The Shc family of proteins consists four members, ShcA, ShcB, ShcC, and ShcD, of which the best characterized to date is ShcA (Rozakis-Adcock et al. 1992). ShcA, or simply Shc, was identified in 1992 as an adaptor protein which linked the activated EGFR (epidermal growth factor receptor) to Ras and the MAP (mitogen-activated protein) kinase cascade (Ravichandran 2001). Shc is expressed as three isoforms which have the molecular weights of 66, 52, and 46 kDa, respectively. These isoforms are designated according to their molecular weight. p66Shc is the longest isoform of the three and also consists of the collagen homology domain (CH2), which is unique to it.
P66Shc and Cell Signaling
Consequences of P66Shc Phosphorylations
Under oxidative stress the S36 residue of p66Shc is phosphorylated. Treatment with an iron-containing porphyrin, hemin, increased the phosphorylation of p66Shc at the S36 residue. In hemin-treated K562 erythroleukemic cells, p66Shc was transcriptionally activated through the ARE (antioxidant response element)-Nrf2 (NF-E2-related factor 2) pathway (Miyazawa and Tsuji 2014). In human colon carcinoma cell line RKO and in diploid human dermal fibroblasts, suppression in the production of ROS was seen in shRNA-mediated knockdown of p66Shc, and an increase in the production of ROS was observed upon overexpression of a recombinant p66Shc. These effects were not seen in the electron transport chain-deficient ρ0-RKO cells. These ρ0-RKO cells are mitochondrial DNA-depleted cells.
p66Shc, an adaptor protein, is the longest isoform of the ShcA family. p66Shc has an additional CH domain at the N-terminal, called the CH2 domain, which is not present in the other isoforms. This CH2 domain contains a very crucial S36 residue which is phosphorylated in response to oxidative stress and plays a role in apoptosis. This adaptor protein has been shown to be involved in mediating and executing the post effects of oxidative stress, and increasing body of evidence is pinpointing to its role in carcinogenesis as well. This multitasking protein is involved in regulating different networks of cell signaling. On one hand, it shows an increased expression profile in different cancers and has a positive role in cell proliferation and migration, whereas on the other hand, it promotes apoptosis under oxidative stress conditions by acting as a sensor of ROS. p66Shc by regulating intracellular ROS levels plays a crucial role in regulating longevity and cell senescence. These multifaceted properties of p66Shc make it a perfect candidate protein for further studies in various cancers and aging-related diseases. p66Shc can be targeted in terms of it being used as a possible therapeutic target in various diseases.