Full text data of SHC1
SHC1
(SHC, SHCA)
[Confidence: low (only semi-automatic identification from reviews)]
SHC-transforming protein 1 (SHC-transforming protein 3; SHC-transforming protein A; Src homology 2 domain-containing-transforming protein C1; SH2 domain protein C1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
SHC-transforming protein 1 (SHC-transforming protein 3; SHC-transforming protein A; Src homology 2 domain-containing-transforming protein C1; SH2 domain protein C1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P29353
ID SHC1_HUMAN Reviewed; 583 AA.
AC P29353; B5BU19; D3DV78; O15290; Q5T180; Q5T183; Q5T184; Q5T185;
read moreAC Q5T186; Q8N4K5; Q96CL1;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
DT 08-APR-2008, sequence version 4.
DT 22-JAN-2014, entry version 168.
DE RecName: Full=SHC-transforming protein 1;
DE AltName: Full=SHC-transforming protein 3;
DE AltName: Full=SHC-transforming protein A;
DE AltName: Full=Src homology 2 domain-containing-transforming protein C1;
DE Short=SH2 domain protein C1;
GN Name=SHC1; Synonyms=SHC, SHCA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS P46SHC AND P52SHC).
RX PubMed=1623525; DOI=10.1016/0092-8674(92)90536-L;
RA Pelicci G., Lanfrancone L., Grignani F., McGlade J., Cavallo F.,
RA Forni G., Nicoletti I., Grignani F., Pawson T., Pelicci P.-G.;
RT "A novel transforming protein (SHC) with an SH2 domain is implicated
RT in mitogenic signal transduction.";
RL Cell 70:93-104(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P66SHC).
RX PubMed=9049300; DOI=10.1093/emboj/16.4.706;
RA Migliaccio E., Mele S., Salcini A.E., Pelicci G., Lai K.M.,
RA Superti-Furga G., Pawson T., Di Fiore P.P., Lanfrancone L.,
RA Pelicci P.-G.;
RT "Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on
RT the EGF receptor-MAP kinase-fos signalling pathway.";
RL EMBO J. 16:706-716(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Fibroblast;
RX PubMed=9192859; DOI=10.1006/geno.1997.4728;
RA Harun R.B., Smith K.K., Leek J.P., Markham A.F., Norris A.,
RA Morrison J.F.;
RT "Characterization of human SHC p66 cDNA and its processed pseudogene
RT mapping to Xq12-q13.1.";
RL Genomics 42:349-352(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P52SHC).
RC TISSUE=Mammary gland, and Synovium;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6).
RX PubMed=19054851; DOI=10.1038/nmeth.1273;
RA Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R.,
RA Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y.,
RA Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B.,
RA Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H.,
RA Maruyama Y., Matsuo K., Minami K., Mitsubori M., Mori M.,
RA Morishita R., Murase A., Nishikawa A., Nishikawa S., Okamoto T.,
RA Sakagami N., Sakamoto Y., Sasaki Y., Seki T., Sono S., Sugiyama A.,
RA Sumiya T., Takayama T., Takayama Y., Takeda H., Togashi T., Yahata K.,
RA Yamada H., Yanagisawa Y., Endo Y., Imamoto F., Kisu Y., Tanaka S.,
RA Isogai T., Imai J., Watanabe S., Nomura N.;
RT "Human protein factory for converting the transcriptome into an in
RT vitro-expressed proteome.";
RL Nat. Methods 5:1011-1017(2008).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS P52SHC AND 7).
RC TISSUE=Choriocarcinoma, and Neuroblastoma;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP INTERACTION WITH PDGFRB AND GRB2, AND PHOSPHORYLATION.
RX PubMed=8195171;
RA Yokote K., Mori S., Hansen K., McGlade J., Pawson T., Heldin C.H.,
RA Claesson-Welsh L.;
RT "Direct interaction between Shc and the platelet-derived growth factor
RT beta-receptor.";
RL J. Biol. Chem. 269:15337-15343(1994).
RN [10]
RP INTERACTION WITH NTRK1.
RX PubMed=8155326; DOI=10.1016/0896-6273(94)90223-2;
RA Stephens R.M., Loeb D.M., Copeland T.D., Pawson T., Greene L.A.,
RA Kaplan D.R.;
RT "Trk receptors use redundant signal transduction pathways involving
RT SHC and PLC-gamma 1 to mediate NGF responses.";
RL Neuron 12:691-705(1994).
RN [11]
RP INTERACTION WITH IGF1R.
RX PubMed=7541045; DOI=10.1074/jbc.270.26.15639;
RA Craparo A., O'Neill T.J., Gustafson T.A.;
RT "Non-SH2 domains within insulin receptor substrate-1 and SHC mediate
RT their phosphotyrosine-dependent interaction with the NPEY motif of the
RT insulin-like growth factor I receptor.";
RL J. Biol. Chem. 270:15639-15643(1995).
RN [12]
RP INTERACTION WITH INSR.
RX PubMed=7559478; DOI=10.1074/jbc.270.40.23258;
RA He W., O'Neill T.J., Gustafson T.A.;
RT "Distinct modes of interaction of SHC and insulin receptor substrate-1
RT with the insulin receptor NPEY region via non-SH2 domains.";
RL J. Biol. Chem. 270:23258-23262(1995).
RN [13]
RP INTERACTION WITH INSR.
RX PubMed=7537849;
RA Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.;
RT "Phosphotyrosine-dependent interaction of SHC and insulin receptor
RT substrate 1 with the NPEY motif of the insulin receptor via a novel
RT non-SH2 domain.";
RL Mol. Cell. Biol. 15:2500-2508(1995).
RN [14]
RP INTERACTION WITH INPP5D.
RX PubMed=8874179;
RA Ware M.D., Rosten P., Damen J.E., Liu L., Humphries R.K., Krystal G.;
RT "Cloning and characterization of human SHIP, the 145-kD inositol 5-
RT phosphatase that associates with SHC after cytokine stimulation.";
RL Blood 88:2833-2840(1996).
RN [15]
RP PHOSPHORYLATION AT TYR-349 AND TYR-350.
RX PubMed=8939605; DOI=10.1016/S0960-9822(96)00748-8;
RA van der Geer P., Wiley S., Gish G.D., Pawson T.;
RT "The Shc adaptor protein is highly phosphorylated at conserved, twin
RT tyrosine residues (Y239/240) that mediate protein-protein
RT interactions.";
RL Curr. Biol. 6:1435-1444(1996).
RN [16]
RP INTERACTION WITH GRB7.
RX PubMed=8940081; DOI=10.1074/jbc.271.48.30942;
RA Yokote K., Margolis B., Heldin C.H., Claesson-Welsh L.;
RT "Grb7 is a downstream signaling component of platelet-derived growth
RT factor alpha- and beta-receptors.";
RL J. Biol. Chem. 271:30942-30949(1996).
RN [17]
RP INTERACTION WITH KIT.
RX PubMed=9038210; DOI=10.1074/jbc.272.9.5915;
RA Price D.J., Rivnay B., Fu Y., Jiang S., Avraham S., Avraham H.;
RT "Direct association of Csk homologous kinase (CHK) with the
RT diphosphorylated site Tyr568/570 of the activated c-KIT in
RT megakaryocytes.";
RL J. Biol. Chem. 272:5915-5920(1997).
RN [18]
RP PHOSPHORYLATION.
RX PubMed=9148935; DOI=10.1074/jbc.272.20.13189;
RA Schlaepfer D.D., Hunter T.;
RT "Focal adhesion kinase overexpression enhances ras-dependent integrin
RT signaling to ERK2/mitogen-activated protein kinase through
RT interactions with and activation of c-Src.";
RL J. Biol. Chem. 272:13189-13195(1997).
RN [19]
RP PHOSPHORYLATION AT TYR-349; TYR-350 AND TYR-427.
RX PubMed=9121430;
RA Gotoh N., Toyoda M., Shibuya M.;
RT "Tyrosine phosphorylation sites at amino acids 239 and 240 of Shc are
RT involved in epidermal growth factor-induced mitogenic signaling that
RT is distinct from Ras/mitogen-activated protein kinase activation.";
RL Mol. Cell. Biol. 17:1824-1831(1997).
RN [20]
RP INTERACTION WITH APS.
RX PubMed=9233773; DOI=10.1038/sj.onc.1201163;
RA Yokouchi M., Suzuki R., Masuhara M., Komiya S., Inoue A.,
RA Yoshimura A.;
RT "Cloning and characterization of APS, an adaptor molecule containing
RT PH and SH2 domains that is tyrosine phosphorylated upon B-cell
RT receptor stimulation.";
RL Oncogene 15:7-15(1997).
RN [21]
RP INTERACTION WITH INPP5D AND INPPL1.
RX PubMed=9660833; DOI=10.1074/jbc.273.29.18605;
RA Habib T., Hejna J.A., Moses R.E., Decker S.J.;
RT "Growth factors and insulin stimulate tyrosine phosphorylation of the
RT 51C/SHIP2 protein.";
RL J. Biol. Chem. 273:18605-18609(1998).
RN [22]
RP PHOSPHORYLATION, DEPHOSPHORYLATION BY PTPN2, MUTAGENESIS OF TYR-349
RP AND TYR-427, AND INTERACTION WITH GRB2.
RX PubMed=9488479;
RA Tiganis T., Bennett A.M., Ravichandran K.S., Tonks N.K.;
RT "Epidermal growth factor receptor and the adaptor protein p52Shc are
RT specific substrates of T-cell protein tyrosine phosphatase.";
RL Mol. Cell. Biol. 18:1622-1634(1998).
RN [23]
RP PHOSPHORYLATION AT TYR-349; TYR-350 AND TYR-427.
RX PubMed=9566877;
RA Schlaepfer D.D., Jones K.C., Hunter T.;
RT "Multiple Grb2-mediated integrin-stimulated signaling pathways to
RT ERK2/mitogen-activated protein kinase: summation of both c-Src- and
RT focal adhesion kinase-initiated tyrosine phosphorylation events.";
RL Mol. Cell. Biol. 18:2571-2585(1998).
RN [24]
RP INTERACTION WITH INPPL1.
RX PubMed=10194451;
RA Wisniewski D., Strife A., Swendeman S., Erdjument-Bromage H.,
RA Geromanos S., Kavanaugh W.M., Tempst P., Clarkson B.;
RT "A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-
RT phosphatase (SHIP2) is constitutively tyrosine phosphorylated and
RT associated with src homologous and collagen gene (SHC) in chronic
RT myelogenous leukemia progenitor cells.";
RL Blood 93:2707-2720(1999).
RN [25]
RP INTERACTION WITH ERBB4.
RX PubMed=10867024; DOI=10.1074/jbc.C901015199;
RA Sweeney C., Lai C., Riese D.J. II, Diamonti A.J., Cantley L.C.,
RA Carraway K.L. III;
RT "Ligand discrimination in signaling through an ErbB4 receptor
RT homodimer.";
RL J. Biol. Chem. 275:19803-19807(2000).
RN [26]
RP INTERACTION WITH INPPL1.
RX PubMed=11349134; DOI=10.1074/jbc.M103537200;
RA Pesesse X., Dewaste V., De Smedt F., Laffargue M., Giuriato S.,
RA Moreau C., Payrastre B., Erneux C.;
RT "The Src homology 2 domain containing inositol 5-phosphatase SHIP2 is
RT recruited to the epidermal growth factor (EGF) receptor and
RT dephosphorylates phosphatidylinositol 3,4,5-trisphosphate in EGF-
RT stimulated COS-7 cells.";
RL J. Biol. Chem. 276:28348-28355(2001).
RN [27]
RP INTERACTION WITH PTK2/FAK1, AND PHOSPHORYLATION.
RX PubMed=11980671;
RA Hecker T.P., Grammer J.R., Gillespie G.Y., Stewart J. Jr.,
RA Gladson C.L.;
RT "Focal adhesion kinase enhances signaling through the
RT Shc/extracellular signal-regulated kinase pathway in anaplastic
RT astrocytoma tumor biopsy samples.";
RL Cancer Res. 62:2699-2707(2002).
RN [28]
RP ALTERNATIVE PROMOTER USAGE.
