an adaptor protein containing a SH2 domain and a PID domain within a PH domain-like fold. Couples activated growth factor receptors to signaling pathways. Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Six human isoforms are produced by alternative promoter usage and alternative splicing. Isoforms p66, p52 and p46 (P29353-1, -2, and -3), produced by alternative initiation, variously regulate growth factor signaling, oncogenesis, intracellular oxidant levels, and apoptosis. Isoforms p46 and p52, once phosphorylated, couple activated receptor tyrosine kinases to Ras via the recruitment of the GRB2/SOS complex, thus initiating the cytoplasmic proliferative Ras signaling cascade in various non-neuronal systems. Isoform p66 does not mediate Ras activation, but associates with mitochondria where it controls intracellular redox status, mitochondrial permeability, life span, and stress-induced apoptosis. p66 acts as a downstream target of the tumor suppressor p53 and is required for the ability of stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release and apoptosis. P66 deletion in mice decreases the incidence of aging-associated diseases, such as atherosclerosis, and significantly prolongs life span. Participates in signaling downstream of TIE2, the tyrosine kinase receptor for angiopoietin, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis. Interacts with tyrosine-phosphorylated CD3T, DDR2, LRP1, IRS4, SHP, FLT4, PDGFRB, TIE2, TrkA, -B and -C. Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR in vitro via the PID domain. p66Shc is known to be activated by the mutant SOD1 associated with familial forms of amyotrophic lateral sclerosis (ALS), causing a decrease in the activity of Rac1 through a redox-sensitive regulation. In case of oxidative conditions, phosphorylation at S36 of isoform p66Shc, leads to mitochondrial accumulation p66 plays a role in mediating mitophagy and determining neuronal cell fate following acute oxygen glucose deprivation. Isoform p46 is localized to the mitochondria matrix. Targeting of isoform p46Shc to mitochondria is mediated by its first 32 amino acids, which behave as a bona fide mitochondrial targeting sequence. Isoform p52Shc and isoform p66Shc, that contain the same sequence but more internally located, display a different subcellular localization. Note: This description may include information from UniProtKB.
Protein type: Motility/polarity/chemotaxis; Apoptosis; Adaptor/scaffold; Mitochondrial
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.