin, X. Chen, H. Yu, Y. Liu, X. Lu, H. Yin, W. Dai, COA6 promotes the oncogenesis and progression of breast cancer by oxidative phosphorylation pathway, J. Cancer 15 (2024) 5072–5084, https://doi.org/10.7150/jca.98570.

[188] M. Zhang, X. Liao, G. Ji, X. Fan, Q. Wu, High expression of COA6 is related to unfavorable prognosis and enhanced oxidative phosphorylation in lung adenocarcinoma, IJMS 24 (2023) 5705, https://doi.org/10.3390/ijms24065705.

[189] W. Liu, Y. Jiang, G. Li, D. Huang, T. Qin, Oxidative phosphorylation related gene COA6 is a novel indicator for the prognosis and immune response in lung adenocarcinoma, Sci. Rep. 14 (2024) 25970, https://doi.org/10.1038/s41598-024-77775-y.

[190] J.G. Routsias, D. Marinou, M. Mavrouli, A. Tsakris, V.C. Pitiriga, Major vault protein/lung resistance-related protein: a novel biomarker for inflammation and acute infections, Microorganisms 12 (2024) 1762, https://doi.org/10.3390/microorganisms12091762.

[191] E. Steiner, K. Holzmann, L. Elbling, M. Micksche, W. Berger, Cellular functions of vaults and their involvement in multidrug resistance, CDT 7 (2006) 923–934, https://doi.org/10.2174/138945006778019345.

[192] P.C. Lara, M. Pruschy, M. Zimmermann, L.A. Henríquez-Hernández, MVP and vaults: a role in the radiation response, Radiat. Oncol. 6 (2011) 148, https://doi.org/10.1186/1748-717X-6-148.

[193] D. Lötsch, E. Steiner, K. Holzmann, S. Spiegl-Kreinecker, C. Pirker, J. Hlavaty, H. Petznek, B. Hegedus, T. Garay, T. Mohr, W. Sommergruber, M. Grusch, W. Berger, Major vault protein supports glioblastoma survival and migration by upregulating the EGFR/PI3K signalling axis, Oncotarget 4 (2013) 1904–1918, https://doi.org/10.18632/oncotarget.1264.

[194] K. Iwashita, R. Ikeda, Y. Takeda, T. Sumizawa, T. Furukawa, T. Yamaguchi, S. Akiyama, K. Yamada, Major vault protein forms complexes with hypoxia-inducible factor (HIF)-1α and reduces HIF-1α level in ACHN human renal adenocarcinoma cells, Cancer Sci. 101 (2010) 920–926, https://doi.org/10.1111/j.1349-7006.2009.01481.x.

[195] H. Bai, C. Wang, Y. Qi, J. Xu, N. Li, L. Chen, B. Jiang, X. Zhu, H. Zhang, X. Li, Q. Yang, J. Ma, Y. Xu, J. Ben, Q. Chen, J. Yue, Y. Tang, L. Tian, G. Frascotti, E. Galbiati, M. Mazzucchelli, M. Pozzi, L. Salvioni, J. Vertemara, P. Tortora, The vault nanoparticle: a gigantic ribonucleoprotein assembly involved in diverse physiological and pathological phenomena and an ideal Nanovector for drug delivery and therapy, Cancers 13 (2021) 707, https://doi.org/10.3390/cancers13040707.

[196] S. Kolli, C.I. Zito, M.H. Mossink, E.A.C. Wiemer, A.M. Bennett, The major vault protein is a novel substrate for the tyrosine phosphatase SHP-2 and scaffold protein in epidermal growth factor signaling, J. Biol. Chem. 279 (2004) 29374–29385, https://doi.org/10.1074/jbc.M313955200.

[197] L. Gong, M. Zhong, K. Gong, Z. Wang, Y. Zhong, Y. Jin, H. Chen, P. Tai, X. Chen, A. Chen, K. Cao, Multi-omics analysis and verification of the oncogenic value of CCT8 in Pan-cancers, JIR Volume 16 (2023) 2297–2315. doi: https://doi.org/10.2147/JIR.S403499.

[198] R. Du, Z. Zhou, Y. Huang, K. Li, K. Guo, L. Han, H. Bian, Chaperonin-containing TCP-1 subunit genes are potential prognostic biomarkers and are correlated with Th2 cell infiltration in lung adenocarcinoma: An observational study, Medicine 103 (2024) e38387, https://doi.org/10.1097/MD.00000000000038387.

