SHC-transforming protein 1; SHC-transforming protein A; Src homology 2 domain-containing-transforming protein C1; SH2 domain protein C1 (SHC1, SHC, SHCA)
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Function
- signaling adapter
- couples activated growth factor receptors to signaling pathways
- isoform p46Shc & isoform p52Shc, once phosphorylated, couple activated receptor tyrosine kinases to Ras via recruitment of the GRB2/SOS complex & are implicated in the cytoplasmic propagation of mitogenic signals
- conveys signal from src to ras
- isoform p46Shc & 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
- isoform p66Shc acts as a downstream target of p53 & is required for stress-activated p53 to induce elevation of intracellular oxidants, cytochrome c release & apoptosis
- expression of isoform p66Shc has been correlated with life span
- phosphorylated by activated epidermal growth factor receptor
- isoform p46Shc & isoform p52Shc are phosphorylated on Tyr of the Pro-rich domain
- isoform p66Shc is phosphorylated on Ser-36 by PRKCBB upon treatment with insulin, hydrogen peroxide or irradiation with ultraviolet light (putative)
- interacts with the Trk receptors(phospho-Tyr-dependent)
- interacts with the NPXY motif of Tyr-phosphorylated IGF1R & INSR in vitro via the PID domain
- once activated, binds to GRB2
- interacts with Tyr-phosphorylated CD3T
- interacts with the N-terminal region of APS
- interacts with phosphorylated LRP1 & IRS4.
- interacts with INPP5D/SHIP1 & INPPL1/SHIP2
- interacts with TRIM31 (putative)
- interacts with GAB2
Structure
- in response to a variety of growth factors, isoform p46Shc & isoform p52Shc bind to phosphorylated Trk receptors through their PID domains &/or SH2 domains
- the PID domain & SH2 domain bind to specific phosphorylated Tyr in the Asn-Pro-Xaa-Tyr(P) motif of the Trk receptors
- isoform p46Shc & isoform p52Shc are in turn phosphorylated on 3 Tyr within the extended proline-rich domain
- these phospho-Tyr act as docking site for GRB2 & thereby are involved in Ras activation (putative)
- contains 1 PID domain
- contains 1 SH2 domain
Compartment
- cytoplasm
- isoform p46Shc:
- mitochondrial 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 & isoform p66Shc, that contain the same sequence but more internally located, display a different subcellular localization
- mitochondrial matrix
- isoform p66Shc:
- mitochondria
- in case of oxidative conditions, phosphorylation at Ser-36 of isoform p66Shc, leads to mitochondrial accumulation
Alternative splicing
Expression
- widely expressed
- expressed in neural stem cells
- absent in mature neurons
More general terms
References
- ↑ Rozakis-Adcock M et al Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature 360:689 1992 PMID: https://www.ncbi.nlm.nih.gov/pubmed/1465135
- ↑ Pawson T. Protein modules and signalling networks. Nature. 1995 Feb 16;373(6515):573-80. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7531822