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Gene Review

Shc1  -  src homology 2 domain-containing...

Mus musculus

Synonyms: SH2 domain protein C1, SHC-transforming protein 1, SHC-transforming protein A, Shc, ShcA, ...
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Disease relevance of Shc1


High impact information on Shc1


Chemical compound and disease context of Shc1


Biological context of Shc1


Anatomical context of Shc1


Associations of Shc1 with chemical compounds

  • Shc proteins possess SH2 and PTB domains and serve a scaffolding function in signaling by a variety of receptor tyrosine kinases [23].
  • A mammalian adaptor protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is specifically expressed in the brain [24].
  • Together, these data indicate that the serine/threonine phosphorylation of 66-kDa Shc impairs its ability to associate with the tyrosine-phosphorylated EGF receptor and can function in a dominant-interfering manner by inhibiting EGF receptor downstream signaling pathways [17].
  • Inhibiting JAK2 activity with the specific inhibitor AG-490 prevented H(2)O(2) stimulated Shc and Ras activation [25].
  • SH2-containing inositol 5'-phosphatase (SHIP) modulates the activation of immune cells after recruitment to the membrane by Shc and the cytoplasmic tails of receptors [26].

Physical interactions of Shc1

  • While the function of Shc in the activation of the Ras pathway via binding to Grb2 has been well characterized, it is becoming increasingly apparent that Shc participates in additional signaling pathways through interactions with other cytoplasmic proteins [27].
  • Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST [28].
  • We have shown that the SH2 domain of the adaptor protein Shc coimmunoprecipitates with all the Ret and Trk oncoproteins as well as with NGF-activated proto-Trk receptor [29].
  • The development of mice carrying a point mutation of the Shc binding site (Y515F) in the trkB gene (trkB(shc)) provided an opportunity to test the hypothesis that trkB is the neurotrophin receptor undergoing phosphorylation [30].
  • However, Shc binding to cadherin did negatively influence beta-catenin binding to the same molecule [31].

Enzymatic interactions of Shc1

  • In FGF-2 treated proliferating EC, FRS2 as well as Shc are tyrosine phosphorylated and interact with Grb2 [32].
  • We cloned a fragment of Shc when screening a bacterial expression library with tyrosine-phosphorylated epidermal growth factor (EGF) receptor [15].
  • (ii) In vivo, mutant IL-2R beta chains lacking the acidic region of IL-2Rbeta (which contains Y338) fail to phosphorylate Shc [33].
  • Shc was found to be tyrosine-phosphorylated upon IL-2 stimulation in CTLL-20 cells [34].
  • Shc proteins contain a carboxy terminal SH2 domain and a novel non-SH2 phosphotyrosine-binding (PTB) domain that specifically recognizes a phosphorylated NPXpY motif in target proteins such as the epidermal growth factor receptor [11].

Regulatory relationships of Shc1


Other interactions of Shc1

  • There are three known mammalian Shc genes, of which ShcB and ShcC are primarily expressed in the nervous system [23].
  • HBx induced the association of Ras upstream activating proteins Shc, Grb2, and Sos and stimulated GTP loading onto Ras, but without directly participating in complex formation [39].
  • Examining the molecular mechanism for this antiproliferative effect, we determined that SFK inhibitors did not affect tyrosine phosphorylation of Janus kinase 2 (JAK2), Shc, signal transducer and activator of transcription (STAT)5, or STAT3 [40].
  • However, phosphorylation of Shc on Tyr(239), the Src phosphorylation site, was normal [41].
  • The 66-kDa Shc isoform is a negative regulator of the epidermal growth factor-stimulated mitogen-activated protein kinase pathway [17].

Analytical, diagnostic and therapeutic context of Shc1

  • 7. Shc, an SH2 domain containing adaptor protein, was immunoprecipitated from lysates of taxol-treated cells with anti-phosphotyrosine antibody and its identity determined by Western blotting with anti-Shc antibody [20].
  • These phosphopeptides have been screened for their capacity to bind to the SH2 domains of Shc and Grb in a solution phase enzyme-linked immunosorbent assay [42].
  • SHIP-2 shows a maximal tyrosine phosphorylation and association to Shc after ligation of BCR to FcgammaRIIB but not after stimulation of BCR alone [43].
  • In contrast to the 52-kDa Shc isoform, insulin stimulation caused a quantitative, time-dependent decrease in the SDS-PAGE mobility of 66-kDa Shc in both Chinese hamster ovary/IR cells and 3T3L1 adipocytes [38].
  • Microinjection experiments demonstrated that a Shc molecule carrying mutations of tyrosines 239 and 240, in conjunction with an SH2 domain mutation, interfered with PDGF-stimulated DNA synthesis [44].