RX PubMed=11948181; DOI=10.1074/jbc.M200280200;
RA Ventura A., Luzi L., Pacini S., Baldari C.T., Pelicci P.-G.;
RT "The p66Shc longevity gene is silenced through epigenetic
RT modifications of an alternative promoter.";
RL J. Biol. Chem. 277:22370-22376(2002).
RN [29]
RP INTERACTION WITH EPHB1 AND GRB2.
RX PubMed=12925710; DOI=10.1083/jcb.200302073;
RA Vindis C., Cerretti D.P., Daniel T.O., Huynh-Do U.;
RT "EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote
RT chemotaxis.";
RL J. Cell Biol. 162:661-671(2003).
RN [30]
RP INTERACTION WITH NTRK1.
RX PubMed=15488758; DOI=10.1016/j.ccr.2004.09.011;
RA Tacconelli A., Farina A.R., Cappabianca L., Desantis G., Tessitore A.,
RA Vetuschi A., Sferra R., Rucci N., Argenti B., Screpanti I., Gulino A.,
RA Mackay A.R.;
RT "TrkA alternative splicing: a regulated tumor-promoting switch in
RT human neuroblastoma.";
RL Cancer Cell 6:347-360(2004).
RN [31]
RP REVIEW ON ROLE IN KIT SIGNALING, AND PHOSPHORYLATION.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [32]
RP FUNCTION, PHOSPHORYLATION, AND INTERACTION WITH TEK.
RX PubMed=14665640; DOI=10.1074/jbc.M307456200;
RA Audero E., Cascone I., Maniero F., Napione L., Arese M.,
RA Lanfrancone L., Bussolino F.;
RT "Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and
RT regulates migration and sprouting but not survival of endothelial
RT cells.";
RL J. Biol. Chem. 279:13224-13233(2004).
RN [33]
RP INTERACTION WITH FLT4.
RX PubMed=15102829; DOI=10.1074/jbc.M314015200;
RA Wang J.F., Zhang X., Groopman J.E.;
RT "Activation of vascular endothelial growth factor receptor-3 and its
RT downstream signaling promote cell survival under oxidative stress.";
RL J. Biol. Chem. 279:27088-27097(2004).
RN [34]
RP INTERACTION WITH IRS4.
RX PubMed=15316024; DOI=10.1074/jbc.M404537200;
RA Hinsby A.M., Olsen J.V., Mann M.;
RT "Tyrosine phosphoproteomics of fibroblast growth factor signaling: a
RT role for insulin receptor substrate-4.";
RL J. Biol. Chem. 279:46438-46447(2004).
RN [35]
RP SUBCELLULAR LOCATION (ISOFORM P46SHC).
RX PubMed=14573619; DOI=10.1074/jbc.M307655200;
RA Ventura A., Maccarana M., Raker V.A., Pelicci P.-G.;
RT "A cryptic targeting signal induces isoform-specific localization of
RT p46Shc to mitochondria.";
RL J. Biol. Chem. 279:2299-2306(2004).
RN [36]
RP INTERACTION WITH LRP1.
RX PubMed=15272003; DOI=10.1074/jbc.M407592200;
RA Ranganathan S., Liu C.-X., Migliorini M.M., Von Arnim C.A.F.,
RA Peltan I.D., Mikhailenko I., Hyman B.T., Strickland D.K.;
RT "Serine and threonine phosphorylation of the low density lipoprotein
RT receptor-related protein by protein kinase Calpha regulates
RT endocytosis and association with adaptor molecules.";
RL J. Biol. Chem. 279:40536-40544(2004).
RN [37]
RP PHOSPHORYLATION AT SER-36.
RX PubMed=15837797; DOI=10.1083/jcb.200410041;
RA Smith W.W., Norton D.D., Gorospe M., Jiang H., Nemoto S.,
RA Holbrook N.J., Finkel T., Kusiak J.W.;
RT "Phosphorylation of p66Shc and forkhead proteins mediates Abeta
RT toxicity.";
RL J. Cell Biol. 169:331-339(2005).
RN [38]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [39]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-139, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [40]
RP INTERACTION WITH ALK, AND PHOSPHORYLATION.
RX PubMed=17274988; DOI=10.1016/j.febslet.2007.01.039;
RA Degoutin J., Vigny M., Gouzi J.Y.;
RT "ALK activation induces Shc and FRS2 recruitment: Signaling and
RT phenotypic outcomes in PC12 cells differentiation.";
RL FEBS Lett. 581:727-734(2007).
RN [41]
RP INTERACTION WITH GAB2.
RX PubMed=19172738; DOI=10.1038/emboj.2008.159;
RA Brummer T., Larance M., Herrera Abreu M.T., Lyons R.J., Timpson P.,
RA Emmerich C.H., Fleuren E.D.G., Lehrbach G.M., Schramek D.,
RA Guilhaus M., James D.E., Daly R.J.;
RT "Phosphorylation-dependent binding of 14-3-3 terminates signalling by
RT the Gab2 docking protein.";
RL EMBO J. 27:2305-2316(2008).
RN [42]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-139 AND TYR-427, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [43]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [44]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-427, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [45]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [46]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [47]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-139, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [48]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [49]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 482-583.
RX PubMed=7473762; DOI=10.1006/jmbi.1995.0601;
RA Mikol V., Baumann G., Zurini M.G.M., Hommel U.;
RT "Crystal structure of the SH2 domain from the adaptor protein SHC: a
RT model for peptide binding based on X-ray and NMR data.";
RL J. Mol. Biol. 254:86-95(1995).
RN [50]
RP STRUCTURE BY NMR OF 127-317.
RX PubMed=8524391; DOI=10.1038/378584a0;
RA Zhou M.-M., Ravichandran K.S., Olejniczak E.F., Petros A.M.,
RA Meadows R.P., Sattler M., Harlan J.E., Wade W.S., Burakoff S.J.,
RA Fesik S.W.;
RT "Structure and ligand recognition of the phosphotyrosine binding
RT domain of Shc.";
RL Nature 378:584-592(1995).
RN [51]
RP STRUCTURE BY NMR OF 480-583 IN COMPLEX WITH TYROSINE-PHOSPHORYLATED
RP CD3Z.
RX PubMed=7544002; DOI=10.1073/pnas.92.17.7784;
RA Zhou M.-M., Meadows R.P., Logan T.M., Yoon H.S., Wade W.S.,
RA Ravichandran K.S., Burakoff S.J., Fesik S.W.;
RT "Solution structure of the Shc SH2 domain complexed with a tyrosine-
RT phosphorylated peptide from the T-cell receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7784-7788(1995).
CC -!- FUNCTION: Signaling adapter that couples activated growth factor
CC receptors to signaling pathways. Participates in a signaling
CC cascade initiated by activated KIT and KITLG/SCF. Isoform p46Shc
CC and isoform p52Shc, once phosphorylated, couple activated receptor
CC tyrosine kinases to Ras via the recruitment of the GRB2/SOS
CC complex and are implicated in the cytoplasmic propagation of
CC mitogenic signals. Isoform p46Shc and isoform p52Shc may thus
CC function as initiators of the Ras signaling cascade in various
CC non-neuronal systems. Isoform p66Shc does not mediate Ras
CC activation, but is involved in signal transduction pathways that
CC regulate the cellular response to oxidative stress and life span.
CC Isoform p66Shc acts as a downstream target of the tumor suppressor
CC p53 and is indispensable for the ability of stress-activated p53
CC to induce elevation of intracellular oxidants, cytochrome c
CC release and apoptosis. The expression of isoform p66Shc has been
CC correlated with life span (By similarity). Participates in
CC signaling downstream of the angiopoietin receptor TEK/TIE2, and
CC plays a role in the regulation of endothelial cell migration and
CC sprouting angiogenesis.
CC -!- SUBUNIT: Interacts with the NPXY motif of tyrosine-phosphorylated
CC IGF1R and INSR in vitro via the PID domain. Once activated, binds
CC to GRB2. Interacts with tyrosine-phosphorylated CD3T and DDR2.
CC Interacts with the N-terminal region of APS. Interacts with
CC phosphorylated LRP1 and IRS4. Interacts with INPP5D/SHIP1 and
CC INPPL1/SHIP2. Interacts with TRIM31. Interacts with PTPN6/SHP
CC (tyrosine phosphorylated). Identified in a complex containing
CC FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTT (By
CC similarity). Interacts with ALK, GAB2, GRB7 and KIT. Interacts
CC with FLT4 (tyrosine-phosphorylated). Interacts with EPHB1 and
CC GRB2; activates the MAPK/ERK cascade to regulate cell migration.
CC Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with
CC ERBB4. Interacts with TEK/TIE2 (tyrosine-phosphorylated).
CC Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a
CC phosphotyrosine-dependent manner. Interacts with PTK2/FAK1.
CC -!- INTERACTION:
CC P05067:APP; NbExp=5; IntAct=EBI-78835, EBI-77613;
CC P46108:CRK; NbExp=3; IntAct=EBI-78835, EBI-886;
CC P00533:EGFR; NbExp=25; IntAct=EBI-78835, EBI-297353;
CC P04626:ERBB2; NbExp=9; IntAct=EBI-78835, EBI-641062;
CC P21860:ERBB3; NbExp=5; IntAct=EBI-78835, EBI-720706;
CC Q15303:ERBB4; NbExp=2; IntAct=EBI-78835, EBI-80371;
CC P03372-4:ESR1; NbExp=2; IntAct=EBI-78835, EBI-4309277;
CC P62993:GRB2; NbExp=22; IntAct=EBI-78835, EBI-401755;
CC P08069:IGF1R; NbExp=2; IntAct=EBI-1000553, EBI-475981;
CC P06213:INSR; NbExp=2; IntAct=EBI-78835, EBI-475899;
CC Q62120:Jak2 (xeno); NbExp=2; IntAct=EBI-78835, EBI-646604;
CC P27986:PIK3R1; NbExp=3; IntAct=EBI-78835, EBI-79464;
CC Q07889:SOS1; NbExp=2; IntAct=EBI-78835, EBI-297487;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- SUBCELLULAR LOCATION: Isoform p46Shc: Mitochondrion matrix.
CC Note=Localized to the mitochondria matrix. Targeting of isoform
CC p46Shc to mitochondria is mediated by its first 32 amino acids,
CC which behave as a bona fide mitochondrial targeting sequence.
CC Isoform p52Shc and isoform p66Shc, that contain the same sequence
CC but more internally located, display a different subcellular
CC localization.
CC -!- SUBCELLULAR LOCATION: Isoform p66Shc: Mitochondrion (By
CC similarity). Note=In case of oxidative conditions, phosphorylation
CC at 'Ser-36' of isoform p66Shc, leads to mitochondrial accumulation
CC (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=6;
CC Name=p66Shc;
CC IsoId=P29353-1; Sequence=Displayed;
CC Note=Regulated by epigenetic modifications of its promoter
CC region;
CC Name=p52Shc;
CC IsoId=P29353-2; Sequence=VSP_016108;
CC Name=p46Shc;
CC IsoId=P29353-3; Sequence=VSP_016107;
CC Name=5;
CC IsoId=P29353-5; Sequence=VSP_040090, VSP_040091;
CC Note=Produced by alternative splicing;
CC Name=6;
CC IsoId=P29353-6; Sequence=VSP_040092;
CC Note=Produced by alternative splicing;
CC Name=7;
CC IsoId=P29353-7; Sequence=VSP_016108, VSP_040092;
CC Note=Produced by alternative splicing;
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed in neural stem
CC cells but absent in mature neurons.
CC -!- DOMAIN: In response to a variety of growth factors, isoform p46Shc
CC and isoform p52Shc bind to phosphorylated Trk receptors through
CC their phosphotyrosine binding (PID) and/or SH2 domains. The PID
CC and SH2 domains bind to specific phosphorylated tyrosine residues
CC in the Asn-Pro-Xaa-Tyr(P) motif of the Trk receptors. Isoform
CC p46Shc and isoform p52Shc are in turn phosphorylated on three
CC tyrosine residues within the extended proline-rich domain. These
CC phosphotyrosines act as docking site for GRB2 and thereby are
CC involved in Ras activation (By similarity).
