SII-SWORD/CoKE huggingface dataset:
SOCS1, SH2 domain (SOCS1_SH2)
Type: Domain

This entry represents the SH2 domain of SOCS1.

Cytokine signaling mediated by the JAK-STAT pathway plays essential roles in differentiation, maturation, proliferation and apoptosis of a various types of cells. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of the JAK-STAT signaling pathway. SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers . All SOCS share a central SH2 domain and a C-terminal SOCS box, but only SOCS1 and SOCS3 possess a kinase inhibitory region immediately upstream of the central SH2 .

SOCS1 plays a key role in the negative regulation of interferon-gamma signaling and in T cell differentiation .
SOCS2, SH2 domain (SOCS2_SH2)
Type: Domain

This entry represents the SH2 domain of SOCS2.

Cytokine signaling mediated by the JAK-STAT pathway plays essential roles in differentiation, maturation, proliferation and apoptosis of a various types of cells. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of the JAK-STAT signaling pathway. SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers . All SOCS share a central SH2 domain and a C-terminal SOCS box, but only SOCS1 and SOCS3 possess a kinase inhibitory region immediately upstream of the central SH2 .

SOCS2 is necessary for normal growth regulation . It appears to be a negative regulator in the growth hormone/IGF1 signaling pathway .
SOCS3, SH2 domain (SOCS3_SH2)
Type: Domain

This entry represents the SH2 domain of SOCS3.

Cytokine signaling mediated by the JAK-STAT pathway plays essential roles in differentiation, maturation, proliferation and apoptosis of a various types of cells. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of the JAK-STAT signaling pathway. SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers . All SOCS share a central SH2 domain and a C-terminal SOCS box, but only SOCS1 and SOCS3 possess a kinase inhibitory region immediately upstream of the central SH2 .

SOCS3 interacts with gp130, a common cytokine receptor for interleukin (IL)-6, leukemia inhibitory factor (LIF) and other members of the IL-6 family of cytokines. SOCS3 has been reported also to interact with the leptin receptor, erythropoietin receptor, insulin receptor, IL-12beta receptor and granulocyte-colony stimulating factor receptor .
SOCS4, SH2 domain (SOCS4_SH2)
Type: Domain

SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS4 (Suppressor of cytokine signalling 4) is the substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins . SOCS4 and SOCS5 regulate epidermal growth factor receptor signaling .

This entry represents the SH3 domain of SOCS4.
SOCS6, SH2 domain (SOCS6_SH2)
Type: Domain

Suppressor of cytokine signaling (SOCS) family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. However, SOCS6 does not interact with cytokine signaling intermediate molecules or inhibit cytokine receptor signaling. SOCS6 can interact with c-KIT, a receptor tyrosine kinase that mediates the cellular response to stem cell factor (SCF). SOCS6 has ubiquitin ligase activity toward c-KIT and regulates c-KIT protein turnover in cells, suppressing c-KIT-dependent pathways . SOCS6 negatively regulates receptor tyrosine kinase Flt3 activation, the downstream Erk signaling pathway, and cell proliferation .

This entry represents the SH2 domain of SOCS6.
SOCS7, SH2 domain (SOCS7_SH2)
Type: Domain

SOCS7 is a member of the suppressor of cytokine signaling family of proteins. SOCS7 functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation . SOCS7 inhibits also prolactin, growth hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA .

This entry represents the SH2 domain of SOCS7.
Ras and Rab interactor 1, SH2 domain (RIN1_SH2)
Type: Domain

RIN1, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs . Previous studies showed that RIN1 interacts with EGF receptors via its SH2 domain and regulates trafficking and degradation of EGF receptors via its interaction with STAM, indicating a vital role for RIN1 in regulating endosomal trafficking of receptor tyrosine kinases (RTKs) . RIN1 was first identified as a Ras-binding protein that suppresses the activated RAS2 allele in S. cerevisiae. RIN1 binds to the activated Ras through its carboxyl-terminal domain and this Ras-binding domain also binds to 14-3-3 proteins as Raf-1 does .

