Redox Circuitries Driving Src Regulation.

Abstract SIGNIFICANCE: Here, we review recent advances with regard to the role of Src kinase in the regulation of cytoskeleton organization, cell adhesion, and motility, focusing on redox circuitries engaging this kinase for anchorage and motility, control of cell survival to anoikis, as well as metabolic deregulation, all features belonging to the new hallmarks of cancer. RECENT ADVANCES: Several recent insights have reported that, alongside the well-known phosphorylation/dephosphorylation control, cysteine oxidation is a further mechanism of enzyme activation for both c-Src kinase and its oncogenic counterparts. Indeed, mounting evidence portrays redox regulation of Src kinase as a compulsory outcome in growth factors/cytokines signaling, integrin engagement, motility and invasiveness of tissues, receptor cross-talking at plasmamembrane, as well as during carcinogenesis and progression toward tumor malignancy or fibrotic disease. In addition, the kinase is an upstream regulator of NADPH oxidase-driven oxidants, a critical step for invadopodia formation and metastatic spread. CRITICAL ISSUES: Not satisfactorily unraveled yet, the exact role of Src kinase in redox cancer biology needs to be implemented with studies that are aimed at clarifying (i) the exact hierarchy between oxidants sources, Src redox-dependent activation and the regulation of cell motility, and (ii) the actual susceptibility of invading cells to redox-based treatments, owing to the well-recognized ability of cancer cells to find new strategies to adapt to new environments. FUTURE DIRECTIONS: Once these critical issues are addressed, redox circuitries involving Src kinase should potentially be used as both biomarkers and targets for personalized therapies in the fight against cancer or fibrotic diseases.