CC -!- PTM: Phosphorylated by activated epidermal growth factor receptor.
CC Phosphorylated in response to FLT4 and KIT signaling. Isoform
CC p46Shc and isoform p52Shc are phosphorylated on tyrosine residues
CC of the Pro-rich domain. Isoform p66Shc is phosphorylated on Ser-36
CC by PRKCB upon treatment with insulin, hydrogen peroxide or
CC irradiation with ultraviolet light (By similarity). Tyrosine
CC phosphorylated in response to FLT3 signaling (By similarity).
CC Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity).
CC Tyrosine phosphorylated by ligand-activated ALK. Tyrosine
CC phosphorylated by ligand-activated PDGFRB. Tyrosine phosphorylated
CC by TEK/TIE2. May be tyrosine phosphorylated by activated
CC PTK2/FAK1; tyrosine phosphorylation was seen in an astrocytoma
CC biopsy, where PTK2/FAK1 kinase activity is high, but not in normal
CC brain tissue. Isoform p52Shc dephosphorylation by PTPN2 may
CC regulate interaction with GRB2.
CC -!- SIMILARITY: Contains 1 PID domain.
CC -!- SIMILARITY: Contains 1 SH2 domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAI13254.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SHC1ID42287ch1q21.html";
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DR EMBL; X68148; CAA48251.1; -; mRNA.
DR EMBL; U73377; AAB49972.1; -; mRNA.
DR EMBL; Y09847; CAA70977.1; -; Genomic_DNA.
DR EMBL; AK292143; BAF84832.1; -; mRNA.
DR EMBL; AK315842; BAF98733.1; -; mRNA.
DR EMBL; AB451255; BAG70069.1; -; mRNA.
DR EMBL; AB451379; BAG70193.1; -; mRNA.
DR EMBL; AL451085; CAI13248.1; -; Genomic_DNA.
DR EMBL; AL451085; CAI13249.1; -; Genomic_DNA.
DR EMBL; AL451085; CAI13250.1; -; Genomic_DNA.
DR EMBL; AL451085; CAI13251.1; -; Genomic_DNA.
DR EMBL; AL451085; CAI13254.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471121; EAW53168.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53169.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53170.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53171.1; -; Genomic_DNA.
DR EMBL; BC014158; AAH14158.1; -; mRNA.
DR EMBL; BC033925; AAH33925.1; -; mRNA.
DR PIR; S25776; S25776.
DR RefSeq; NP_001123512.1; NM_001130040.1.
DR RefSeq; NP_001123513.1; NM_001130041.1.
DR RefSeq; NP_001189788.1; NM_001202859.1.
DR RefSeq; NP_003020.2; NM_003029.4.
DR RefSeq; NP_892113.4; NM_183001.4.
DR UniGene; Hs.433795; -.
DR PDB; 1MIL; X-ray; 2.70 A; A=482-583.
DR PDB; 1N3H; NMR; -; A=111-317.
DR PDB; 1OY2; NMR; -; A=111-317.
DR PDB; 1QG1; NMR; -; I=423-435.
DR PDB; 1SHC; NMR; -; A=127-317.
DR PDB; 1TCE; NMR; -; A=480-583.
DR PDB; 1WCP; Model; -; A=127-583.
DR PDB; 2L1C; NMR; -; A=127-317.
DR PDBsum; 1MIL; -.
DR PDBsum; 1N3H; -.
DR PDBsum; 1OY2; -.
DR PDBsum; 1QG1; -.
DR PDBsum; 1SHC; -.
DR PDBsum; 1TCE; -.
DR PDBsum; 1WCP; -.
DR PDBsum; 2L1C; -.
DR DisProt; DP00154; -.
DR ProteinModelPortal; P29353; -.
DR SMR; P29353; 111-317, 482-583.
DR DIP; DIP-699N; -.
DR IntAct; P29353; 78.
DR MINT; MINT-123530; -.
DR BindingDB; P29353; -.
DR ChEMBL; CHEMBL5626; -.
DR PhosphoSite; P29353; -.
DR DMDM; 182676455; -.
DR PaxDb; P29353; -.
DR PRIDE; P29353; -.
DR DNASU; 6464; -.
DR Ensembl; ENST00000368445; ENSP00000357430; ENSG00000160691.
DR Ensembl; ENST00000368450; ENSP00000357435; ENSG00000160691.
DR Ensembl; ENST00000368453; ENSP00000357438; ENSG00000160691.
DR Ensembl; ENST00000448116; ENSP00000401303; ENSG00000160691.
DR GeneID; 6464; -.
DR KEGG; hsa:6464; -.
DR UCSC; uc001ffv.3; human.
DR CTD; 6464; -.
DR GeneCards; GC01M154934; -.
DR HGNC; HGNC:10840; SHC1.
DR HPA; CAB005374; -.
DR HPA; CAB016305; -.
DR HPA; HPA001844; -.
DR MIM; 600560; gene.
DR neXtProt; NX_P29353; -.
DR PharmGKB; PA35746; -.
DR eggNOG; NOG315087; -.
DR HOVERGEN; HBG050121; -.
DR KO; K06279; -.
DR OMA; HMDNHLP; -.
DR OrthoDB; EOG7MD4QK; -.
DR PhylomeDB; P29353; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P29353; -.
DR ChiTaRS; SHC1; human.
DR EvolutionaryTrace; P29353; -.
DR GeneWiki; SHC1; -.
DR GenomeRNAi; 6464; -.
DR NextBio; 25115; -.
DR PRO; PR:P29353; -.
DR ArrayExpress; P29353; -.
DR Bgee; P29353; -.
DR Genevestigator; P29353; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0070435; C:Shc-EGFR complex; ISS:BHF-UCL.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; ISS:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; TAS:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; TAS:Reactome.
DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; TAS:UniProtKB.
DR GO; GO:0031532; P:actin cytoskeleton reorganization; IEA:Ensembl.
DR GO; GO:0000187; P:activation of MAPK activity; IDA:UniProtKB.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0016337; P:cell-cell adhesion; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0000165; P:MAPK cascade; IDA:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0008284; P:positive regulation of cell proliferation; NAS:UniProtKB.
DR GO; GO:0045740; P:positive regulation of DNA replication; ISS:BHF-UCL.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
DR GO; GO:0007176; P:regulation of epidermal growth factor-activated receptor activity; TAS:ProtInc.
DR GO; GO:0040008; P:regulation of growth; IEA:UniProtKB-KW.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR006019; PID_Shc-like.
DR InterPro; IPR006020; PTB/PI_dom.
DR InterPro; IPR000980; SH2.
DR Pfam; PF00640; PID; 1.
DR Pfam; PF00017; SH2; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR PRINTS; PR00629; SHCPIDOMAIN.
DR SMART; SM00462; PTB; 1.
DR SMART; SM00252; SH2; 1.
DR PROSITE; PS01179; PID; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative promoter usage;
KW Alternative splicing; Angiogenesis; Complete proteome; Cytoplasm;
KW Growth regulation; Mitochondrion; Phosphoprotein; Polymorphism;
KW Reference proteome; SH2 domain.
FT CHAIN 1 583 SHC-transforming protein 1.
FT /FTId=PRO_0000097731.
FT DOMAIN 156 339 PID.
FT DOMAIN 488 579 SH2.
FT REGION 340 487 CH1.
FT COMPBIAS 411 474 Pro-rich.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 36 36 Phosphoserine.
FT MOD_RES 139 139 Phosphoserine.
FT MOD_RES 349 349 Phosphotyrosine.
FT MOD_RES 350 350 Phosphotyrosine.
FT MOD_RES 426 426 Phosphoserine.
FT MOD_RES 427 427 Phosphotyrosine.
FT VAR_SEQ 1 214 Missing (in isoform 5).
FT /FTId=VSP_040090.
FT VAR_SEQ 1 155 Missing (in isoform p46Shc).
FT /FTId=VSP_016107.
FT VAR_SEQ 1 110 Missing (in isoform p52Shc and isoform
FT 7).
FT /FTId=VSP_016108.
FT VAR_SEQ 215 221 PLSSILG -> MSLCHRW (in isoform 5).
FT /FTId=VSP_040091.
FT VAR_SEQ 417 417 P -> PA (in isoform 7 and isoform 6).
FT /FTId=VSP_040092.
FT VARIANT 205 205 A -> V (in dbSNP:rs8191981).
FT /FTId=VAR_042428.
FT VARIANT 410 410 M -> V (in dbSNP:rs8191979).
FT /FTId=VAR_051353.
FT MUTAGEN 349 349 Y->F: Alters interaction with GRB2;
FT isoform p52Shc (in vitro).
FT MUTAGEN 427 427 Y->F: No effect on interaction with GRB2;
FT isoform p52Shc (in vitro).
FT CONFLICT 2 2 D -> N (in Ref. 3; CAA70977).
FT CONFLICT 21 21 L -> M (in Ref. 3; CAA70977).
FT CONFLICT 38 38 S -> P (in Ref. 3; CAA70977).
FT CONFLICT 95 95 V -> D (in Ref. 2; AAB49972).
FT CONFLICT 101 101 D -> E (in Ref. 2; AAB49972).
FT CONFLICT 430 430 V -> A (in Ref. 5; BAG70069/BAG70193).
FT STRAND 113 115
FT STRAND 142 145
FT STRAND 148 150
FT HELIX 152 156
FT STRAND 160 167
FT STRAND 169 171
FT TURN 176 178
FT STRAND 179 181
FT HELIX 184 198
FT HELIX 200 202
FT STRAND 206 208
FT STRAND 215 218
FT STRAND 222 224
FT STRAND 229 237
FT STRAND 240 245
FT TURN 246 249
FT STRAND 251 255
FT STRAND 256 259
FT STRAND 261 263
FT STRAND 265 267
FT STRAND 270 272
FT STRAND 274 278
FT STRAND 281 283
FT STRAND 286 291
FT STRAND 293 295
FT HELIX 297 302
FT STRAND 311 314
FT TURN 483 485
FT STRAND 487 489
FT HELIX 495 499
FT STRAND 507 512
FT STRAND 514 516
FT STRAND 518 526
FT STRAND 529 536
FT STRAND 540 543
FT STRAND 548 551
FT HELIX 552 562
FT STRAND 566 568
FT STRAND 571 573
SQ SEQUENCE 583 AA; 62822 MW; 7EFA5CB185A548D1 CRC64;
MDLLPPKPKY NPLRNESLSS LEEGASGSTP PEELPSPSAS SLGPILPPLP GDDSPTTLCS
FFPRMSNLRL ANPAGGRPGS KGEPGRAADD GEGIVGAAMP DSGPLPLLQD MNKLSGGGGR
RTRVEGGQLG GEEWTRHGSF VNKPTRGWLH PNDKVMGPGV SYLVRYMGCV EVLQSMRALD
FNTRTQVTRE AISLVCEAVP GAKGATRRRK PCSRPLSSIL GRSNLKFAGM PITLTVSTSS
LNLMAADCKQ IIANHHMQSI SFASGGDPDT AEYVAYVAKD PVNQRACHIL ECPEGLAQDV
ISTIGQAFEL RFKQYLRNPP KLVTPHDRMA GFDGSAWDEE EEEPPDHQYY NDFPGKEPPL
GGVVDMRLRE GAAPGAARPT APNAQTPSHL GATLPVGQPV GGDPEVRKQM PPPPPCPGRE
LFDDPSYVNV QNLDKARQAV GGAGPPNPAI NGSAPRDLFD MKPFEDALRV PPPPQSVSMA
EQLRGEPWFH GKLSRREAEA LLQLNGDFLV RESTTTPGQY VLTGLQSGQP KHLLLVDPEG
VVRTKDHRFE SVSHLISYHM DNHLPIISAG SELCLQQPVE RKL
//
ID SHC1_HUMAN Reviewed; 583 AA.
AC P29353; B5BU19; D3DV78; O15290; Q5T180; Q5T183; Q5T184; Q5T185;
read moreAC Q5T186; Q8N4K5; Q96CL1;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
DT 08-APR-2008, sequence version 4.
DT 22-JAN-2014, entry version 168.