The SH2 domain of RIN1 are thought to interact with the phosphotyrosine-containing proteins, but the physiological partners for this domain are unknown. The proline-rich domain in RIN1 is similar to the consensus SH3 binding regions.
Ras and Rab interactor 2, SH2 domain (RIN2_SH2)
Type: Domain

RIN2, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs. Ras induces activation of Rab5 through RIN2, which is a direct downstream target of Ras and a direct upstream regulator of Rab5. In other words, it is the binding of the GTP-bound form of Ras to the RA domain of RIN2 that enhances the GEF activity toward Rab5. It is thought that the RA domain negatively regulates the Rab5 GEF activity. In steady state, RIN2 is likely to form a closed conformation by an intramolecular interaction between the RA domain and the Vps9p-like (Rab5 GEF) domain, negatively regulating the Rab5 GEF activity. In the active state, the binding of Ras to the RA domain may reduce the intramolecular interaction and stabilize an open conformation of RIN2 .
Ras and Rab interactor 3, SH2 domain (RIN3_SH2)
Type: Domain

RIN3, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs. RIN3 stimulates the formation of GTP-bound Rab31, a Rab5-subfamily GTPase, and forms enlarged vesicles and tubular structures, where it colocalizes with Rab31. Transferrin appears to be transported partly through the RIN3-positive vesicles to early endosomes. RIN3 interacts via its Pro-rich domain with amphiphysin II, which contains an SH3 domain and participates in receptor-mediated endocytosis. RIN3, a Rab5 and Rab31 GEF, plays an important role in the transport pathway from plasma membrane to early endosomes. Mutations in the region between the SH2 and RH domain of RIN3 specifically abolished its GEF action on Rab31, but not Rab5. RIN3 was also found to partially translocate the cation-dependent mannose 6-phosphate receptor from the trans-Golgi network to peripheral vesicles and that this is dependent on its Rab31-GEF activity. These data indicate that RIN3 specifically acts as a GEF for Rab31 .
Tyrosine-protein kinase TXK, SH2 domain (Txk_SH2)
Type: Domain

Txk is a member of the Tec protein tyrosine kinase family. It plays a role in TCR signal transduction, T cell development, and selection which is analogous to the function of Itk. Txk has been shown to interact with IFN-gamma . Unlike most of the Tec family members Txk lacks a PH domain. Instead Txk has a unique region containing a palmitoylated cysteine string which has a similar membrane tethering function as the PH domain .

The Tec protein tyrosine kinase family includes Tec,Btk, Itk, Bmx, and Txk. They contain an NH2-terminal pleckstrin homology (PH) domain (absent in Txk), a proline-rich region, Src-homology 3 (SH3) and SH2 domains, and a COOH-terminal PTK domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP and crucial to the function of the PH domain. It is not present in Txk which is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homologue also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state .
Growth hormone-inducible transmembrane protein (GHITM)
Type: Domain

GHITM (also known as MICS1) appears to be ubiquitiously expressed in mammalian cells and expression has also been observed in various cancer cell lines . It is involved in maintenance of mitochondrial morphology and apoptotic release of cytochrome c . It is closely related to the BAX inhibitor (BI)-1 like family of small transmembrane proteins, which have been shown to have an anti-apoptotic effect .
2-epi-5-epi-valiolone synthase-like (EEVS-like)
Type: Family

This entry includes 2-epi-5-epi-valiolone synthases (EEVS) and desmethyl-4-deoxygadusol synthases (DDGS). They are sedoheptulose 7-phophate cyclases .

2-epi-5-epi-valiolone synthases catalyze the cyclization of sedoheptulose 7-phosphate to 2-epi-5-epi-valiolone in the biosynthesis of C(7)N-aminocyclitol-containing products. The cyclization product, 2-epi-5-epi-valiolone ((2S,3S,4S,5R)-5-(hydroxymethyl)cyclohexanon-2,3,4,5-tetrol), is a precursor of the valienamine moiety. The valienamine unit is responsible for their biological activities as various glycosidic hydrolases inhibitors. Two important microbial secondary metabolites, i.e., validamycin and acarbose, are used in agricultural and biomedical applications. Validamycine A is an antifungal antibiotic which has a strong trehalase inhibitory activity and has been used to control sheath blight disease in rice caused by Rhizoctonia solani. Acarbose is an alpha-glucosidase inhibitor used for the treatment of type II insulin-independent diabetes. Salbostatin produced by Streptomyces albus also belongs to this family. It exhibits strong trehalase inhibitory activity .
Phosphonoacetaldehyde reductase (PhpC)
Type: Family

Phosphonoacetaldehyde reductase (phpC) catalyzes the reduction of phosphonoacetaldehyde to 2-hydroxyethylphosphonate, a step in the biosynthesis of phosphinothricin tripeptide (PTT). PTT is a natural-product antibiotic and potent herbicide that is produced by Streptomyces hygroscopicus ATCC 21705 .
Iduronate-2-sulfatase (IDS)
Type: Family

