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Gene Review

SHC1  -  SHC (Src homology 2 domain containing)...

Homo sapiens

Synonyms: SH2 domain protein C1, SHC, SHC-transforming protein 1, SHC-transforming protein 3, SHC-transforming protein A, ...
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Disease relevance of SHC1


Psychiatry related information on SHC1


High impact information on SHC1

  • The activated Jaks phosphorylate both themselves and the receptor subunits, creating docking sites for SH2-containing proteins including SHC, which couples receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which negatively affects the response [7].
  • A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction [8].
  • Anti-SHC antibodies recognized three proteins of 46, 52, and 66 kd in a wide range of mammalian cell lines [8].
  • NIH 3T3 mouse fibroblasts that constitutively overexpressed SHC acquired a transformed phenotype in culture and formed tumors in nude mice [8].
  • The SHC cDNA is predicted to encode overlapping proteins of 46.8 and 51.7 kd that contain a single C-terminal SH2 domain, and an adjacent glycine/proline-rich motif with regions of homology with the alpha 1 chain of collagen, but no identifiable catalytic domain [8].

Chemical compound and disease context of SHC1

  • Alanine-scanning mutations in the "primer grip" of p66 HIV-1 reverse transcriptase result in selective loss of RNA priming activity [9].
  • Cross-linking experiments were performed with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) mutants with unique cysteine residues at several positions (positions 65, 67, 70, and 74) in the fingers subdomain of the p66 subunit [10].
  • Here we show that antagonistic activity can be conferred to peptides of HIV envelope glycoprotein gp120 and reverse transcriptase p66 by adding flanking polypeptide sequences at the C or at the N terminus by genetic engineering, rather than by introducing substitutions by synthesis [11].
  • Antibody responses to p66, a candidate integrin ligand of Borrelia burgdorferi, were studied in 79 patients with early or late manifestations of Lyme disease [12].
  • A binding site for TSAO-m(3)T at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT) and distinct from that of "classical" HIV-1 non-nucleoside inhibitors is proposed [13].

Biological context of SHC1


Anatomical context of SHC1


Associations of SHC1 with chemical compounds

  • SHC contains two phosphotyrosine interaction domains: a PTB (Phosphotyrosine Binding) and a SH2 (Src Homology 2) domain [22].
  • Cloning and characterization of human SHIP, the 145-kD inositol 5-phosphatase that associates with SHC after cytokine stimulation [23].
  • Treatment of WB cells with hormones linked to Ca2+ mobilization and protein kinase C (PKC) activation, including angiotensin II, [Arg8]vasopressin, or epinephrine, stimulated rapid (less than or equal to 15-s) and transient increases in the P-Tyr content of several proteins (p120/125, p75/78, and p66) [24].
  • Within 2 min of stimulation, we also observed increased tyrosine phosphorylation of SHC, activation of the guanidine nucleotide exchange activity on p21(ras), and an electrophoretic mobility shift of MAP kinase [25].
  • The SH2 domain interaction with CD45 was specific as glutathione S-transferase-SH2 fusion proteins from p85 alpha subunit of phosphatidylinositol 3-kinase and SHC did not bind to CD45 [26].

Physical interactions of SHC1


Enzymatic interactions of SHC1

  • Previous studies have shown that SHC proteins are phosphorylated on Y239/Y240 and Y313 (Y317 in humans) by tyrosine kinases such as the EGF and IL3 receptors [22].
  • SHC was tyrosine phosphorylated in response to Fc gamma RI stimulation of U937IF cells and bound to the SH2 domain of GRB2 in a stimulation-dependent manner [32].
  • We examined the classical signal pathway in which SHC is phosphorylated and binds to SOS and GRB-2 to activate Ras, Raf, and MAP kinase [33].
  • Also the SHC-derived SH2 domain formed complexes with the tyrosine-phosphorylated Ig-alpha/beta heterodimer, while the C- and N-terminal SH2 domains of GTPase-activating protein displayed completely different binding preferences [34].

Regulatory relationships of SHC1


Other interactions of SHC1

  • In contrast, under the same treatment, tyrosine phosphorylation of Src-homology/collagen proteins (SHC; another substrate of the IGF-IR) and SHC/GRB2 binding were elevated [38].
  • The protein levels of the IGF-IR and IRS-1 were not modified by Tam, whereas SHC protein expression was either not affected or moderately decreased by the treatment [38].
  • Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling [22].
  • IRS1, IRS2 and SHC1 are the key mediators for the downstream pathway processes [1].
  • Additionally, NCK and SHC genes were more narrowly localized by chromosomal in situ hybridization [14].