DE RecName: Full=SHC-transforming protein 1;
DE AltName: Full=SHC-transforming protein 3;
DE AltName: Full=SHC-transforming protein A;
DE AltName: Full=Src homology 2 domain-containing-transforming protein C1;
DE Short=SH2 domain protein C1;
GN Name=SHC1; Synonyms=SHC, SHCA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS P46SHC AND P52SHC).
RX PubMed=1623525; DOI=10.1016/0092-8674(92)90536-L;
RA Pelicci G., Lanfrancone L., Grignani F., McGlade J., Cavallo F.,
RA Forni G., Nicoletti I., Grignani F., Pawson T., Pelicci P.-G.;
RT "A novel transforming protein (SHC) with an SH2 domain is implicated
RT in mitogenic signal transduction.";
RL Cell 70:93-104(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM P66SHC).
RX PubMed=9049300; DOI=10.1093/emboj/16.4.706;
RA Migliaccio E., Mele S., Salcini A.E., Pelicci G., Lai K.M.,
RA Superti-Furga G., Pawson T., Di Fiore P.P., Lanfrancone L.,
RA Pelicci P.-G.;
RT "Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on
RT the EGF receptor-MAP kinase-fos signalling pathway.";
RL EMBO J. 16:706-716(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Fibroblast;
RX PubMed=9192859; DOI=10.1006/geno.1997.4728;
RA Harun R.B., Smith K.K., Leek J.P., Markham A.F., Norris A.,
RA Morrison J.F.;
RT "Characterization of human SHC p66 cDNA and its processed pseudogene
RT mapping to Xq12-q13.1.";
RL Genomics 42:349-352(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM P52SHC).
RC TISSUE=Mammary gland, and Synovium;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6).
RX PubMed=19054851; DOI=10.1038/nmeth.1273;
RA Goshima N., Kawamura Y., Fukumoto A., Miura A., Honma R., Satoh R.,
RA Wakamatsu A., Yamamoto J., Kimura K., Nishikawa T., Andoh T., Iida Y.,
RA Ishikawa K., Ito E., Kagawa N., Kaminaga C., Kanehori K., Kawakami B.,
RA Kenmochi K., Kimura R., Kobayashi M., Kuroita T., Kuwayama H.,
RA Maruyama Y., Matsuo K., Minami K., Mitsubori M., Mori M.,
RA Morishita R., Murase A., Nishikawa A., Nishikawa S., Okamoto T.,
RA Sakagami N., Sakamoto Y., Sasaki Y., Seki T., Sono S., Sugiyama A.,
RA Sumiya T., Takayama T., Takayama Y., Takeda H., Togashi T., Yahata K.,
RA Yamada H., Yanagisawa Y., Endo Y., Imamoto F., Kisu Y., Tanaka S.,
RA Isogai T., Imai J., Watanabe S., Nomura N.;
RT "Human protein factory for converting the transcriptome into an in
RT vitro-expressed proteome.";
RL Nat. Methods 5:1011-1017(2008).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS P52SHC AND 7).
RC TISSUE=Choriocarcinoma, and Neuroblastoma;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP INTERACTION WITH PDGFRB AND GRB2, AND PHOSPHORYLATION.
RX PubMed=8195171;
RA Yokote K., Mori S., Hansen K., McGlade J., Pawson T., Heldin C.H.,
RA Claesson-Welsh L.;
RT "Direct interaction between Shc and the platelet-derived growth factor
RT beta-receptor.";
RL J. Biol. Chem. 269:15337-15343(1994).
RN [10]
RP INTERACTION WITH NTRK1.
RX PubMed=8155326; DOI=10.1016/0896-6273(94)90223-2;
RA Stephens R.M., Loeb D.M., Copeland T.D., Pawson T., Greene L.A.,
RA Kaplan D.R.;
RT "Trk receptors use redundant signal transduction pathways involving
RT SHC and PLC-gamma 1 to mediate NGF responses.";
RL Neuron 12:691-705(1994).
RN [11]
RP INTERACTION WITH IGF1R.
RX PubMed=7541045; DOI=10.1074/jbc.270.26.15639;
RA Craparo A., O'Neill T.J., Gustafson T.A.;
RT "Non-SH2 domains within insulin receptor substrate-1 and SHC mediate
RT their phosphotyrosine-dependent interaction with the NPEY motif of the
RT insulin-like growth factor I receptor.";
RL J. Biol. Chem. 270:15639-15643(1995).
RN [12]
RP INTERACTION WITH INSR.
RX PubMed=7559478; DOI=10.1074/jbc.270.40.23258;
RA He W., O'Neill T.J., Gustafson T.A.;
RT "Distinct modes of interaction of SHC and insulin receptor substrate-1
RT with the insulin receptor NPEY region via non-SH2 domains.";
RL J. Biol. Chem. 270:23258-23262(1995).
RN [13]
RP INTERACTION WITH INSR.
RX PubMed=7537849;
RA Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.;
RT "Phosphotyrosine-dependent interaction of SHC and insulin receptor
RT substrate 1 with the NPEY motif of the insulin receptor via a novel
RT non-SH2 domain.";
RL Mol. Cell. Biol. 15:2500-2508(1995).
RN [14]
RP INTERACTION WITH INPP5D.
RX PubMed=8874179;
RA Ware M.D., Rosten P., Damen J.E., Liu L., Humphries R.K., Krystal G.;
RT "Cloning and characterization of human SHIP, the 145-kD inositol 5-
RT phosphatase that associates with SHC after cytokine stimulation.";
RL Blood 88:2833-2840(1996).
RN [15]
RP PHOSPHORYLATION AT TYR-349 AND TYR-350.
RX PubMed=8939605; DOI=10.1016/S0960-9822(96)00748-8;
RA van der Geer P., Wiley S., Gish G.D., Pawson T.;
RT "The Shc adaptor protein is highly phosphorylated at conserved, twin
RT tyrosine residues (Y239/240) that mediate protein-protein
RT interactions.";
RL Curr. Biol. 6:1435-1444(1996).
RN [16]
RP INTERACTION WITH GRB7.
RX PubMed=8940081; DOI=10.1074/jbc.271.48.30942;
RA Yokote K., Margolis B., Heldin C.H., Claesson-Welsh L.;
RT "Grb7 is a downstream signaling component of platelet-derived growth
RT factor alpha- and beta-receptors.";
RL J. Biol. Chem. 271:30942-30949(1996).
RN [17]
RP INTERACTION WITH KIT.
RX PubMed=9038210; DOI=10.1074/jbc.272.9.5915;
RA Price D.J., Rivnay B., Fu Y., Jiang S., Avraham S., Avraham H.;
RT "Direct association of Csk homologous kinase (CHK) with the
RT diphosphorylated site Tyr568/570 of the activated c-KIT in
RT megakaryocytes.";
RL J. Biol. Chem. 272:5915-5920(1997).
RN [18]
RP PHOSPHORYLATION.
RX PubMed=9148935; DOI=10.1074/jbc.272.20.13189;
RA Schlaepfer D.D., Hunter T.;
RT "Focal adhesion kinase overexpression enhances ras-dependent integrin
RT signaling to ERK2/mitogen-activated protein kinase through
RT interactions with and activation of c-Src.";
RL J. Biol. Chem. 272:13189-13195(1997).
RN [19]
RP PHOSPHORYLATION AT TYR-349; TYR-350 AND TYR-427.
RX PubMed=9121430;
RA Gotoh N., Toyoda M., Shibuya M.;
RT "Tyrosine phosphorylation sites at amino acids 239 and 240 of Shc are
RT involved in epidermal growth factor-induced mitogenic signaling that
RT is distinct from Ras/mitogen-activated protein kinase activation.";
RL Mol. Cell. Biol. 17:1824-1831(1997).
RN [20]
RP INTERACTION WITH APS.
RX PubMed=9233773; DOI=10.1038/sj.onc.1201163;
RA Yokouchi M., Suzuki R., Masuhara M., Komiya S., Inoue A.,
RA Yoshimura A.;
RT "Cloning and characterization of APS, an adaptor molecule containing
RT PH and SH2 domains that is tyrosine phosphorylated upon B-cell
RT receptor stimulation.";
RL Oncogene 15:7-15(1997).
RN [21]
RP INTERACTION WITH INPP5D AND INPPL1.
RX PubMed=9660833; DOI=10.1074/jbc.273.29.18605;
RA Habib T., Hejna J.A., Moses R.E., Decker S.J.;
RT "Growth factors and insulin stimulate tyrosine phosphorylation of the
RT 51C/SHIP2 protein.";
RL J. Biol. Chem. 273:18605-18609(1998).
RN [22]
RP PHOSPHORYLATION, DEPHOSPHORYLATION BY PTPN2, MUTAGENESIS OF TYR-349
RP AND TYR-427, AND INTERACTION WITH GRB2.
RX PubMed=9488479;
RA Tiganis T., Bennett A.M., Ravichandran K.S., Tonks N.K.;
RT "Epidermal growth factor receptor and the adaptor protein p52Shc are
RT specific substrates of T-cell protein tyrosine phosphatase.";
RL Mol. Cell. Biol. 18:1622-1634(1998).
RN [23]
RP PHOSPHORYLATION AT TYR-349; TYR-350 AND TYR-427.
RX PubMed=9566877;
RA Schlaepfer D.D., Jones K.C., Hunter T.;
RT "Multiple Grb2-mediated integrin-stimulated signaling pathways to
RT ERK2/mitogen-activated protein kinase: summation of both c-Src- and
RT focal adhesion kinase-initiated tyrosine phosphorylation events.";
RL Mol. Cell. Biol. 18:2571-2585(1998).
RN [24]
RP INTERACTION WITH INPPL1.
RX PubMed=10194451;
RA Wisniewski D., Strife A., Swendeman S., Erdjument-Bromage H.,
RA Geromanos S., Kavanaugh W.M., Tempst P., Clarkson B.;
RT "A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-
RT phosphatase (SHIP2) is constitutively tyrosine phosphorylated and
RT associated with src homologous and collagen gene (SHC) in chronic
RT myelogenous leukemia progenitor cells.";
RL Blood 93:2707-2720(1999).
RN [25]
RP INTERACTION WITH ERBB4.
RX PubMed=10867024; DOI=10.1074/jbc.C901015199;
RA Sweeney C., Lai C., Riese D.J. II, Diamonti A.J., Cantley L.C.,
RA Carraway K.L. III;
RT "Ligand discrimination in signaling through an ErbB4 receptor
RT homodimer.";
RL J. Biol. Chem. 275:19803-19807(2000).
RN [26]
RP INTERACTION WITH INPPL1.
RX PubMed=11349134; DOI=10.1074/jbc.M103537200;
RA Pesesse X., Dewaste V., De Smedt F., Laffargue M., Giuriato S.,
RA Moreau C., Payrastre B., Erneux C.;
RT "The Src homology 2 domain containing inositol 5-phosphatase SHIP2 is
RT recruited to the epidermal growth factor (EGF) receptor and
RT dephosphorylates phosphatidylinositol 3,4,5-trisphosphate in EGF-
RT stimulated COS-7 cells.";
RL J. Biol. Chem. 276:28348-28355(2001).
RN [27]
RP INTERACTION WITH PTK2/FAK1, AND PHOSPHORYLATION.
RX PubMed=11980671;
RA Hecker T.P., Grammer J.R., Gillespie G.Y., Stewart J. Jr.,
RA Gladson C.L.;
RT "Focal adhesion kinase enhances signaling through the
RT Shc/extracellular signal-regulated kinase pathway in anaplastic
RT astrocytoma tumor biopsy samples.";
RL Cancer Res. 62:2699-2707(2002).
RN [28]
RP ALTERNATIVE PROMOTER USAGE.
RX PubMed=11948181; DOI=10.1074/jbc.M200280200;
RA Ventura A., Luzi L., Pacini S., Baldari C.T., Pelicci P.-G.;
RT "The p66Shc longevity gene is silenced through epigenetic
RT modifications of an alternative promoter.";
RL J. Biol. Chem. 277:22370-22376(2002).
RN [29]
RP INTERACTION WITH EPHB1 AND GRB2.