Iduronate 2-sulfatase is a sulfatase enzyme that catalyze the hydrolysis of sulfate ester bonds from a wide variety of substrates, including steroids, carbohydrates and proteins. Iduronate 2-sulfatase is required for the lysosomal degradation of heparan sulfate and dermatan sulfate . Mutations in the iduronate 2-sulfatase gene that result in enzymatic deficiency lead to the sex-linked mucopolysaccharidosis type II, also known as Hunter syndrome .
BMX, SH2 domain (BMX_SH2)
Type: Domain

Cytoplasmic tyrosine-protein kinase BMX (bone marrow tyrosine kinase gene on chromosome X, also known as ETK) is a non-receptor tyrosine kinase (

). It plays central but diverse modulator roles in various signalling processes involved in the regulation of actin reorganisation, cell migration, cell proliferation and survival, cell adhesion, and apoptosis . It has a role in inflammation, cardiovascular disease, and cancer . It is activated downstream of phosphatidylinositol-3 kinase (PI3K) and the kinase Src .

This entry represents the SH2 domain of BMX.
SH2D1A, SH2 domain (SH2D1A_SH2)
Type: Domain

SH2 domain-containing protein 1A (SH2D1A) is an adaptor protein that appears to regulate B-cell differentiation via switching of SLAM (CD150)-mediated signalling pathways . The SLAM receptor is expressed on activated T and B lymphocytes. SH2D1A inhibits SLAM self-association. SH2D1A acts by blocking the recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region .

Defects in SH2D1A are a cause of lymphoproliferative syndrome X-linked type 1 (XLP1) , which is also known as X-linked lymphoproliferative disease (XLPD) or Duncan disease . XLP is a rare immunodeficiency characterised by extreme susceptibility to infection with Epstein-Barr virus (EBV) (HHV-4) (Human herpesvirus 4). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.

This entry represents the SH2 domain of SH2D1A.
STAP1, SH2 domain (STAP1_SH2)
Type: Domain

STAP1 is a signal-transducing adaptor protein. It is composed of a Pleckstrin Homology (PH) and SH2 domains along with several tyrosine phosphorylation sites. STAP-1 is an orthologue of BRDG1 (also known as BCR downstream signaling 1). STAP1 protein functions as a docking protein acting downstream of Tec tyrosine kinase in B cell antigen receptor signaling. The protein is phosphorylated by Tec and participates in a positive feedback loop, increasing Tec activity . STAP-1 has been shown to interact with STAT5 .

This entry represents the SH2 domain of STAP1.

In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites .
STAP2, SH2 domain (STAP2_SH2)
Type: Domain

STAP2 belongs to the STAP family, whose members are adaptor proteins that play a crucial role in a variety of cellular signal transduction pathways by interacting with signaling or transcriptional molecules. It is composed of a Pleckstrin homology (PH) and a SH2 domain along with several tyrosine phosphorylation sites. It plays an important role in modulating both the innate and adaptive immune systems . It is a substrate of breast tumour kinase, an Src-type non-receptor tyrosine kinase that mediates the interactions linking proteins involved in signal transduction pathways .

This entry represents the SH2 domain of STAP2.
VAV1, SH2 domain (VAV1_SH2)
Type: Domain

This entry represents the SH2 domain of VAV1 from vertebrates.

VAV1 (also known as proto-oncogene vav) is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells . It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization . It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others .

The VAV protein family members are multiple domain proteins, including Vav from flies and VAV1/2/3 from mammals. VAV1 predominates in hematopoietic cells, whereas VAV2 and VAV3 are more broadly expressed. They have a calponin homology (CH) domain, an acidic domain (AC), a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich (CR) domain containing a zinc finger, and a complex region with SH2 and SH3 domains. Therefore they may participate in the activity of several pathways . They are signal transducer proteins that couple tyrosine kinase signals with the activation of the Rho/Rac GTPases, .
VAV2, SH2 domain (VAV2_SH2)
Type: Domain

This entry represents the SH2 domain of VAV2, which is a member of the VAV family. The SH2 domain of VAV2 has been shown to interact with PPxY motifs of TXNIP (thioredoxin-interacting protein) .

The VAV protein family members are multiple domain proteins, including Vav from flies and VAV1/2/3 from mammals. VAV1 predominates in hematopoietic cells, whereas VAV2 and VAV3 are more broadly expressed. They have a calponin homology (CH) domain, an acidic domain (AC), a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich (CR) domain containing a zinc finger, and a complex region with SH2 and SH3 domains. Therefore they may participate in the activity of several pathways . They are signal transducer proteins that couple tyrosine kinase signals with the activation of the Rho/Rac GTPases, .
VAV3, SH2 domain (VAV3_SH2)
Type: Domain

This entry represents the SH2 domain of VAV3, which belongs to the VAV family. VAV3 is involved in the regulation of osteoclast function and in central nervous system development and plasticity .

