Structure-functional implications of longevity protein p66Shc in health and disease

ShcA (Src homologous- collagen homologue), family of adapter proteins, consists of three isoforms which integrate and transduce external stimuli to different signaling networks. ShcA family consists of p46Shc, p52Shc and p66Shc isoforms, characterized by having multiple protein-lipid and protein-protein interaction domains implying their functional diversity. Among the three isoforms p66Shc is structurally different containing an additional CH2 domain which attributes to its dual functionality in cell growth, mediating both cell proliferation and apoptosis. Besides, p66Shc is also involved in different biological processes including reactive oxygen species (ROS) production, cell migration, ageing, cytoskeletal reorganization and cell adhesion. Moreover, the interplay between p66Shc and ROS is implicated in the pathology of various dreadful diseases. Accordingly, here we discuss the recent structural aspects of all ShcA adaptor proteins but are highlighting the case of p66Shc as model isoform. Furthermore, this review insights the role of p66Shc in progression of chronic age-related diseases like neuro diseases, metabolic disorders (non-alcoholic fatty liver, obesity, diabetes, cardiovascular diseases, vascular endothelial dysfunction) and cancer in relation to ROS. We finally conclude that p66Shc might act as a valuable biomarker for the prognosis of these diseases and could be used as a potential therapeutic target.