RX PubMed=12925710; DOI=10.1083/jcb.200302073;
RA Vindis C., Cerretti D.P., Daniel T.O., Huynh-Do U.;
RT "EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote
RT chemotaxis.";
RL J. Cell Biol. 162:661-671(2003).
RN [30]
RP INTERACTION WITH NTRK1.
RX PubMed=15488758; DOI=10.1016/j.ccr.2004.09.011;
RA Tacconelli A., Farina A.R., Cappabianca L., Desantis G., Tessitore A.,
RA Vetuschi A., Sferra R., Rucci N., Argenti B., Screpanti I., Gulino A.,
RA Mackay A.R.;
RT "TrkA alternative splicing: a regulated tumor-promoting switch in
RT human neuroblastoma.";
RL Cancer Cell 6:347-360(2004).
RN [31]
RP REVIEW ON ROLE IN KIT SIGNALING, AND PHOSPHORYLATION.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [32]
RP FUNCTION, PHOSPHORYLATION, AND INTERACTION WITH TEK.
RX PubMed=14665640; DOI=10.1074/jbc.M307456200;
RA Audero E., Cascone I., Maniero F., Napione L., Arese M.,
RA Lanfrancone L., Bussolino F.;
RT "Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and
RT regulates migration and sprouting but not survival of endothelial
RT cells.";
RL J. Biol. Chem. 279:13224-13233(2004).
RN [33]
RP INTERACTION WITH FLT4.
RX PubMed=15102829; DOI=10.1074/jbc.M314015200;
RA Wang J.F., Zhang X., Groopman J.E.;
RT "Activation of vascular endothelial growth factor receptor-3 and its
RT downstream signaling promote cell survival under oxidative stress.";
RL J. Biol. Chem. 279:27088-27097(2004).
RN [34]
RP INTERACTION WITH IRS4.
RX PubMed=15316024; DOI=10.1074/jbc.M404537200;
RA Hinsby A.M., Olsen J.V., Mann M.;
RT "Tyrosine phosphoproteomics of fibroblast growth factor signaling: a
RT role for insulin receptor substrate-4.";
RL J. Biol. Chem. 279:46438-46447(2004).
RN [35]
RP SUBCELLULAR LOCATION (ISOFORM P46SHC).
RX PubMed=14573619; DOI=10.1074/jbc.M307655200;
RA Ventura A., Maccarana M., Raker V.A., Pelicci P.-G.;
RT "A cryptic targeting signal induces isoform-specific localization of
RT p46Shc to mitochondria.";
RL J. Biol. Chem. 279:2299-2306(2004).
RN [36]
RP INTERACTION WITH LRP1.
RX PubMed=15272003; DOI=10.1074/jbc.M407592200;
RA Ranganathan S., Liu C.-X., Migliorini M.M., Von Arnim C.A.F.,
RA Peltan I.D., Mikhailenko I., Hyman B.T., Strickland D.K.;
RT "Serine and threonine phosphorylation of the low density lipoprotein
RT receptor-related protein by protein kinase Calpha regulates
RT endocytosis and association with adaptor molecules.";
RL J. Biol. Chem. 279:40536-40544(2004).
RN [37]
RP PHOSPHORYLATION AT SER-36.
RX PubMed=15837797; DOI=10.1083/jcb.200410041;
RA Smith W.W., Norton D.D., Gorospe M., Jiang H., Nemoto S.,
RA Holbrook N.J., Finkel T., Kusiak J.W.;
RT "Phosphorylation of p66Shc and forkhead proteins mediates Abeta
RT toxicity.";
RL J. Cell Biol. 169:331-339(2005).
RN [38]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [39]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-139, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [40]
RP INTERACTION WITH ALK, AND PHOSPHORYLATION.
RX PubMed=17274988; DOI=10.1016/j.febslet.2007.01.039;
RA Degoutin J., Vigny M., Gouzi J.Y.;
RT "ALK activation induces Shc and FRS2 recruitment: Signaling and
RT phenotypic outcomes in PC12 cells differentiation.";
RL FEBS Lett. 581:727-734(2007).
RN [41]
RP INTERACTION WITH GAB2.
RX PubMed=19172738; DOI=10.1038/emboj.2008.159;
RA Brummer T., Larance M., Herrera Abreu M.T., Lyons R.J., Timpson P.,
RA Emmerich C.H., Fleuren E.D.G., Lehrbach G.M., Schramek D.,
RA Guilhaus M., James D.E., Daly R.J.;
RT "Phosphorylation-dependent binding of 14-3-3 terminates signalling by
RT the Gab2 docking protein.";
RL EMBO J. 27:2305-2316(2008).
RN [42]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-139 AND TYR-427, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [43]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [44]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-427, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [45]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [46]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [47]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-139, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [48]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [49]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 482-583.
RX PubMed=7473762; DOI=10.1006/jmbi.1995.0601;
RA Mikol V., Baumann G., Zurini M.G.M., Hommel U.;
RT "Crystal structure of the SH2 domain from the adaptor protein SHC: a
RT model for peptide binding based on X-ray and NMR data.";
RL J. Mol. Biol. 254:86-95(1995).
RN [50]
RP STRUCTURE BY NMR OF 127-317.
RX PubMed=8524391; DOI=10.1038/378584a0;
RA Zhou M.-M., Ravichandran K.S., Olejniczak E.F., Petros A.M.,
RA Meadows R.P., Sattler M., Harlan J.E., Wade W.S., Burakoff S.J.,
RA Fesik S.W.;
RT "Structure and ligand recognition of the phosphotyrosine binding
RT domain of Shc.";
RL Nature 378:584-592(1995).
RN [51]
RP STRUCTURE BY NMR OF 480-583 IN COMPLEX WITH TYROSINE-PHOSPHORYLATED
RP CD3Z.
RX PubMed=7544002; DOI=10.1073/pnas.92.17.7784;
RA Zhou M.-M., Meadows R.P., Logan T.M., Yoon H.S., Wade W.S.,
RA Ravichandran K.S., Burakoff S.J., Fesik S.W.;
RT "Solution structure of the Shc SH2 domain complexed with a tyrosine-
RT phosphorylated peptide from the T-cell receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7784-7788(1995).
CC -!- FUNCTION: Signaling adapter that couples activated growth factor
CC receptors to signaling pathways. Participates in a signaling
CC cascade initiated by activated KIT and KITLG/SCF. Isoform p46Shc
CC and isoform p52Shc, once phosphorylated, couple activated receptor
CC tyrosine kinases to Ras via the recruitment of the GRB2/SOS
CC complex and are implicated in the cytoplasmic propagation of
CC mitogenic signals. Isoform p46Shc and isoform p52Shc may thus
CC function as initiators of the Ras signaling cascade in various
CC non-neuronal systems. Isoform p66Shc does not mediate Ras
CC activation, but is involved in signal transduction pathways that
CC regulate the cellular response to oxidative stress and life span.
CC Isoform p66Shc acts as a downstream target of the tumor suppressor
CC p53 and is indispensable for the ability of stress-activated p53
CC to induce elevation of intracellular oxidants, cytochrome c
CC release and apoptosis. The expression of isoform p66Shc has been
CC correlated with life span (By similarity). Participates in
CC signaling downstream of the angiopoietin receptor TEK/TIE2, and
CC plays a role in the regulation of endothelial cell migration and
CC sprouting angiogenesis.
CC -!- SUBUNIT: Interacts with the NPXY motif of tyrosine-phosphorylated
CC IGF1R and INSR in vitro via the PID domain. Once activated, binds
CC to GRB2. Interacts with tyrosine-phosphorylated CD3T and DDR2.
CC Interacts with the N-terminal region of APS. Interacts with
CC phosphorylated LRP1 and IRS4. Interacts with INPP5D/SHIP1 and
CC INPPL1/SHIP2. Interacts with TRIM31. Interacts with PTPN6/SHP
CC (tyrosine phosphorylated). Identified in a complex containing
CC FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTT (By
CC similarity). Interacts with ALK, GAB2, GRB7 and KIT. Interacts
CC with FLT4 (tyrosine-phosphorylated). Interacts with EPHB1 and
CC GRB2; activates the MAPK/ERK cascade to regulate cell migration.
CC Interacts with PDGFRB (tyrosine-phosphorylated). Interacts with
CC ERBB4. Interacts with TEK/TIE2 (tyrosine-phosphorylated).
CC Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a
CC phosphotyrosine-dependent manner. Interacts with PTK2/FAK1.
CC -!- INTERACTION:
CC P05067:APP; NbExp=5; IntAct=EBI-78835, EBI-77613;
CC P46108:CRK; NbExp=3; IntAct=EBI-78835, EBI-886;
CC P00533:EGFR; NbExp=25; IntAct=EBI-78835, EBI-297353;
CC P04626:ERBB2; NbExp=9; IntAct=EBI-78835, EBI-641062;
CC P21860:ERBB3; NbExp=5; IntAct=EBI-78835, EBI-720706;
CC Q15303:ERBB4; NbExp=2; IntAct=EBI-78835, EBI-80371;
CC P03372-4:ESR1; NbExp=2; IntAct=EBI-78835, EBI-4309277;
CC P62993:GRB2; NbExp=22; IntAct=EBI-78835, EBI-401755;
CC P08069:IGF1R; NbExp=2; IntAct=EBI-1000553, EBI-475981;
CC P06213:INSR; NbExp=2; IntAct=EBI-78835, EBI-475899;
CC Q62120:Jak2 (xeno); NbExp=2; IntAct=EBI-78835, EBI-646604;
CC P27986:PIK3R1; NbExp=3; IntAct=EBI-78835, EBI-79464;
CC Q07889:SOS1; NbExp=2; IntAct=EBI-78835, EBI-297487;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- SUBCELLULAR LOCATION: Isoform p46Shc: Mitochondrion matrix.
CC Note=Localized to the mitochondria matrix. Targeting of isoform
CC p46Shc to mitochondria is mediated by its first 32 amino acids,
CC which behave as a bona fide mitochondrial targeting sequence.
CC Isoform p52Shc and isoform p66Shc, that contain the same sequence
CC but more internally located, display a different subcellular
CC localization.
CC -!- SUBCELLULAR LOCATION: Isoform p66Shc: Mitochondrion (By
CC similarity). Note=In case of oxidative conditions, phosphorylation
CC at 'Ser-36' of isoform p66Shc, leads to mitochondrial accumulation
CC (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=6;
CC Name=p66Shc;
CC IsoId=P29353-1; Sequence=Displayed;
CC Note=Regulated by epigenetic modifications of its promoter
CC region;
CC Name=p52Shc;
CC IsoId=P29353-2; Sequence=VSP_016108;
CC Name=p46Shc;
CC IsoId=P29353-3; Sequence=VSP_016107;
CC Name=5;
CC IsoId=P29353-5; Sequence=VSP_040090, VSP_040091;
CC Note=Produced by alternative splicing;
CC Name=6;
CC IsoId=P29353-6; Sequence=VSP_040092;
CC Note=Produced by alternative splicing;
CC Name=7;
CC IsoId=P29353-7; Sequence=VSP_016108, VSP_040092;
CC Note=Produced by alternative splicing;
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed in neural stem
CC cells but absent in mature neurons.
CC -!- DOMAIN: In response to a variety of growth factors, isoform p46Shc
CC and isoform p52Shc bind to phosphorylated Trk receptors through
CC their phosphotyrosine binding (PID) and/or SH2 domains. The PID
CC and SH2 domains bind to specific phosphorylated tyrosine residues
CC in the Asn-Pro-Xaa-Tyr(P) motif of the Trk receptors. Isoform
CC p46Shc and isoform p52Shc are in turn phosphorylated on three
CC tyrosine residues within the extended proline-rich domain. These
CC phosphotyrosines act as docking site for GRB2 and thereby are
CC involved in Ras activation (By similarity).
CC -!- PTM: Phosphorylated by activated epidermal growth factor receptor.
