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MGP002824

UniProt Annotations

Entry Information

Gene Name	SHC (Src homology 2 domain containing) transforming protein 1
Protein Entry	SHC1_HUMAN
UniProt ID	P29353
Species	Human

Comments

Comment type	Description
Alternative Products	Event=Alternative promoter usage, Alternative splicing; Named isoforms=6; Name=p66Shc; IsoId=P29353-1; Sequence=Displayed; Note=Regulated by epigenetic modifications of its promoter region.; Name=p52Shc; IsoId=P29353-2; Sequence=VSP_016108; Name=p46Shc; IsoId=P29353-3; Sequence=VSP_016107; Name=5; IsoId=P29353-5; Sequence=VSP_040090, VSP_040091; Note=Produced by alternative splicing.; Name=6; IsoId=P29353-6; Sequence=VSP_040092; Note=Produced by alternative splicing.; Name=7; IsoId=P29353-7; Sequence=VSP_016108, VSP_040092; Note=Produced by alternative splicing.;
Domain	In response to a variety of growth factors, isoform p46Shc and isoform p52Shc bind to phosphorylated Trk receptors through their phosphotyrosine binding (PID) and/or SH2 domains. The PID and SH2 domains bind to specific phosphorylated tyrosine residues in the Asn-Pro-Xaa-Tyr(P) motif of the Trk receptors. Isoform p46Shc and isoform p52Shc are in turn phosphorylated on three tyrosine residues within the extended proline-rich domain. These phosphotyrosines act as docking site for GRB2 and thereby are involved in Ras activation (By similarity). {ECO:0000250}.
Function	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. {ECO:0000250, ECO:0000269\|PubMed:14665640}.
Interaction	P05067:APP; NbExp=5; IntAct=EBI-78835, EBI-77613; P10275:AR; NbExp=14; IntAct=EBI-78835, EBI-608057; P46108:CRK; NbExp=3; IntAct=EBI-78835, EBI-886; P00533:EGFR; NbExp=26; IntAct=EBI-78835, EBI-297353; P04626:ERBB2; NbExp=9; IntAct=EBI-78835, EBI-641062; P21860:ERBB3; NbExp=5; IntAct=EBI-78835, EBI-720706; Q15303:ERBB4; NbExp=2; IntAct=EBI-78835, EBI-80371; P03372-4:ESR1; NbExp=2; IntAct=EBI-78835, EBI-4309277; Q13480:GAB1; NbExp=9; IntAct=EBI-78835, EBI-517684; P62993:GRB2; NbExp=22; IntAct=EBI-78835, EBI-401755; P08069:IGF1R; NbExp=2; IntAct=EBI-1000553, EBI-475981; P06213:INSR; NbExp=2; IntAct=EBI-78835, EBI-475899; Q62120:Jak2 (xeno); NbExp=2; IntAct=EBI-78835, EBI-646604; P10721:KIT; NbExp=8; IntAct=EBI-78835, EBI-1379503; P08581:MET; NbExp=5; IntAct=EBI-78835, EBI-1039152; P03495:NS (xeno); NbExp=2; IntAct=EBI-78835, EBI-2548993; P27986:PIK3R1; NbExp=3; IntAct=EBI-78835, EBI-79464; Q07889:SOS1; NbExp=2; IntAct=EBI-78835, EBI-297487;
Ptm	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. {ECO:0000250, ECO:0000269\|PubMed:11980671, ECO:0000269\|PubMed:14665640, ECO:0000269\|PubMed:15526160, ECO:0000269\|PubMed:15837797, ECO:0000269\|PubMed:17081983, ECO:0000269\|PubMed:17274988, ECO:0000269\|PubMed:18669648, ECO:0000269\|PubMed:19690332, ECO:0000269\|PubMed:21406692, ECO:0000269\|PubMed:8195171, ECO:0000269\|PubMed:8939605, ECO:0000269\|PubMed:9121430, ECO:0000269\|PubMed:9148935, ECO:0000269\|PubMed:9488479, ECO:0000269\|PubMed:9566877}.
Sequence Caution	Sequence=CAI13254.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
Similarity	Contains 1 PID domain. {ECO:0000255\|PROSITE- ProRule:PRU00148}.
Similarity	Contains 1 SH2 domain. {ECO:0000255\|PROSITE- ProRule:PRU00191}.
Subcellular Location	Cytoplasm.
Subcellular Location	Isoform p46Shc: Mitochondrion matrix {ECO:0000269\|PubMed:14573619}. Note=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.
Subcellular Location	Isoform p66Shc: Mitochondrion {ECO:0000250}. Note=In case of oxidative conditions, phosphorylation at 'Ser-36' of isoform p66Shc, leads to mitochondrial accumulation. {ECO:0000250}.
Subunit	Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR in vitro via the PID domain. Once activated, binds to GRB2. Interacts with tyrosine-phosphorylated CD3T and DDR2. Interacts with the N-terminal region of APS. Interacts with phosphorylated LRP1 and IRS4. Interacts with INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with TRIM31. Interacts with PTPN6/SHP (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTT (By similarity). Interacts with ALK, GAB2, GRB7 and KIT. Interacts with FLT4 (tyrosine-phosphorylated). Interacts with EPHB1 and GRB2; activates the MAPK/ERK cascade to regulate cell migration. Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with ERBB4. Interacts with TEK/TIE2 (tyrosine-phosphorylated). Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a phosphotyrosine-dependent manner. Interacts with PTK2/FAK1. {ECO:0000250, ECO:0000269\|PubMed:10194451, ECO:0000269\|PubMed:10867024, ECO:0000269\|PubMed:11349134, ECO:0000269\|PubMed:11980671, ECO:0000269\|PubMed:12925710, ECO:0000269\|PubMed:14665640, ECO:0000269\|PubMed:15102829, ECO:0000269\|PubMed:15272003, ECO:0000269\|PubMed:15316024, ECO:0000269\|PubMed:15488758, ECO:0000269\|PubMed:17274988, ECO:0000269\|PubMed:19172738, ECO:0000269\|PubMed:7537849, ECO:0000269\|PubMed:7541045, ECO:0000269\|PubMed:7544002, ECO:0000269\|PubMed:7559478, ECO:0000269\|PubMed:8155326, ECO:0000269\|PubMed:8195171, ECO:0000269\|PubMed:8874179, ECO:0000269\|PubMed:8940081, ECO:0000269\|PubMed:9038210, ECO:0000269\|PubMed:9233773, ECO:0000269\|PubMed:9488479, ECO:0000269\|PubMed:9660833}.
Tissue Specificity	Widely expressed. Expressed in neural stem cells but absent in mature neurons.
Web Resource	Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/SHC1ID42287ch1q21.html";