The VAV protein family members are multiple domain proteins, including Vav from flies and VAV1/2/3 from mammals. VAV1 predominates in hematopoietic cells, whereas VAV2 and VAV3 are more broadly expressed. They have a calponin homology (CH) domain, an acidic domain (AC), a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich (CR) domain containing a zinc finger, and a complex region with SH2 and SH3 domains. Therefore they may participate in the activity of several pathways . They are signal transducer proteins that couple tyrosine kinase signals with the activation of the Rho/Rac GTPases, .
Nck1, SH2 domain (Nck1_SH2)
Type: Domain

Cytoplasmic proteins Nck are non-enzymatic adaptor proteins composed of three SH3 (Src homology 3) domains and a C-terminal SH2 domain . They regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates . They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics . They associate with tyrosine-phosphorylated growth factor receptors or their cellular substrates . There are two vertebrate Nck proteins, Nck1 and Nck2.

Nck1 (also called Nck-alpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling . It binds and activates RasGAP, resulting in the downregulation of Ras . It is also involved in the signaling of endothilin-mediated inhibition of cell migration .

This entry represents the SH2 domain of Nck1.
Nck2, SH2 domain (Nck2_SH2)
Type: Domain

Cytoplasmic proteins Nck are non-enzymatic adaptor proteins composed of three SH3 (Src homology 3) domains and a C-terminal SH2 domain . They regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates . They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics . They associate with tyrosine-phosphorylated growth factor receptors or their cellular substrates . There are two vertebrate Nck proteins, Nck1 and Nck2.

This entry represents the SH2 domain of Nck2.
SH2D2A, SH2 domain (SH2D2A_SH2)
Type: Domain

This entry includes the single SH2 domain of SH2D2A. SH2D2A interacts with and modulates Lck activity .

In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites .
SH2D7, SH2 domain (SH2D7_SH2)
Type: Domain

This entry includes the single SH2 domain of SH2D7.

In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites .
STAT5b, SH2 domain (STAT5b_SH2)
Type: Domain

This entry represents the SH2 domain of STAT5b.

STAT5 is a member of the STAT family of transcription factors. Two highly related proteins, STAT5a and STAT5b are encoded by separate genes, but are 90% identical at the amino acid level. Both STAT5a and STAT5b are ubiquitously expressed and functionally interchangeable. They regulate B and T cell development . These proteins are central signalling molecules in leukaemias driven by Abelson fusion tyrosine kinases, having a key role in resistance of leukaemic cells against treatment with tyrosine kinase inhibitors (TKI) . They differentially regulate cellular behaviour in human mammary carcinoma .

STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins . Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes . STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 .
CIS, SH2 domain (CIS_SH2)
Type: Domain

Cytokine-inducible SH2-containing protein (CIS) is a member of the suppressor of cytokine signaling (SOCS) family proteins. CIS is involved in the negative regulation of cytokines that signal through the JAK-STAT5 pathway such as erythropoietin, prolactin and interleukin 3 (IL3) receptor. It inhibits STAT5 trans-activation by suppressing its tyrosine phosphorylation .

Suppressor of cytokine signalling (SOCS) was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain .

This entry represents the SH2 domain of CIS.
MTMR3, PH-GRAM domain (MTMR3_PH-GRAM)
Type: Domain

MTMR3 is a member of the myotubularin dual specificity protein phosphatase gene family. MTMR3 binds to phosphoinositide lipids through its PH-GRAM domain, and can hydrolyze phosphatidylinositol(3)-phosphate and phosphatidylinositol(3,5)-biphosphate in vitro . The protein can self-associate and also form heteromers with MTMR4 .

Both MTMR3 and MTMR4 contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an active PTP domain, a SET-interaction domain, a coiled-coil region, and a C-terminal lipid-binding FYVE domain which binds phosphotidylinositol-3-phosphate. Myotubularin-related proteins are a subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids. Mutations in this family cause the human neuromuscular disorders myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome . Six of the 13 MTMRs (MTMRs 5, 9-13) contain naturally occurring substitutions of residues required for catalysis by PTP family enzymes. Although these proteins are predicted to be enzymatically inactive, they are thought to function as antagonists of endogenous phosphatase activity or interaction modules .

This entry represents the PH-GRAM domain of myotubularin-related protein 3.