CC Phosphorylated in response to FLT4 and KIT signaling. Isoform
CC p46Shc and isoform p52Shc are phosphorylated on tyrosine residues
CC of the Pro-rich domain. Isoform p66Shc is phosphorylated on Ser-36
CC by PRKCB upon treatment with insulin, hydrogen peroxide or
CC irradiation with ultraviolet light (By similarity). Tyrosine
CC phosphorylated in response to FLT3 signaling (By similarity).
CC Tyrosine phosphorylated by activated PTK2B/PYK2 (By similarity).
CC Tyrosine phosphorylated by ligand-activated ALK. Tyrosine
CC phosphorylated by ligand-activated PDGFRB. Tyrosine phosphorylated
CC by TEK/TIE2. May be tyrosine phosphorylated by activated
CC PTK2/FAK1; tyrosine phosphorylation was seen in an astrocytoma
CC biopsy, where PTK2/FAK1 kinase activity is high, but not in normal
CC brain tissue. Isoform p52Shc dephosphorylation by PTPN2 may
CC regulate interaction with GRB2.
CC -!- SIMILARITY: Contains 1 PID domain.
CC -!- SIMILARITY: Contains 1 SH2 domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAI13254.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SHC1ID42287ch1q21.html";
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DR EMBL; X68148; CAA48251.1; -; mRNA.
DR EMBL; U73377; AAB49972.1; -; mRNA.
DR EMBL; Y09847; CAA70977.1; -; Genomic_DNA.
DR EMBL; AK292143; BAF84832.1; -; mRNA.
DR EMBL; AK315842; BAF98733.1; -; mRNA.
DR EMBL; AB451255; BAG70069.1; -; mRNA.
DR EMBL; AB451379; BAG70193.1; -; mRNA.
DR EMBL; AL451085; CAI13248.1; -; Genomic_DNA.
DR EMBL; AL451085; CAI13249.1; -; Genomic_DNA.
DR EMBL; AL451085; CAI13250.1; -; Genomic_DNA.
DR EMBL; AL451085; CAI13251.1; -; Genomic_DNA.
DR EMBL; AL451085; CAI13254.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471121; EAW53168.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53169.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53170.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53171.1; -; Genomic_DNA.
DR EMBL; BC014158; AAH14158.1; -; mRNA.
DR EMBL; BC033925; AAH33925.1; -; mRNA.
DR PIR; S25776; S25776.
DR RefSeq; NP_001123512.1; NM_001130040.1.
DR RefSeq; NP_001123513.1; NM_001130041.1.
DR RefSeq; NP_001189788.1; NM_001202859.1.
DR RefSeq; NP_003020.2; NM_003029.4.
DR RefSeq; NP_892113.4; NM_183001.4.
DR UniGene; Hs.433795; -.
DR PDB; 1MIL; X-ray; 2.70 A; A=482-583.
DR PDB; 1N3H; NMR; -; A=111-317.
DR PDB; 1OY2; NMR; -; A=111-317.
DR PDB; 1QG1; NMR; -; I=423-435.
DR PDB; 1SHC; NMR; -; A=127-317.
DR PDB; 1TCE; NMR; -; A=480-583.
DR PDB; 1WCP; Model; -; A=127-583.
DR PDB; 2L1C; NMR; -; A=127-317.
DR PDBsum; 1MIL; -.
DR PDBsum; 1N3H; -.
DR PDBsum; 1OY2; -.
DR PDBsum; 1QG1; -.
DR PDBsum; 1SHC; -.
DR PDBsum; 1TCE; -.
DR PDBsum; 1WCP; -.
DR PDBsum; 2L1C; -.
DR DisProt; DP00154; -.
DR ProteinModelPortal; P29353; -.
DR SMR; P29353; 111-317, 482-583.
DR DIP; DIP-699N; -.
DR IntAct; P29353; 78.
DR MINT; MINT-123530; -.
DR BindingDB; P29353; -.
DR ChEMBL; CHEMBL5626; -.
DR PhosphoSite; P29353; -.
DR DMDM; 182676455; -.
DR PaxDb; P29353; -.
DR PRIDE; P29353; -.
DR DNASU; 6464; -.
DR Ensembl; ENST00000368445; ENSP00000357430; ENSG00000160691.
DR Ensembl; ENST00000368450; ENSP00000357435; ENSG00000160691.
DR Ensembl; ENST00000368453; ENSP00000357438; ENSG00000160691.
DR Ensembl; ENST00000448116; ENSP00000401303; ENSG00000160691.
DR GeneID; 6464; -.
DR KEGG; hsa:6464; -.
DR UCSC; uc001ffv.3; human.
DR CTD; 6464; -.
DR GeneCards; GC01M154934; -.
DR HGNC; HGNC:10840; SHC1.
DR HPA; CAB005374; -.
DR HPA; CAB016305; -.
DR HPA; HPA001844; -.
DR MIM; 600560; gene.
DR neXtProt; NX_P29353; -.
DR PharmGKB; PA35746; -.
DR eggNOG; NOG315087; -.
DR HOVERGEN; HBG050121; -.
DR KO; K06279; -.
DR OMA; HMDNHLP; -.
DR OrthoDB; EOG7MD4QK; -.
DR PhylomeDB; P29353; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P29353; -.
DR ChiTaRS; SHC1; human.
DR EvolutionaryTrace; P29353; -.
DR GeneWiki; SHC1; -.
DR GenomeRNAi; 6464; -.
DR NextBio; 25115; -.
DR PRO; PR:P29353; -.
DR ArrayExpress; P29353; -.
DR Bgee; P29353; -.
DR Genevestigator; P29353; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0070435; C:Shc-EGFR complex; ISS:BHF-UCL.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; ISS:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; TAS:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; TAS:Reactome.
DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; TAS:UniProtKB.
DR GO; GO:0031532; P:actin cytoskeleton reorganization; IEA:Ensembl.
DR GO; GO:0000187; P:activation of MAPK activity; IDA:UniProtKB.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0016337; P:cell-cell adhesion; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0000165; P:MAPK cascade; IDA:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0008284; P:positive regulation of cell proliferation; NAS:UniProtKB.
DR GO; GO:0045740; P:positive regulation of DNA replication; ISS:BHF-UCL.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
DR GO; GO:0007176; P:regulation of epidermal growth factor-activated receptor activity; TAS:ProtInc.
DR GO; GO:0040008; P:regulation of growth; IEA:UniProtKB-KW.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR006019; PID_Shc-like.
DR InterPro; IPR006020; PTB/PI_dom.
DR InterPro; IPR000980; SH2.
DR Pfam; PF00640; PID; 1.
DR Pfam; PF00017; SH2; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR PRINTS; PR00629; SHCPIDOMAIN.
DR SMART; SM00462; PTB; 1.
DR SMART; SM00252; SH2; 1.
DR PROSITE; PS01179; PID; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative promoter usage;
KW Alternative splicing; Angiogenesis; Complete proteome; Cytoplasm;
KW Growth regulation; Mitochondrion; Phosphoprotein; Polymorphism;
KW Reference proteome; SH2 domain.
FT CHAIN 1 583 SHC-transforming protein 1.
FT /FTId=PRO_0000097731.
FT DOMAIN 156 339 PID.
FT DOMAIN 488 579 SH2.
FT REGION 340 487 CH1.
FT COMPBIAS 411 474 Pro-rich.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 36 36 Phosphoserine.
FT MOD_RES 139 139 Phosphoserine.
FT MOD_RES 349 349 Phosphotyrosine.
FT MOD_RES 350 350 Phosphotyrosine.
FT MOD_RES 426 426 Phosphoserine.
FT MOD_RES 427 427 Phosphotyrosine.
FT VAR_SEQ 1 214 Missing (in isoform 5).
FT /FTId=VSP_040090.
FT VAR_SEQ 1 155 Missing (in isoform p46Shc).
FT /FTId=VSP_016107.
FT VAR_SEQ 1 110 Missing (in isoform p52Shc and isoform
FT 7).
FT /FTId=VSP_016108.
FT VAR_SEQ 215 221 PLSSILG -> MSLCHRW (in isoform 5).
FT /FTId=VSP_040091.
FT VAR_SEQ 417 417 P -> PA (in isoform 7 and isoform 6).
FT /FTId=VSP_040092.
FT VARIANT 205 205 A -> V (in dbSNP:rs8191981).
FT /FTId=VAR_042428.
FT VARIANT 410 410 M -> V (in dbSNP:rs8191979).
FT /FTId=VAR_051353.
FT MUTAGEN 349 349 Y->F: Alters interaction with GRB2;
FT isoform p52Shc (in vitro).
FT MUTAGEN 427 427 Y->F: No effect on interaction with GRB2;
FT isoform p52Shc (in vitro).
FT CONFLICT 2 2 D -> N (in Ref. 3; CAA70977).
FT CONFLICT 21 21 L -> M (in Ref. 3; CAA70977).
FT CONFLICT 38 38 S -> P (in Ref. 3; CAA70977).
FT CONFLICT 95 95 V -> D (in Ref. 2; AAB49972).
FT CONFLICT 101 101 D -> E (in Ref. 2; AAB49972).
FT CONFLICT 430 430 V -> A (in Ref. 5; BAG70069/BAG70193).
FT STRAND 113 115
FT STRAND 142 145
FT STRAND 148 150
FT HELIX 152 156
FT STRAND 160 167
FT STRAND 169 171
FT TURN 176 178
FT STRAND 179 181
FT HELIX 184 198
FT HELIX 200 202
FT STRAND 206 208
FT STRAND 215 218
FT STRAND 222 224
FT STRAND 229 237
FT STRAND 240 245
FT TURN 246 249
FT STRAND 251 255
FT STRAND 256 259
FT STRAND 261 263
FT STRAND 265 267
FT STRAND 270 272
FT STRAND 274 278
FT STRAND 281 283
FT STRAND 286 291
FT STRAND 293 295
FT HELIX 297 302
FT STRAND 311 314
FT TURN 483 485
FT STRAND 487 489
FT HELIX 495 499
FT STRAND 507 512
FT STRAND 514 516
FT STRAND 518 526
FT STRAND 529 536
FT STRAND 540 543
FT STRAND 548 551
FT HELIX 552 562
FT STRAND 566 568
FT STRAND 571 573
SQ SEQUENCE 583 AA; 62822 MW; 7EFA5CB185A548D1 CRC64;
MDLLPPKPKY NPLRNESLSS LEEGASGSTP PEELPSPSAS SLGPILPPLP GDDSPTTLCS
FFPRMSNLRL ANPAGGRPGS KGEPGRAADD GEGIVGAAMP DSGPLPLLQD MNKLSGGGGR
RTRVEGGQLG GEEWTRHGSF VNKPTRGWLH PNDKVMGPGV SYLVRYMGCV EVLQSMRALD
FNTRTQVTRE AISLVCEAVP GAKGATRRRK PCSRPLSSIL GRSNLKFAGM PITLTVSTSS
LNLMAADCKQ IIANHHMQSI SFASGGDPDT AEYVAYVAKD PVNQRACHIL ECPEGLAQDV
ISTIGQAFEL RFKQYLRNPP KLVTPHDRMA GFDGSAWDEE EEEPPDHQYY NDFPGKEPPL
GGVVDMRLRE GAAPGAARPT APNAQTPSHL GATLPVGQPV GGDPEVRKQM PPPPPCPGRE
LFDDPSYVNV QNLDKARQAV GGAGPPNPAI NGSAPRDLFD MKPFEDALRV PPPPQSVSMA
EQLRGEPWFH GKLSRREAEA LLQLNGDFLV RESTTTPGQY VLTGLQSGQP KHLLLVDPEG
VVRTKDHRFE SVSHLISYHM DNHLPIISAG SELCLQQPVE RKL
//
MIM
600560
*RECORD*
*FIELD* NO
600560
*FIELD* TI
*600560 SHC TRANSFORMING PROTEIN; SHC1
;;SHCA
p46, INCLUDED;;
p52, INCLUDED;;
p66, INCLUDED
read more*FIELD* TX
CLONING
The SHC gene encodes a signaling and transforming protein containing Src
homology 2 and 3 (SH2 and SH3) domains. The SHC gene encodes 2 widely
expressed overlapping proteins of 46 and 52 kD, both containing a
C-terminal SH2 domain (Pelicci et al., 1992). Adjacent to the SH2 region
is a glycine- and proline-rich region. The 2 proteins differ in their N
terminals. SHC proteins are involved in mitogenic signal transduction
and act by coupling growth factor receptors to the RAS (see 190020)
signaling pathway. The protein encoded by the SHC1 gene is thought to
act as an adaptor in many signal transduction pathways, for example,
facilitating the activation of RAS proteins in response to a variety of
factors (Yulug et al., 1995). SHC proteins are rapidly associated with
and phosphorylated by growth factor receptors with intrinsic tyrosine
kinase activity (McGlade et al., 1992).