  1. Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: implications for human breast cancer. Dankort, D., Maslikowski, B., Warner, N., Kanno, N., Kim, H., Wang, Z., Moran, M.F., Oshima, R.G., Cardiff, R.D., Muller, W.J. Mol. Cell. Biol. (2001) [Pubmed]
  2. Mechanism of the mitogenic effect of fluoride on osteoblast-like cells: evidences for a G protein-dependent tyrosine phosphorylation process. Caverzasio, J., Palmer, G., Suzuki, A., Bonjour, J.P. J. Bone Miner. Res. (1997) [Pubmed]
  3. Sustained activation of MAPK/ERKs signaling pathway in cystic kidneys from bcl-2 -/- mice. Sorenson, C.M., Sheibani, N. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  4. Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. Hecker, T.P., Grammer, J.R., Gillespie, G.Y., Stewart, J., Gladson, C.L. Cancer Res. (2002) [Pubmed]
  5. Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc. Tarr, P.E., Roncarati, R., Pelicci, G., Pelicci, P.G., D'Adamio, L. J. Biol. Chem. (2002) [Pubmed]
  6. Antagonism of p66shc by melanoma inhibitory activity. Kasuno, K., Naqvi, A., Dericco, J., Yamamori, T., Santhanam, L., Mattagajasingh, I., Yang, S., Meyskens, F.L., Bosserhoff, A.K., Irani, K. Cell Death Differ. (2007) [Pubmed]
  7. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Kousteni, S., Bellido, T., Plotkin, L.I., O'Brien, C.A., Bodenner, D.L., Han, L., Han, K., DiGregorio, G.B., Katzenellenbogen, J.A., Katzenellenbogen, B.S., Roberson, P.K., Weinstein, R.S., Jilka, R.L., Manolagas, S.C. Cell (2001) [Pubmed]
  8. A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Trusolino, L., Bertotti, A., Comoglio, P.M. Cell (2001) [Pubmed]
  9. A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Wary, K.K., Mariotti, A., Zurzolo, C., Giancotti, F.G. Cell (1998) [Pubmed]
  10. The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Wary, K.K., Mainiero, F., Isakoff, S.J., Marcantonio, E.E., Giancotti, F.G. Cell (1996) [Pubmed]
  11. A tyrosine-phosphorylated protein of 140 kD is constitutively associated with the phosphotyrosine binding domain of Shc and the SH3 domains of Grb2 in acute myeloid leukemia cells. Jücker, M., Schiffer, C.A., Feldman, R.A. Blood (1997) [Pubmed]
  12. Rac is required for v-Abl tyrosine kinase to activate mitogenesis. Renshaw, M.W., Lea-Chou, E., Wang, J.Y. Curr. Biol. (1996) [Pubmed]
  13. Characterization of highly immunogenic p66/p51 as the reverse transcriptase of HTLV-III/LAV. di Marzo Veronese, F., Copeland, T.D., DeVico, A.L., Rahman, R., Oroszlan, S., Gallo, R.C., Sarngadharan, M.G. Science (1986) [Pubmed]
  14. ShcA and Grb2 mediate polyoma middle T antigen-induced endothelial transformation and Gab1 tyrosine phosphorylation. Ong, S.H., Dilworth, S., Hauck-Schmalenberger, I., Pawson, T., Kiefer, F. EMBO J. (2001) [Pubmed]
  15. A region in Shc distinct from the SH2 domain can bind tyrosine-phosphorylated growth factor receptors. Blaikie, P., Immanuel, D., Wu, J., Li, N., Yajnik, V., Margolis, B. J. Biol. Chem. (1994) [Pubmed]
  16. c-Cbl is a suppressor of the neu oncogene. Levkowitz, G., Oved, S., Klapper, L.N., Harari, D., Lavi, S., Sela, M., Yarden, Y. J. Biol. Chem. (2000) [Pubmed]
  17. The 66-kDa Shc isoform is a negative regulator of the epidermal growth factor-stimulated mitogen-activated protein kinase pathway. Okada, S., Kao, A.W., Ceresa, B.P., Blaikie, P., Margolis, B., Pessin, J.E. J. Biol. Chem. (1997) [Pubmed]
  18. Shc products are substrates of erbB-2 kinase. Segatto, O., Pelicci, G., Giuli, S., Digiesi, G., Di Fiore, P.P., McGlade, J., Pawson, T., Pelicci, P.G. Oncogene (1993) [Pubmed]
  19. p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinases, Grb2 and Shc adaptors, and the p85 subunit of phosphatidylinositol 3-kinase. Panchamoorthy, G., Fukazawa, T., Miyake, S., Soltoff, S., Reedquist, K., Druker, B., Shoelson, S., Cantley, L., Band, H. J. Biol. Chem. (1996) [Pubmed]
  20. Taxol induces tyrosine phosphorylation of Shc and its association with Grb2 in murine RAW 264.7 cells. Wolfson, M., Yang, C.P., Horwitz, S.B. Int. J. Cancer (1997) [Pubmed]
  21. Specificity of insulin-like growth factor I and insulin on Shc phosphorylation and Grb2 recruitment in caveolae. Biedi, C., Panetta, D., Segat, D., Cordera, R., Maggi, D. Endocrinology (2003) [Pubmed]
  22. The ShcA phosphotyrosine docking protein sensitizes cardiovascular signaling in the mouse embryo. Lai, K.M., Pawson, T. Genes Dev. (2000) [Pubmed]