[199] K.R. Willson, The structure and evolution of eukaryotic chaperonin-containing TCP-1 and its mechanism that folds actin into a protein spring, Biochem. J. 475 (2018) 3009–3034, https://doi.org/10.1042/BCJ20170378.

[200] X. Yang, H. Ren, Y. Shao, Y. Sun, L. Zhang, H. Li, X. Zhang, X. Yang, W. Yu, J. Fu, Chaperonin-containing T-complex protein 1 subunit 8 promotes cell migration and invasion in human esophageal squamous cell carcinoma by regulating α-actin and β-tubulin expression, Int. J. Oncol. (2018), https://doi.org/10.3892/ijeo.2018.4335.

[201] S. Grant, FAM83A and FAM83B: candidate oncogenes and TKI resistance mediators, J. Clin. Invest. 122 (2012) 3048–3051, https://doi.org/10.1172/JCI64412.

[202] R. Cipriano, B.L. Bryson, K.L.S. Miskimen, C.A. Bartel, W. Hernandez-Sanchez, R. C. Bruntz, S.A. Scott, C.W. Lindsley, H.A. Brown, M.W. Jackson, Hyperactivation of EGFR and downstream effector phospholipase D1 by oncogenic FAM83B, Oncogene 33 (2014) 3298–3306, https://doi.org/10.1038/onc.2013.293.

[203] R. Cipriano, J. Graham, K.L.S. Miskimen, B.L. Bryson, R.C. Bruntz, S.A. Scott, H. A. Brown, G.R. Stark, M.W. Jackson, FAM83B mediates EGFR- and RAS-driven oncogenic transformation, J. Clin. Invest. 122 (2012) 3197–3210, https://doi.org/10.1172/JCI60517.

[204] R. Cipriano, K.L.S. Miskimen, B.L. Bryson, C.R. Foy, C.A. Bartel, M.W. Jackson, FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates to promote epithelial cell transformation and resistance to targeted therapies, Oncotarget 4 (2013) 729–738, https://doi.org/10.18632/oncotarget.1027.

[205] R. Cipriano, K.L.S. Miskimen, B.L. Bryson, C.R. Foy, C.A. Bartel, M.W. Jackson, FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates to promote epithelial cell transformation and resistance to targeted therapies, Oncotarget 4 (2013) 729–738, https://doi.org/10.18632/oncotarget.1027.

[206] J. Ji, X. Cheng, R. Du, Y. Xie, Y. Zhang, Advances in research on autophagy mechanisms in resistance to endometrial cancer treatment, Front. Oncl. 14 (2024) 1364070, https://doi.org/10.3389/fonc.2024.1364070.

[207] J. Wang, P. Li, L. Sun, J. Zhang, K. Yue, Y. Wang, X. Wu, FAM83B regulates mitochondrial metabolism and anti-apoptotic activity in pulmonary adenocarcinoma, Apoptosis 29 (2024) 743–756, https://doi.org/10.1007/s10495-024-01944-7.

[208] L. Manganaro, S. Bianco, P. Bironzo, F. Cipollini, D. Colombi, D. Corà, G. Corti, G. Doronzo, L. Errico, P. Falco, L. Gandolfi, F. Guerrera, V. Monica, S. Novello, M. Papotti, S. Parab, A. Pittaro, L. Primo, L. Righi, G. Sabbatini, A. Sandri, S. Vattakunnel, F. Bussolino, G.V. Scagliotti, Consensus clustering methodology to improve molecular stratification of non-small cell lung cancer, Sci. Rep. 13 (2023) 7759, https://doi.org/10.1038/s41598-023-33954-x.

[209] Y.-W. Zheng, Z.-H. Li, L. Lei, C.-C. Liu, Z. Wang, L.-R. Fei, M.-Q. Yang, W.-J. Huang, H.-T. Xu, FAM83A promotes lung Cancer progression by regulating the Wnt and hippo signaling pathways and indicates Poor prognosis, Front. Oncol. 10 (2020) 180, https://doi.org/10.3389/fonc.2020.00180.