In addition to p52 and p46, a 66-kD protein is also encoded by the SHC
locus. p66 shares the SH2 domain, a collagen homology domain, and a
phosphotyrosine-binding domain. However, p66 contains a unique
N-terminal region. Like p52 and p46, p66 becomes tyrosine phosphorylated
upon activation of growth factor receptors and forms stable complexes
with GRB2 (108355), an adaptor protein for the RAS exchange factor SOS
(see 182530). However, it does not affect mitogen-activated protein
kinase activity (MAPK) and inhibits c-fos (164810) promoter activation,
indicating that p66 may not be involved in RAS activation (Migliaccio et
al., 1999).
GENE FUNCTION
Nemoto and Finkel (2002) observed that exposure to intracellular
reactive oxygen species (ROS) induced an increase in phosphorylated
Fkhrl1 (602681) and a shift from a nuclear to a cytosolic localization.
They found that serum starvation, a stimulus that increases oxidative
stress, resulted in lower levels of hydrogen peroxide in Shc1 -/- cells
or in cells expressing a ser36-to-ala (S36A) Shc1 mutant compared with
wildtype cells. Serum starvation also increased Fkhrl1-dependent
transcriptional activity, which was further augmented in the
Shc1-deficient cells. Increased ROS exposure failed to induce increased
Fkhrl1 phosphorylation in the mutant cells. Promoter analysis of the
catalase (CAT; 115500) gene established the presence of FKHRL1-binding
sequences. Reporter assays showed FKHRL1 transactivates CAT, suggesting
a capacity to augment antioxidant scavenging. Nemoto and Finkel (2002)
concluded that there is an important functional relationship between
forkhead proteins (e.g., FKHRL1), SHC1, and intracellular oxidants, all
of which are thought to be involved in the aging process in worms and
mammals.
The 66-kD isoform of the growth factor adaptor SHC, p66(SHC), translates
oxidative damage into cell death by acting as a reactive oxygen species
producer within mitochondria. Pinton et al. (2007) demonstrated that
protein kinase C-beta (see 176970), activated by oxidative conditions in
the cell, induces phosphorylation of p66(SHC) and triggers mitochondrial
accumulation of the protein after it is recognized by the prolyl
isomerase PIN1 (601052). Once imported, p66(Shc) causes alterations of
mitochondrial calcium ion responses and 3-dimensional structure, thus
causing apoptosis. Pinton et al. (2007) concluded that their data
identified a signaling route that activates an apoptotic inducer
shortening the life span.
Using quantitative mass spectrometry, Zheng et al. (2013) showed that
mammalian Shc1 responds to epidermal growth factor (EGF; 131530)
stimulation through multiple waves of distinct phosphorylation events
and protein interactions. After stimulation, Shc1 rapidly binds a group
of proteins that activate promitogenic or survival pathways dependent on
recruitment of the Grb2 (108355) adaptor to Shc1 phosphotyrosine sites.
Akt (164730)-mediated feedback phosphorylation of Shc1 ser29 then
recruits the Ptpn12 (600079) tyrosine phosphatase. This is followed by
interaction with a subnetwork of proteins involved in cytoskeletal
reorganization, trafficking, and signal termination that binds Shc1 with
delayed kinetics, largely through the SgK269 pseudokinase/adaptor
protein (614248). Ptpn12 acts as a switch to convert Shc1 from
phosphotyrosine/Grb2-based signaling to the SgK269-mediated pathways
that regulate cell invasion and morphogenesis. Zheng et al. (2013)
concluded that the Shc1 scaffold therefore directs the temporal flow of
signaling information after EGF stimulation.
MAPPING
By Southern analysis of somatic cell hybrids followed by both isotopic
and fluorescence in situ hybridization, Huebner et al. (1994) assigned
the SHC1 gene to 1q21. Yulug et al. (1995) used fluorescence in situ
hybridization to map the SHC1 gene to 1q21. By the same method, an
SHC-related sequence (SHCL1; 600739) was mapped to 17q21-q22. By FISH
analysis and direct sequencing of vectorette library PCR products, Harun
et al. (1997) identified SHC1P1, a 3.2-kb processed pseudogene, in
Xq12-q13.1. SHC1P1 is 85% identical to mouse Shc p66.
MOLECULAR GENETICS
Almind et al. (1999) sought to determine if genetic variability of the
SHC1 isoforms causes a decrease in cell growth and cell differentiation
that could be manifested by a decrease in birth weight and length,
impaired acute insulin secretion after intravenous glucose, insulin
resistance, and eventually a higher prevalence of type II diabetes
(125853). By SSCP-heteroduplex analysis of 70 patients with diabetes
mellitus, and subsequent nucleotide sequencing of an identified SSCP
variant, the authors discovered a met300-to-val (M300V) substitution in
the 52-kD isoform. The amino acid variant was predicted to be present in
all 3 isoforms of SHC1. In a genotype-phenotype study of 360 young,
healthy subjects, the allelic frequency of the M300V allele was 4.2%. In
this cohort, no significant differences could be shown between carriers
and noncarriers in birth weight and length, the acute insulin response
to intravenous glucose, or the insulin sensitivity index, as estimated
from an intravenous glucose tolerance test. In an association study of
313 type II diabetic patients and 226 matched glucose-tolerant subjects,
there was no significant difference in allelic frequency of the SHC1
variant (5.1% in diabetic patients vs 3.1% in control subjects; P of
0.11). Almind et al. (1999) concluded that by itself, the M300V allele
of SHC1 has no major impact on birth weight and length, insulin
sensitivity index, acute glucose-induced insulin secretion, or
prevalence of random type II diabetes mellitus.
ANIMAL MODEL
Migliaccio et al. (1999) found that targeted disruption of p66
expression in mice induced stress resistance and prolonged life span.
They demonstrated that p66 is serine phosphorylated upon treatment with
hydrogen peroxide or irradiation with UV light, and that ablation of p66
enhances cellular resistance to apoptosis induced by hydrogen peroxide
or ultraviolet light. A serine phosphorylation-defective mutant of p66
could not restore the normal stress response in p66 -/- cells. The p53
(191170) and p21 (116899) stress response was impaired in p66 -/- cells.
p66 -/- mice have increased resistance to paraquat and a 30% increase in
life span. Migliaccio et al. (1999) proposed that p66 is part of a
signal transduction pathway that regulates stress apoptotic responses
and life span in mammals.
Using transgenic Cre/loxP-mediated inducible expression of a
phosphorylation-defective Shc mutant and, alternatively, conditional
deletion of the Shc gene in mouse thymocytes, Zhang et al. (2002) showed
that both expression and tyrosine phosphorylation of Shc have essential
roles in thymic T-cell development. They also provided a concise summary
of SHC biology.
*FIELD* RF
1. Almind, K.; Ahlgren, M. G.; Hansen, T.; Urhammer, S. A.; Clausen,
J. O.; Pedersen, O.: Discovery of a Met300Val variant in Shc and
studies of its relationship to birth weight and length, impaired insulin
secretion, insulin resistance, and type 2 diabetes mellitus. J. Clin.
Endocr. Metab. 84: 2241-2244, 1999.
2. Harun, R. B.; Smith, K. K.; Leek, J. P.; Markham, A. F.; Norris,
A.; Morrison, J. F. J.: Characterization of human SHC p66 cDNA and
its processed pseudogene mapping to Xq12-q13.1. Genomics 42: 349-352,
1997.
3. Huebner, K.; Kastury, K.; Druck, T.; Salcini, A. E.; Lanfrancone,
L.; Pelicci, G.; Lowenstein, E.; Li, W.; Park, S.-H.; Cannizzaro,
L.; Pelicci, P. G.; Schlessinger, J.: Chromosome locations of genes
encoding human signal transduction adapter proteins, Nck (NCK), Shc
(SHC1), and Grb2 (GRB2). Genomics 22: 281-287, 1994.
4. McGlade, J.; Cheng, A.; Pelicci, G.; Pelicci, P. G.; Pawson, T.
: Shc proteins are phosphorylated and regulated by the v-src and v-fps
protein-tyrosine-kinases. Proc. Nat. Acad. Sci. 89: 8869-8873, 1992.
5. Migliaccio, E.; Giorgio, M.; Mele, S.; Pelicci, G.; Reboldi, P.;
Pandolfi, P. P.; Lanfrancone, L.; Pelicci, P. G.: The p66(shc) adaptor
protein controls oxidative stress response and life span in mammals. Nature 402:
309-313, 1999.
6. Nemoto, S.; Finkel, T.: Redox regulation of forkhead proteins
through a p66shc-dependent signaling pathway. Science 295: 2450-2452,
2002.
7. Pelicci, G.; Lanfrancone, L.; Grignani, F.; McGlade, J.; Cavallo,
F.; Forni, G.; Nicoletti, I.; Grignani, F.; Pawson, T.; Pelicci, P.
G.: A novel transforming protein (SHC) with an SH2 domain is implicated
in mitogenic signal transduction. Cell 70: 93-104, 1992.
8. Pinton, P.; Rimessi, A.; Marchi, S.; Orsini, F.; Migliaccio, E.;
Giorgio, M.; Contursi, C.; Minucci, S.; Mantovani, F.; Wieckowski,
M. R.; Del Sal, G.; Pelicci, P. G.; Rizzuto, R.: Protein kinase C-beta
and prolyl isomerase 1 regulate mitochondrial effects of the life-span
determinant p66(Shc) Science 315: 659-663, 2007.
9. Yulug, I. G.; Egan, S. E.; See, C. G.; Fisher, E. M. C.: A human
SHC-related sequence maps to chromosome 17, the SHC gene maps to chromosome
1. Hum. Genet. 96: 245-248, 1995.
10. Zhang, L.; Camerini, V.; Bender, T. P.; Ravichandran, K. S.:
A nonredundant role for the adapter protein Shc in thymic T cell development. Nature
Immun. 3: 749-755, 2002.
11. Zheng, Y.; Zhang, C.; Croucher, D. R.; Soliman, M. A.; St-Denis,
N.; Pasculescu, A.; Taylor, L.; Tate, S. A.; Hardy, W. R.; Colwill,
K.; Dai, A. Y.; Bagshaw, R.; Dennis, J. W.; Gingras, A.-C.; Daly,
R. J.; Pawson, T.: Temporal regulation of EGF signalling networks
by the scaffold protein Shc1. Nature 499: 166-171, 2013.
*FIELD* CN
Ada Hamosh - updated: 8/29/2013
Ada Hamosh - updated: 4/25/2007
Paul J. Converse - updated: 7/11/2002
Paul J. Converse - updated: 4/3/2002
Paul J. Converse - updated: 7/14/2000
John A. Phillips, III - updated: 3/7/2000
Ada Hamosh - updated: 11/22/1999
*FIELD* CD
Victor A. McKusick: 5/24/1995
*FIELD* ED
alopez: 08/29/2013
alopez: 8/29/2013
wwang: 4/20/2009
alopez: 5/1/2007
terry: 4/25/2007
carol: 4/27/2004
alopez: 8/6/2002
mgross: 7/11/2002
mgross: 4/3/2002
mgross: 7/14/2000
mgross: 3/7/2000
mgross: 12/2/1999
alopez: 11/22/1999
terry: 11/22/1999
terry: 11/17/1995
mark: 10/16/1995
mark: 5/24/1995
*RECORD*
*FIELD* NO
600560
*FIELD* TI
*600560 SHC TRANSFORMING PROTEIN; SHC1
;;SHCA
p46, INCLUDED;;
p52, INCLUDED;;
p66, INCLUDED
read more*FIELD* TX
CLONING
The SHC gene encodes a signaling and transforming protein containing Src
homology 2 and 3 (SH2 and SH3) domains. The SHC gene encodes 2 widely
expressed overlapping proteins of 46 and 52 kD, both containing a
C-terminal SH2 domain (Pelicci et al., 1992). Adjacent to the SH2 region
is a glycine- and proline-rich region. The 2 proteins differ in their N
terminals. SHC proteins are involved in mitogenic signal transduction
and act by coupling growth factor receptors to the RAS (see 190020)
signaling pathway. The protein encoded by the SHC1 gene is thought to
act as an adaptor in many signal transduction pathways, for example,
facilitating the activation of RAS proteins in response to a variety of
factors (Yulug et al., 1995). SHC proteins are rapidly associated with
and phosphorylated by growth factor receptors with intrinsic tyrosine
kinase activity (McGlade et al., 1992).