Analytical, diagnostic and therapeutic context of SHC1


  1. The insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer. Wagner, K., Hemminki, K., Grzybowska, E., Klaes, R., Butkiewicz, D., Pamula, J., Pekala, W., Zientek, H., Mielzynska, D., Siwinska, E., Försti, A. Carcinogenesis (2004) [Pubmed]
  2. A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells. Wisniewski, D., Strife, A., Swendeman, S., Erdjument-Bromage, H., Geromanos, S., Kavanaugh, W.M., Tempst, P., Clarkson, B. Blood (1999) [Pubmed]
  3. Characterization of human immunodeficiency virus gag/pol gene products expressed by recombinant vaccinia viruses. Flexner, C., Broyles, S.S., Earl, P., Chakrabarti, S., Moss, B. Virology (1988) [Pubmed]
  4. Enhanced expression of p46 Shc in the nucleus and p52 Shc in the cytoplasm of human gastric cancer. Yukimasa, S., Masaki, T., Yoshida, S., Uchida, N., Watanabe, S., Usuki, H., Yoshiji, H., Maeta, T., Ebara, K., Nakatsu, T., Kurokohchi, K., Kuriyama, S. Int. J. Oncol. (2005) [Pubmed]
  5. Expression and activation of SHC/MAP kinase pathway in primary acute myeloid leukemia blasts. Lunghi, P., Tabilio, A., Pinelli, S., Valmadre, G., Ridolo, E., Albertini, R., Carlo-Stella, C., Dall'Aglio, P.P., Pelicci, P.G., Bonati, A. Hematol. J. (2001) [Pubmed]
  6. The effects of the SHCP on selected aspects of decision-making among fifth graders. Lammers, J.W., Kreuter, M.W., Smith, B.C. Health education. (1984) [Pubmed]
  7. Signaling through the hematopoietic cytokine receptors. Ihle, J.N., Witthuhn, B.A., Quelle, F.W., Yamamoto, K., Silvennoinen, O. Annu. Rev. Immunol. (1995) [Pubmed]
  8. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Pelicci, G., Lanfrancone, L., Grignani, F., McGlade, J., Cavallo, F., Forni, G., Nicoletti, I., Grignani, F., Pawson, T., Pelicci, P.G. Cell (1992) [Pubmed]
  9. Alanine-scanning mutations in the "primer grip" of p66 HIV-1 reverse transcriptase result in selective loss of RNA priming activity. Powell, M.D., Ghosh, M., Jacques, P.S., Howard, K.J., Le Grice, S.F., Levin, J.G. J. Biol. Chem. (1997) [Pubmed]
  10. Cross-linking of the fingers subdomain of human immunodeficiency virus type 1 reverse transcriptase to template-primer. Peletskaya, E.N., Boyer, P.L., Kogon, A.A., Clark, P., Kroth, H., Sayer, J.M., Jerina, D.M., Hughes, S.H. J. Virol. (2001) [Pubmed]
  11. Antagonistic activity of HIV-1 T helper peptides flanked by an unrelated carrier protein. Fenoglio, D., Li Pira, G., De Berardinis, P., Saverino, D., Terranova, M.P., Ombra, M.N., Bracci, L., Lozzi, L., Viotti, C., Guardiola, J., Manca, F. Eur. J. Immunol. (1999) [Pubmed]
  12. Recognition of multiple antibody epitopes throughout Borrelia burgdorferi p66, a candidate adhesin, in patients with early or late manifestations of Lyme disease. Ntchobo, H., Rothermel, H., Chege, W., Steere, A.C., Coburn, J. Infect. Immun. (2001) [Pubmed]
  13. Identification of a putative binding site for [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)thymine (TSAO) derivatives at the p51-p66 interface of HIV-1 reverse transcriptase. Rodríguez-Barrios, F., Pérez, C., Lobatón, E., Velázquez, S., Chamorro, C., San-Félix, A., Pérez-Pérez, M.J., Camarasa, M.J., Pelemans, H., Balzarini, J., Gago, F. J. Med. Chem. (2001) [Pubmed]
  14. Chromosome locations of genes encoding human signal transduction adapter proteins, Nck (NCK), Shc (SHC1), and Grb2 (GRB2). Huebner, K., Kastury, K., Druck, T., Salcini, A.E., Lanfrancone, L., Pelicci, G., Lowenstein, E., Li, W., Park, S.H., Cannizzaro, L. Genomics (1994) [Pubmed]