[210] S. Richtmann, D. Wilkens, A. Warth, F. Lasitschka, H. Winter, P. Christopoulos, F. J.F. Herth, T. Muley, M. Meister, M.A. Schneider, FAM83A and FAM83B as prognostic biomarkers and potential new therapeutic targets in NSCLC, Cancers 11 (2019) 652, https://doi.org/10.3390/cancers11050652.

[211] L. Cai, D. Luo, B. Yao, D.M. Yang, S. Lin, L. Girard, R.J. DeBerardinis, J.D. Minna, Y. Xie, G. Xiao, Systematic analysis of gene expression in lung adenocarcinoma
and squamous cell carcinoma with a case study of FAM83A and FAM83B, Cancers 11 (2019) 886, https://doi.org/10.3390/cancers11060886.

[212] A. Bhattacharya, R. Torggler, W. Reiter, N. Romanov, M. Licheva, A. Ciftci, M. Mari, L. Kolb, D. Kaiser, F. Reggiori, G. Ammerer, D.M. Hollenstein, C. Kraft, Decoding the function of Atg13 phosphorylation reveals a role of Atg11 in bulk autophagy initiation, EMBO Rep. 25 (2024) 813–831, https://doi.org/10.1038/s44319-023-00055-9.

[213] S.Y. Park, X. Guo, Adaptor protein complexes and intracellular transport, Biosci. Rep. 34 (2014) e00123, https://doi.org/10.1042/BSR20140069.

[214] F. Nakatsu, H. Ohno, Adaptor protein complexes as the key regulators of protein sorting in the post-Golgi network, Cell Struct. Funct. 28 (2003) 419–429, https://doi.org/10.1024/csf.28.419.

[215] J. Jeong, Y.E. Hwang, M. Lee, S. Keum, S. Song, J. Kim, J. Choi, S. Rhee, Downregulation of AP1S1 causes the lysosomal degradation of EGFR in non-small cell lung cancer, journal cellular, Physiology 238 (2023) 2335–2347, https://doi.org/10.1002/jcp.31112.

[216] X. Chen, J. Zhang, P. Liu, Y. Wei, X. Wang, J. Xiao, C. Wang, L. Wang, Proteolytic processing of secretory pathway kinase Fam20C by site-1 protease promotes biomineralization, Proc. Natl. Acad. Sci. USA 118 (2021) e2100133118, https://doi.org/10.1073/pnas.2100133118.

[217] Q.-Q. Li, M. Guo, G.-H. He, K.-H. Xi, M.-Y. Zhou, R.-Y. Shi, G.-Q. Chen, VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement membrane, Oncogene 43 (2024) 1836–1851, https://doi.org/10.1038/s41388-024-03038-9.

[218] C.R.R. Costa, R. Chalgoumi, A. Baker, C. Guillou, P.M. Yamaguti, V. Simancas Escorcia, L. Abbad, B.R. Amorin, C.L. De Lima, V. Cannaya, M. Benassarou, A. Berdal, C. Chatziantoniou, O. Cases, P. Cosette, R. Kozyraki, A.C. Acevedo, Gingival proteomics reveals the role of TGF beta and YAP/TAZ signaling in Raine syndrome fibrosis, Sci. Rep. 14 (2024) 9497, https://doi.org/10.1038/s41598-024-59713-0.

[219] H. Li, L. Tong, H. Tao, Z. Liu, Genome-wide analysis of the hypoxia-related DNA methylation-driven genes in lung adenocarcinoma progression, Biosci. Rep. 40 (2020) BSR20194200, https://doi.org/10.1042/BSR20194200.

[220] I.V. Demidyuk, A.V. Shubin, E.V. Gasanov, A.M. Kurinov, V.V. Demkin, T. V. Vinogradova, M.V. Zinovyeva, A.V. Sass, I.B. Zborovskaya, S.V. Kostrov, Alterations in gene expression of Proprotein convertases in human lung Cancer have a limited number of scenarios, PLoS One 8 (2013) e55752, https://doi.org/10.1371/journal.pone.0055752.

[221] Y. Shionoya, T. Kanaseki, S. Miyamoto, S. Tokita, A. Hongo, Y. Kikuchi, V. Kochin, K. Watanabe, R. Horibe, H. Saijo, T. Tsukahara, Y. Hirohashi, H. Takahashi, N. Sato, T. Torigoe, Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition, OncolImmunology 6 (2017) e1274476, https://doi.org/10.1080/2162402X.2016.1274476.