  23. The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons. Sakai, R., Henderson, J.T., O'Bryan, J.P., Elia, A.J., Saxton, T.M., Pawson, T. Neuron (2000) [Pubmed]
  24. A mammalian adaptor protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is specifically expressed in the brain. O'Bryan, J.P., Songyang, Z., Cantley, L., Der, C.J., Pawson, T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  25. Fyn and JAK2 mediate Ras activation by reactive oxygen species. Abe, J., Berk, B.C. J. Biol. Chem. (1999) [Pubmed]
  26. Embryonic and hematopoietic stem cells express a novel SH2-containing inositol 5'-phosphatase isoform that partners with the Grb2 adapter protein. Tu, Z., Ninos, J.M., Ma, Z., Wang, J.W., Lemos, M.P., Desponts, C., Ghansah, T., Howson, J.M., Kerr, W.G. Blood (2001) [Pubmed]
  27. Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells. Schmandt, R., Liu, S.K., McGlade, C.J. Oncogene (1999) [Pubmed]
  28. Serine/threonine phosphorylation of ShcA. Regulation of protein-tyrosine phosphatase-pest binding and involvement in insulin signaling. Faisal, A., el-Shemerly, M., Hess, D., Nagamine, Y. J. Biol. Chem. (2002) [Pubmed]
  29. The oncogenic versions of the Ret and Trk tyrosine kinases bind Shc and Grb2 adaptor proteins. Borrello, M.G., Pelicci, G., Arighi, E., De Filippis, L., Greco, A., Bongarzone, I., Rizzetti, M., Pelicci, P.G., Pierotti, M.A. Oncogene (1994) [Pubmed]
  30. Immunohistochemical evidence of seizure-induced activation of trkB receptors in the mossy fiber pathway of adult mouse hippocampus. He, X.P., Minichiello, L., Klein, R., McNamara, J.O. J. Neurosci. (2002) [Pubmed]
  31. Identification of cadherin tyrosine residues that are phosphorylated and mediate Shc association. Xu, Y., Carpenter, G. J. Cell. Biochem. (1999) [Pubmed]
  32. Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation. Klint, P., Kanda, S., Kloog, Y., Claesson-Welsh, L. Oncogene (1999) [Pubmed]
  33. Evidence for a role for the phosphotyrosine-binding domain of Shc in interleukin 2 signaling. Ravichandran, K.S., Igras, V., Shoelson, S.E., Fesik, S.W., Burakoff, S.J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  34. The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. Ravichandran, K.S., Burakoff, S.J. J. Biol. Chem. (1994) [Pubmed]
  35. Catalytic activity of the mouse guanine nucleotide exchanger mSOS is activated by Fyn tyrosine protein kinase and the T-cell antigen receptor in T cells. Li, B., Subleski, M., Fusaki, N., Yamamoto, T., Copeland, T., Princler, G.L., Kung, H., Kamata, T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  36. Non-redundant role of Shc in Erk activation by cytoskeletal reorganization. Faisal, A., Kleiner, S., Nagamine, Y. J. Biol. Chem. (2004) [Pubmed]
  37. Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulin-stimulated mitogenesis without affecting glucose transport in 3T3-L1 adipocytes. Sharma, P.M., Egawa, K., Gustafson, T.A., Martin, J.L., Olefsky, J.M. Mol. Cell. Biol. (1997) [Pubmed]
  38. Insulin stimulates the phosphorylation of the 66- and 52-kilodalton Shc isoforms by distinct pathways. Kao, A.W., Waters, S.B., Okada, S., Pessin, J.E. Endocrinology (1997) [Pubmed]
  39. Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras. Klein, N.P., Schneider, R.J. Mol. Cell. Biol. (1997) [Pubmed]
  40. Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors. Lannutti, B.J., Drachman, J.G. Blood (2004) [Pubmed]
  41. Impaired Shc, Ras, and MAPK activation but normal Akt activation in FL5.12 cells expressing an insulin-like growth factor I receptor mutated at tyrosines 1250 and 1251. Leahy, M., Lyons, A., Krause, D., O'Connor, R. J. Biol. Chem. (2004) [Pubmed]
  42. Systematic mapping of potential binding sites for Shc and Grb2 SH2 domains on insulin receptor substrate-1 and the receptors for insulin, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor. Ward, C.W., Gough, K.H., Rashke, M., Wan, S.S., Tribbick, G., Wang, J. J. Biol. Chem. (1996) [Pubmed]
  43. Distribution of the src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells. Muraille, E., Pesesse, X., Kuntz, C., Erneux, C. Biochem. J. (1999) [Pubmed]
  44. SU6656, a selective src family kinase inhibitor, used to probe growth factor signaling. Blake, R.A., Broome, M.A., Liu, X., Wu, J., Gishizky, M., Sun, L., Courtneidge, S.A. Mol. Cell. Biol. (2000) [Pubmed]
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