In addition to p52 and p46, a 66-kD protein is also encoded by the SHC
locus. p66 shares the SH2 domain, a collagen homology domain, and a
phosphotyrosine-binding domain. However, p66 contains a unique
N-terminal region. Like p52 and p46, p66 becomes tyrosine phosphorylated
upon activation of growth factor receptors and forms stable complexes
with GRB2 (108355), an adaptor protein for the RAS exchange factor SOS
(see 182530). However, it does not affect mitogen-activated protein
kinase activity (MAPK) and inhibits c-fos (164810) promoter activation,
indicating that p66 may not be involved in RAS activation (Migliaccio et
al., 1999).
GENE FUNCTION
Nemoto and Finkel (2002) observed that exposure to intracellular
reactive oxygen species (ROS) induced an increase in phosphorylated
Fkhrl1 (602681) and a shift from a nuclear to a cytosolic localization.
They found that serum starvation, a stimulus that increases oxidative
stress, resulted in lower levels of hydrogen peroxide in Shc1 -/- cells
or in cells expressing a ser36-to-ala (S36A) Shc1 mutant compared with
wildtype cells. Serum starvation also increased Fkhrl1-dependent
transcriptional activity, which was further augmented in the
Shc1-deficient cells. Increased ROS exposure failed to induce increased
Fkhrl1 phosphorylation in the mutant cells. Promoter analysis of the
catalase (CAT; 115500) gene established the presence of FKHRL1-binding
sequences. Reporter assays showed FKHRL1 transactivates CAT, suggesting
a capacity to augment antioxidant scavenging. Nemoto and Finkel (2002)
concluded that there is an important functional relationship between
forkhead proteins (e.g., FKHRL1), SHC1, and intracellular oxidants, all
of which are thought to be involved in the aging process in worms and
mammals.
The 66-kD isoform of the growth factor adaptor SHC, p66(SHC), translates
oxidative damage into cell death by acting as a reactive oxygen species
producer within mitochondria. Pinton et al. (2007) demonstrated that
protein kinase C-beta (see 176970), activated by oxidative conditions in
the cell, induces phosphorylation of p66(SHC) and triggers mitochondrial
accumulation of the protein after it is recognized by the prolyl
isomerase PIN1 (601052). Once imported, p66(Shc) causes alterations of
mitochondrial calcium ion responses and 3-dimensional structure, thus
causing apoptosis. Pinton et al. (2007) concluded that their data
identified a signaling route that activates an apoptotic inducer
shortening the life span.
Using quantitative mass spectrometry, Zheng et al. (2013) showed that
mammalian Shc1 responds to epidermal growth factor (EGF; 131530)
stimulation through multiple waves of distinct phosphorylation events
and protein interactions. After stimulation, Shc1 rapidly binds a group
of proteins that activate promitogenic or survival pathways dependent on
recruitment of the Grb2 (108355) adaptor to Shc1 phosphotyrosine sites.
Akt (164730)-mediated feedback phosphorylation of Shc1 ser29 then
recruits the Ptpn12 (600079) tyrosine phosphatase. This is followed by
interaction with a subnetwork of proteins involved in cytoskeletal
reorganization, trafficking, and signal termination that binds Shc1 with
delayed kinetics, largely through the SgK269 pseudokinase/adaptor
protein (614248). Ptpn12 acts as a switch to convert Shc1 from
phosphotyrosine/Grb2-based signaling to the SgK269-mediated pathways
that regulate cell invasion and morphogenesis. Zheng et al. (2013)
concluded that the Shc1 scaffold therefore directs the temporal flow of
signaling information after EGF stimulation.
MAPPING
By Southern analysis of somatic cell hybrids followed by both isotopic
and fluorescence in situ hybridization, Huebner et al. (1994) assigned
the SHC1 gene to 1q21. Yulug et al. (1995) used fluorescence in situ
hybridization to map the SHC1 gene to 1q21. By the same method, an
SHC-related sequence (SHCL1; 600739) was mapped to 17q21-q22. By FISH
analysis and direct sequencing of vectorette library PCR products, Harun
et al. (1997) identified SHC1P1, a 3.2-kb processed pseudogene, in
Xq12-q13.1. SHC1P1 is 85% identical to mouse Shc p66.
MOLECULAR GENETICS
Almind et al. (1999) sought to determine if genetic variability of the
SHC1 isoforms causes a decrease in cell growth and cell differentiation
that could be manifested by a decrease in birth weight and length,
impaired acute insulin secretion after intravenous glucose, insulin
resistance, and eventually a higher prevalence of type II diabetes
(125853). By SSCP-heteroduplex analysis of 70 patients with diabetes
mellitus, and subsequent nucleotide sequencing of an identified SSCP
variant, the authors discovered a met300-to-val (M300V) substitution in
the 52-kD isoform. The amino acid variant was predicted to be present in
all 3 isoforms of SHC1. In a genotype-phenotype study of 360 young,
healthy subjects, the allelic frequency of the M300V allele was 4.2%. In
this cohort, no significant differences could be shown between carriers
and noncarriers in birth weight and length, the acute insulin response
to intravenous glucose, or the insulin sensitivity index, as estimated
from an intravenous glucose tolerance test. In an association study of
313 type II diabetic patients and 226 matched glucose-tolerant subjects,
there was no significant difference in allelic frequency of the SHC1
variant (5.1% in diabetic patients vs 3.1% in control subjects; P of
0.11). Almind et al. (1999) concluded that by itself, the M300V allele
of SHC1 has no major impact on birth weight and length, insulin
sensitivity index, acute glucose-induced insulin secretion, or
prevalence of random type II diabetes mellitus.
ANIMAL MODEL
Migliaccio et al. (1999) found that targeted disruption of p66
expression in mice induced stress resistance and prolonged life span.
They demonstrated that p66 is serine phosphorylated upon treatment with
hydrogen peroxide or irradiation with UV light, and that ablation of p66
enhances cellular resistance to apoptosis induced by hydrogen peroxide
or ultraviolet light. A serine phosphorylation-defective mutant of p66
could not restore the normal stress response in p66 -/- cells. The p53
(191170) and p21 (116899) stress response was impaired in p66 -/- cells.
p66 -/- mice have increased resistance to paraquat and a 30% increase in
life span. Migliaccio et al. (1999) proposed that p66 is part of a
signal transduction pathway that regulates stress apoptotic responses
and life span in mammals.
Using transgenic Cre/loxP-mediated inducible expression of a
phosphorylation-defective Shc mutant and, alternatively, conditional
deletion of the Shc gene in mouse thymocytes, Zhang et al. (2002) showed
that both expression and tyrosine phosphorylation of Shc have essential
roles in thymic T-cell development. They also provided a concise summary
of SHC biology.
*FIELD* RF
1. Almind, K.; Ahlgren, M. G.; Hansen, T.; Urhammer, S. A.; Clausen,
J. O.; Pedersen, O.: Discovery of a Met300Val variant in Shc and
studies of its relationship to birth weight and length, impaired insulin
secretion, insulin resistance, and type 2 diabetes mellitus. J. Clin.
Endocr. Metab. 84: 2241-2244, 1999.
2. Harun, R. B.; Smith, K. K.; Leek, J. P.; Markham, A. F.; Norris,
A.; Morrison, J. F. J.: Characterization of human SHC p66 cDNA and
its processed pseudogene mapping to Xq12-q13.1. Genomics 42: 349-352,
1997.
3. Huebner, K.; Kastury, K.; Druck, T.; Salcini, A. E.; Lanfrancone,
L.; Pelicci, G.; Lowenstein, E.; Li, W.; Park, S.-H.; Cannizzaro,
L.; Pelicci, P. G.; Schlessinger, J.: Chromosome locations of genes
encoding human signal transduction adapter proteins, Nck (NCK), Shc
(SHC1), and Grb2 (GRB2). Genomics 22: 281-287, 1994.
4. McGlade, J.; Cheng, A.; Pelicci, G.; Pelicci, P. G.; Pawson, T.
: Shc proteins are phosphorylated and regulated by the v-src and v-fps
protein-tyrosine-kinases. Proc. Nat. Acad. Sci. 89: 8869-8873, 1992.
5. Migliaccio, E.; Giorgio, M.; Mele, S.; Pelicci, G.; Reboldi, P.;
Pandolfi, P. P.; Lanfrancone, L.; Pelicci, P. G.: The p66(shc) adaptor
protein controls oxidative stress response and life span in mammals. Nature 402:
309-313, 1999.
6. Nemoto, S.; Finkel, T.: Redox regulation of forkhead proteins
through a p66shc-dependent signaling pathway. Science 295: 2450-2452,
2002.
7. Pelicci, G.; Lanfrancone, L.; Grignani, F.; McGlade, J.; Cavallo,
F.; Forni, G.; Nicoletti, I.; Grignani, F.; Pawson, T.; Pelicci, P.
G.: A novel transforming protein (SHC) with an SH2 domain is implicated
in mitogenic signal transduction. Cell 70: 93-104, 1992.
8. Pinton, P.; Rimessi, A.; Marchi, S.; Orsini, F.; Migliaccio, E.;
Giorgio, M.; Contursi, C.; Minucci, S.; Mantovani, F.; Wieckowski,
M. R.; Del Sal, G.; Pelicci, P. G.; Rizzuto, R.: Protein kinase C-beta
and prolyl isomerase 1 regulate mitochondrial effects of the life-span
determinant p66(Shc) Science 315: 659-663, 2007.
9. Yulug, I. G.; Egan, S. E.; See, C. G.; Fisher, E. M. C.: A human
SHC-related sequence maps to chromosome 17, the SHC gene maps to chromosome
1. Hum. Genet. 96: 245-248, 1995.
10. Zhang, L.; Camerini, V.; Bender, T. P.; Ravichandran, K. S.:
A nonredundant role for the adapter protein Shc in thymic T cell development. Nature
Immun. 3: 749-755, 2002.
11. Zheng, Y.; Zhang, C.; Croucher, D. R.; Soliman, M. A.; St-Denis,
N.; Pasculescu, A.; Taylor, L.; Tate, S. A.; Hardy, W. R.; Colwill,
K.; Dai, A. Y.; Bagshaw, R.; Dennis, J. W.; Gingras, A.-C.; Daly,
R. J.; Pawson, T.: Temporal regulation of EGF signalling networks
by the scaffold protein Shc1. Nature 499: 166-171, 2013.
*FIELD* CN
Ada Hamosh - updated: 8/29/2013
Ada Hamosh - updated: 4/25/2007
Paul J. Converse - updated: 7/11/2002
Paul J. Converse - updated: 4/3/2002
Paul J. Converse - updated: 7/14/2000
John A. Phillips, III - updated: 3/7/2000
Ada Hamosh - updated: 11/22/1999
*FIELD* CD
Victor A. McKusick: 5/24/1995
*FIELD* ED
alopez: 08/29/2013
alopez: 8/29/2013
wwang: 4/20/2009
alopez: 5/1/2007
terry: 4/25/2007
carol: 4/27/2004
alopez: 8/6/2002
mgross: 7/11/2002
mgross: 4/3/2002
mgross: 7/14/2000
mgross: 3/7/2000
mgross: 12/2/1999
alopez: 11/22/1999
terry: 11/22/1999
terry: 11/17/1995
mark: 10/16/1995
mark: 5/24/1995