SHC1

This gene encodes three main isoforms that differ in activities and subcellular location. While all three are adapter proteins in signal transduction pathways, the longest (p66Shc) may be involved in regulating life span and the effects of reactive oxygen species. The other two isoforms, p52Shc and p46Shc, link activated receptor tyrosine kinases to the Ras pathway by recruitment of the GRB2/SOS complex. p66Shc is not involved in Ras activation. Unlike the other two isoforms, p46Shc is targeted to the mitochondrial matrix. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

SHC Adaptor Protein 1

Signaling adapter that couples activated growth factor receptors to signaling pathways. Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Isoform p46Shc and isoform p52Shc, once phosphorylated, couple activated receptor tyrosine kinases to Ras via the recruitment of the GRB2/SOS complex and are implicated in the cytoplasmic propagation of mitogenic signals. Isoform p46Shc and isoform p52Shc may thus function as initiators of the Ras signaling cascade in various non-neuronal systems. Isoform p66Shc does not mediate Ras activation, but is involved in signal transduction pathways that regulate the cellular response to oxidative stress and life span. Isoform p66Shc acts as a downstream target of the tumor suppressor p53 and is indispensable for the ability of stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release and apoptosis. The expression of isoform p66Shc has been correlated with life span (By similarity).
Participates in signaling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis.

Biological Process actin cytoskeleton reorganizationIEA:Ensembl
Biological Process angiogenesisIEA:UniProtKB-KW
Biological Process cell-cell adhesionIEA:Ensembl
Biological Process cellular response to growth factor stimulusManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process defense response to bacteriumManual Assertion Based On ExperimentIMP:CAFA
Biological Process epidermal growth factor receptor signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Biological Process heart developmentIEA:Ensembl
Biological Process insulin receptor signaling pathwayISS:BHF-UCL
Biological Process intracellular signal transductionIEA:InterPro
Biological Process negative regulation of angiogenesisIGI:BHF-UCL
Biological Process negative regulation of apoptotic processManual Assertion Based On ExperimentIMP:CAFA
Biological Process negative regulation of DNA-templated transcriptionManual Assertion Based On ExperimentIMP:CAFA
Biological Process positive regulation of cell population proliferationISS:BHF-UCL
Biological Process positive regulation of cell proliferation in bone marrowIGI:BHF-UCL
Biological Process positive regulation of DNA-templated transcriptionManual Assertion Based On ExperimentIMP:CAFA
Biological Process positive regulation of ERK1 and ERK2 cascadeManual Assertion Based On ExperimentIMP:CAFA
Biological Process positive regulation of MAPK cascadeManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process regulation of epidermal growth factor-activated receptor activityManual Assertion Based On ExperimentTAS:ProtInc
Biological Process regulation of superoxide metabolic processIGI:BHF-UCL
Biological Process transmembrane receptor protein tyrosine kinase signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central

Cytoplasm
Isoform p46Shc
Mitochondrion matrix
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.
Isoform p66Shc
Mitochondrion
In case of oxidative conditions, phosphorylation at 'Ser-36' of isoform p66Shc, leads to mitochondrial accumulation.

Phosphorylated by activated epidermal growth factor receptor. Phosphorylated in response to FLT4 and KIT signaling. Isoform p46Shc and isoform p52Shc are phosphorylated on tyrosine residues of the Pro-rich domain. Isoform p66Shc is phosphorylated on Ser-36 by PRKCB upon treatment with insulin, hydrogen peroxide or irradiation with ultraviolet light (By similarity).
Tyrosine phosphorylated in response to FLT3 signaling (By similarity).
Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity).
Tyrosine phosphorylated by ligand-activated ALK. Tyrosine phosphorylated by ligand-activated PDGFRB. Tyrosine phosphorylated by TEK/TIE2. May be tyrosine phosphorylated by activated PTK2/FAK1; tyrosine phosphorylation was seen in an astrocytoma biopsy, where PTK2/FAK1 kinase activity is high, but not in normal brain tissue. Isoform p52Shc dephosphorylation by PTPN2 may regulate interaction with GRB2.