[222] B.A. Peters, H.I. Pass, R.D. Burk, X. Xue, C. Goparaju, C.C. Sollecito, E. Grassi, L. N. Segal, J.-C.J. Tsay, R.B. Hayes, J. Ahn, Lung microbiome, peripheral gene expression, and recurrence-free survival after resection of stage II non-small cell lung cancer, Genome Med. 14 (2022) 121, https://doi.org/10.1186/s13073-022-01126-7.

[223] L. Peng, L. Zhou, H. Li, X. Zhang, S. Li, K. Wang, M. Yang, X. Ma, D. Zhang, S. Xiang, Y. Duan, T. Wang, C. Sun, C. Wang, D. Lu, M. Qian, Z. Wang, Hippo-signaling-controlled MHC class I antigen processing and presentation pathway potentiates antitumor immunity, Cell Rep. 43 (2024) 114003, https://doi.org/10.1016/j.celrep.2024.114003.

[224] N. Carvou, R. Holic, M. Li, C. Futter, A. Skippen, S. Cockcroft, Phosphatidylinositol- and phosphatidylcholine-transfer activity of PITPβ is essential for COP1-mediated retrograde transport from the Golgi to the endoplasmic reticulum, J. Cell Sci. 123 (2010) 1262–1273, https://doi.org/10.1242/jcs.061986.

[225] F.-L. Li, V. Fu, G. Liu, T. Tang, A.W. Konradi, X. Peng, E. Kemper, B.F. Cravatt, J. M. Franklin, Z. Wu, J. Mayfield, J.E. Dixon, W.H. Gerwick, K.-L. Guan, Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides, Nat. Chem. Biol. 18 (2022) 1076–1086, https://doi.org/10.1038/s41589-022-01061-z.

[226] L. Palamiuc, J.L. Johnson, Z. Haratipour, R.M. Loughran, W.J. Choi, G.K. Arora, V. Tieu, K. Ly, A. Llorente, S. Crabtree, J.C.Y. Wong, A. Ravi, T. Wiederhold, R. Murad, R.D. Blind, B.M. Emerling, Hippo and PI3P4K signaling intersect to control the transcriptional activation of YAP, Sci. Signal. 17 (2024) eado6266, https://doi.org/10.1126/scisignal.ado6266.

[227] H. Yang, X. Zhang, C. Wang, H. Zhang, J. Yi, K. Wang, Y. Hou, P. Ji, X. Jin, C. Li, M. Zhang, S. Huang, H. Jia, K. Hu, L. Mou, R. Wang, Microcolin H, a novel autophagy inducer, exerts potent antitumour activity by targeting PITPα/β, Sig Transduct Target Ther 8 (2023) 428, https://doi.org/10.1038/s41392-023-01667-2.

[228] M.S. Khan, B.H. Jaswanth Gowda, W.H. Almalki, T. Singh, A. Sahebkar, P. Kesharwani, Unravelling the potential of mitochondria-targeted liposomes for enhanced cancer treatment, Drug Discov. Today 29 (2024) 103819, https://doi.org/10.1016/j.drudis.2023.103819.

[229] N.K. Farsani, S. Afshari, A.S. Poor, A. Toutouchni, Z. Shahbazi, S. Ramezani, M. Tajik, M.M. Chegeni, N.A. Moghaddam, H. Abbasi, pH-responsive mesoporous silica nanoparticles functionalized with folic acid and chitosan for targeted epirubicin delivery: in vitro and in vivo efficacy in breast cancer, Int. J. Biol. Macromol. (2025) 142558, https://doi.org/10.1016/j.ijbiomac.2025.142558.

[230] S.H. Hassanpour, M. Dehghani, Review of cancer from perspective of molecular, Journal of Cancer Research and Practice 4 (2017) 127–129, https://doi.org/10.1016/j.jcrpr.2017.07.001.

[231] A.M. Grimaldi, M. Salvatore, M. Incoronato, miRNA-based therapeutics in breast Cancer: a systematic review, Front. Oncol. 11 (2021) 668464, https://doi.org/10.3389/foncs.2021.668464.

[232] Z. Liu, Y. Ren, S. Weng, H. Xu, L. Li, X. Han, A new trend in Cancer treatment: the combination of epigenetics and immunotherapy, Front. Immunol. 13 (2022) 809761, https://doi.org/10.3389/fimmu.2022.809761.

