Metabolic pathway Oxidative DNA damage Hyperglycemia c-Abl P P PKCδ c-Abl P PKCδ NPCs cells cytoplasm/ nucleus nucleus P PKCδ c-Abl p53 accumulation Neuronal death DNA mutations c-Abl P 4 International Journal of Cell Biology Parkinson cells cytoplasm P Y143 Parkin Parkin loss of function Neuronal death Oxidative stress H2O2 c-Abl p73 activation SH-SY5Y cells cytoplasm/ nucleus P P Y15 Cdk5 p53 activation Neuronal cell death Figure 1: The ﬁgure illustrates the involvement of c-Abl in many cellular stress pathways. Oxidative stress, hyperglycemia, and DNA damage response induce c-Abl activation. In human neuroblastoma (SH-SY5Y cells), c-Abl targets p73, promoting neuronal death in response to hydrogen peroxide. In addition, c-Abl can also phophorylate Cdk5 and in tandem with Cdk5 can mediate p53 activation, promoting neuronal death. Hyperglycemia-induced apoptosis of NPCs is mediated by the translocation of the PKCδ-Abl complex to the nucleus. This translocation impacts on p53 activation leading to neuronal death. Oxidative DNA damage in Parkinson disorder is associated with increased c-Abl activity. c-Abl mediates tyrosine phosphorylation of Parkin and inhibits parkin’s ubiquitin E3 ligase activity. The interplay between cytoplasmic, nuclear and mitochon- drial localization of c-Abl is an important aspect for oxida- tive stress-induced apoptosis. In concert with this, c-Abl catalytic outcomes are strictly associated with its subcellular localization. TTK, also known as PYT (Phosphotyrosine Picked Threonine Kinase), the human homolog of MSP1 (Monopolar Spindle 1), regulates nuclear targeting of c-Abl through the 14-3-3-coupled phosphorylation site. Nihira et al. demonstrated that TTK-dependent phosphorylation of c-Abl on Y735 is required for the cytoplasmic sequestra- tion/localization of kinase. TTK/Msp1 deﬁciency enhances the oxidative-stress-induced apoptosis while favoring the nuclear accumulation of c-Abl [48]. c-Abl co-localizes with the endoplasmic reticulum (ER)- associated protein grp78 [49]. Subcellular fractionation stud- ies indicate that over 20% of c-Abl is detectable in the ER. Induction of ER stress with the calcium ionophore A23187, brefeldin A, or tunicamycin is linked to translocation of the ER-associated c-Abl fraction to mitochondria. In concert with targeting of c-Abl to mitochondria, cytochrome c is released in response to ER stress through a c-Abl-depend- ent mechanism. In c-Abl-deﬁcient cells, ER-stress-induced apoptosis is attenuated thus implying the involvement of c-Abl in signaling from the ER to mitochondria [49]. Kumar et al. indicated that in response to oxidative stress, cytoplasmic c-Abl moves to mitochondria, where it mediates mitochondrial dysfunction and cell death. Moreover, target- ing of c-Abl to mitochondria is also dependent on activation of PKCδ and relies on c-Abl catalytic activity. In the response to hydrogen peroxide, pharmacological inhibition of c-Abl with STI571 decreases c-Abl targeting to mitochondria and attenuates mitochondrial dysfunction and cell death [50, 51]. Downregulation of c-Abl or PKCδ impaired PARP cleavage, suggesting that both PKCδ and c-Abl can induce apoptosis through the mitochondrial pathway in the absence of p53, p73, and FAS upon genotoxic stress [52]. Taken together all these observations suggest that c-Abl activation can exert a positive role both in the intrinsic and extrinsic apoptotic signaling pathways. 5. Perspectives Signaling networks are composed of multiple layers of interacting proteins. Activation of most cell signaling circuits is modulated by feedback control, and disease conditions are often caused by the loss of the feedback control. A comprehensive understanding of the complexities of the signaling network is required to design therapies that are eﬀective without inducing oﬀ-target consequences [53]. In neurodegenerative disorders, the duration and the spatial organization of signaling complexes can cause a system failure ending in neuronal loss. Evidence compiled above indicates that c-Abl activation could act as an arbiter of neuronal cell fate under various stress conditions. Subcellular localization of c-Abl can play an important role to modulate activation and assembly of signaling networks. Pharmacolog- ical inhibition of the catalytic activity can prevent targeting of c-Abl to mitochondria and the consequent programmed cell death. In the nucleus, c-Abl signaling modulates oxidative- stress-induced transcription resulting in neuronal death. In this scenario, a new therapeutic strategy for degenerative neurological diseases may be based on the possibility to