[233] W. Wei, Z.-N. Chen, K. Wang, CRISPR/Cas9: a powerful strategy to improve CAR-T cell persistence, IJMS 24 (2023) 12317, https://doi.org/10.3390/ijms241512317.

[234] X. Cai, X. Bao, Y. Wu, Metal–Organic Frameworks as Intelligent Drug Nanocarriers for Cancer Therapy, Pharmaceutics 14 (2022) 2641, https://doi.org/10.3390/pharmaceutics14122641.

[235] E. Keles, Y. Song, D. Du, W.-J. Dong, Y. Lin, Recent progress in nanomaterials for gene delivery applications, Biomater. Sci. 4 (2016) 1291–1309, https://doi.org/10.1039/C6BM00441E.

[236] M.S. Khan, M. Fatima, S. Wahab, M. Khalid, P. Kesharwani, Gallic acid loaded self-nano emulsifying hydrogel-based drug delivery system against onychomycosis, Nanomedicine 19 (2024) 2065–2083, https://doi.org/10.1080/17435889.2024.2386923.

[237] M. Sameer Khan, B.H. Jaswanth Gowda, N. Hasan, G. Gupta, T. Singh, S. Md, P. Kesharwani, Carbon nanotube-mediated platinum-based drug delivery for the treatment of cancer: advancements and future perspectives, Eur. Polym. J. 206 (2024) 112800, https://doi.org/10.1016/j.eurpolymj.2024.112800.

[238] M. Fu, Y. Hu, T. Lan, K.-L. Guan, T. Luo, M. Luo, The hippo signalling pathway and its implications in human health and diseases, Sig Transduct Target Ther 7 (2022) 376, https://doi.org/10.1038/s41392-022-01191-9.

[239] E.R. Barry, V. Simov, I. Valtingojer, O. Venier, Recent therapeutic approaches to modulate the hippo pathway in oncology and regenerative medicine, Cells 10 (2021) 2715, https://doi.org/10.3390/cells10102715.

[240] S. Li, L. Hao, N. Li, X. Hu, H. Yan, E. Dai, X. Shi, Targeting the hippo/YAP1 signaling pathway in hepatocellular carcinoma: from mechanisms to therapeutic drugs (review), Int. J. Oncol. 65 (2024) 88, https://doi.org/10.3892/ijo.2024.5676.

[241] F. Fan, Z. He, L.-L. Kong, Q. Chen, Q. Yuan, S. Zhang, J. Ye, H. Liu, X. Sun, J. Geng, L. Yuan, L. Hong, C. Xiao, W. Zhang, X. Sun, Y. Li, P. Wang, L. Huang, X. Wu, Z. Ji, Q. Wu, N.-S. Xia, N.S. Gray, L. Chen, C.-H. Yun, X. Deng, D. Zhou, Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration, Sci. Transl. Med. 8 (2016), https://doi.org/10.1126/scitranslmed.aaf2304.

[242] S. Qi, Y. Zhu, X. Liu, P. Li, Y. Wang, Y. Zeng, A. Yu, Y. Wang, Z. Sha, Z. Zhong, R. Zhu, H. Yuan, D. Ye, S. Huang, C. Ling, Y. Xu, D. Zhou, L. Zhang, F.-X. Yu, WWC proteins mediate LATS1/2 activation by hippo kinases and imply a tumor suppression strategy, Mol. Cell 82 (2022) 1850–1864.e7, https://doi.org/10.1016/j.molcel.2022.03.027.

[243] R. Watkins, A. Gamo, S.H. Choi, M. Kumar, E. Buckarma, M. McCabe, P. Tomlinson, D. Pereya, B. Lupse, S. Geravandi, N.W. Werneburg, C. Wang, P. Tomlinger, S. Zhu, S. Li, S. Yu, M. Surakattula, T. Baguley, A. Ardestani, K. Maedler, J. Roland, V. Nguyen-Tran, S. Joseph, M. Petrassi, N. Rogers, G. Gores, A. Chatterjee, M. Tremblay, W. Shen, R. Smoot, A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis, PNAS Nexus 3 (2024) pgae096, https://doi.org/10.1093/pnasexus/pgae096.

[244] G. Loforese, T. Malinka, A. Keogh, F. Baier, C. Simillion, M. Montani, T. D. Halazonetis, D. Candinas, D. Stroka, Impaired liver regeneration in aged mice can be rescued by silencing hippo core kinases MST1 and MST2, EMBO Mol. Med. 9 (2017) 46–60, https://doi.org/10.15252/emmm.201506089.

[245] W.-W. Pan, T. Moroishi, J.H. Koo, K.-L. Guan, Cell type-dependent function of LATS1/2 in cancer cell growth, Oncogene 38 (2019) 2595–2610, https://doi.org/10.1016/j.c1438-018-0610-8.

[246] J. Brennecke, A. Stark, R.B. Russell, S.M. Cohen, Principles of MicroRNA–target recognition, PLoS Biol. 3 (2005) e85, https://doi.org/10.1371/journal.pbio.0030085.

[247] M. Friedrich, A. Aigner, Therapeutic siRNA: state-of-the-art and future perspectives, BioDrugs 36 (2022) 549–571, https://doi.org/10.1007/s40259-022-00549-9.

[248] C. Selvam, D. Mutisya, S. Prakash, K. Ranganna, R. Thilagavathi, Therapeutic potential of chemically modified si RNA : recent trends, Chem. Biol. Drug Des. 90 (2017) 665–678, https://doi.org/10.1111/cbdd.12993.

[249] Z. Liu, N. Parveen, U. Rehman, A. Aziz, A. Sheikh, M.A.S. Abourehab, W. Guo, J. Huang, Z. Wang, P. Kesharwani, Unravelling the enigma of siRNA and aptamer mediated therapies against pancreatic cancer, Mol. Cancer 22 (2023) 8, https://doi.org/10.1186/s12943-022-01696-5.

[250] A. Wittrup, J. Lieberman, Knocking down disease: a progress report on siRNA therapeutics, Nat. Rev. Genet. 16 (2015) 543–552, https://doi.org/10.1038/nrg3978.

[251] K. Wang, H. Chen, S. Qin, S. Chen, Q. Zhang, J. Chen, D. Di, G. Su, Y. Yuan, Co-delivery of pirfenidone and siRNA in ZIF-based nanoparticles for dual inhibition of hepatic stellate cell activation in liver fibrotic therapy, Colloids Surf. B: Biointerfaces 231 (2023) 113567, https://doi.org/10.1016/j.olsurfib.2023.113567.

[252] Y. Li, K. Zhang, P. Liu, M. Chen, Y. Zhong, Q. Ye, M.Q. Wei, H. Zhao, Z. Tang, Encapsulation of Plasmid DNA by Nanoscale Metal–Organic Frameworks for Efficient Gene Transportation and Expression, Adv. Mater. 31 (2019) 1901570, https://doi.org/10.1002/adma.201901570.

[253] P. Horcajada, T. Chalati, C. Serre, B. Gillet, C. Sebrie, T. Baati, J.F. Eubank, D. Heurtaux, P. Clayette, C. Kreuz, J.-S. Chang, Y.K. Hwang, V. Marsaud, P.-
N. Bories, L. Cynober, S. Gil, G. Férey, P. Couvreur, R. Gref, Porous metal-organic-framework nanoscale carriers as a potential platform for drug delivery and imaging, Nat. Mater. 9 (2010) 172–178, https://doi.org/10.1038/nmat2608.

[254] Y. Yan, X.-Y. Liu, A. Lu, X.-Y. Wang, L.-X. Jiang, J.-C. Wang, Non-viral vectors for RNA delivery, J. Control. Release 342 (2022) 241–279, https://doi.org/10.1016/j.jconrel.2022.01.008.

[255] S. Ghojavand, E. Dib, S. Mintova, Flexibility in zeolites: origin, limits, and evaluation, Chem. Sci. 14 (2023) 12430–12446, https://doi.org/10.1039/D3SC03934J.

[256] S. Mintova, Maximizing catalytic efficiency with bio-inspired hierarchical porous zeolites, Natl. Sci. Rev. 10 (2023) nwad155, https://doi.org/10.1093/nsr/nwad155.

[257] C. Anfray, B. Dong, S. Komaty, S. Mintova, S. Valable, Acute toxicity of Silver free and encapsulated in Nanosized zeolite for eukaryotic cells, ACS Appl. Mater. Interfaces 9 (2017) 13849–13854, https://doi.org/10.1021/acsami.7b00265.