  15. Association analysis of the SHC1 gene locus with longevity in the Japanese population. Kamei, H., Adati, N., Arai, Y., Yamamura, K., Takayama, M., Nakazawa, S., Ebihara, Y., Gondo, Y., Akechi, M., Noguchi, T., Hirose, N., Sakaki, Y., Kojima, T. J. Mol. Med. (2003) [Pubmed]
  16. Signal characteristics of G protein-transactivated EGF receptor. Daub, H., Wallasch, C., Lankenau, A., Herrlich, A., Ullrich, A. EMBO J. (1997) [Pubmed]
  17. Involvement of SHC, GRB2, SOS and RAS in prolactin signal transduction in mammary epithelial cells. Das, R., Vonderhaar, B.K. Oncogene (1996) [Pubmed]
  18. FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates. Lavagna-Sévenier, C., Marchetto, S., Birnbaum, D., Rosnet, O. Leukemia (1998) [Pubmed]
  19. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Daub, H., Weiss, F.U., Wallasch, C., Ullrich, A. Nature (1996) [Pubmed]
  20. p66SHC promotes apoptosis and antagonizes mitogenic signaling in T cells. Pacini, S., Pellegrini, M., Migliaccio, E., Patrussi, L., Ulivieri, C., Ventura, A., Carraro, F., Naldini, A., Lanfrancone, L., Pelicci, P., Baldari, C.T. Mol. Cell. Biol. (2004) [Pubmed]
  21. Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2. VanderKuur, J., Allevato, G., Billestrup, N., Norstedt, G., Carter-Su, C. J. Biol. Chem. (1995) [Pubmed]
  22. Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling. Fournier, E., Blaikie, P., Rosnet, O., Margolis, B., Birnbaum, D., Borg, J.P. Oncogene (1999) [Pubmed]
  23. Cloning and characterization of human SHIP, the 145-kD inositol 5-phosphatase that associates with SHC after cytokine stimulation. Ware, M.D., Rosten, P., Damen, J.E., Liu, L., Humphries, R.K., Krystal, G. Blood (1996) [Pubmed]
  24. Angiotensin II stimulates protein-tyrosine phosphorylation in a calcium-dependent manner. Huckle, W.R., Prokop, C.A., Dy, R.C., Herman, B., Earp, S. Mol. Cell. Biol. (1990) [Pubmed]
  25. Gp130-mediated signal transduction in embryonic stem cells involves activation of Jak and Ras/mitogen-activated protein kinase pathways. Ernst, M., Oates, A., Dunn, A.R. J. Biol. Chem. (1996) [Pubmed]
  26. Demonstration of a direct interaction between p56lck and the cytoplasmic domain of CD45 in vitro. Ng, D.H., Watts, J.D., Aebersold, R., Johnson, P. J. Biol. Chem. (1996) [Pubmed]
  27. Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction. Kurokawa, K., Iwashita, T., Murakami, H., Hayashi, H., Kawai, K., Takahashi, M. Oncogene (2001) [Pubmed]
  28. CRK protein binds to two guanine nucleotide-releasing proteins for the Ras family and modulates nerve growth factor-induced activation of Ras in PC12 cells. Matsuda, M., Hashimoto, Y., Muroya, K., Hasegawa, H., Kurata, T., Tanaka, S., Nakamura, S., Hattori, S. Mol. Cell. Biol. (1994) [Pubmed]
  29. Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain. Gustafson, T.A., He, W., Craparo, A., Schaub, C.D., O'Neill, T.J. Mol. Cell. Biol. (1995) [Pubmed]
  30. The role of ERK 1/2 and p38 MAP-kinase pathways in taxol-induced apoptosis in human ovarian carcinoma cells. Seidman, R., Gitelman, I., Sagi, O., Horwitz, S.B., Wolfson, M. Exp. Cell Res. (2001) [Pubmed]
  31. Erythropoietin: physiology and pharmacology update. Fisher, J.W. Exp. Biol. Med. (Maywood) (2003) [Pubmed]
  32. Protein tyrosine phosphatase inhibitors in Fc gamma RI-induced myeloid oxidant signaling. Erdreich-Epstein, A., Liu, M., Liu, Y., Durden, D.L. Exp. Cell Res. (1997) [Pubmed]
  33. Adaptive hypersensitivity to estradiol: potential mechanism for secondary hormonal responses in breast cancer patients. Santen, R., Jeng, M.H., Wang, J.P., Song, R., Masamura, S., McPherson, R., Santner, S., Yue, W., Shim, W.S. J. Steroid Biochem. Mol. Biol. (2001) [Pubmed]
  34. In vitro characterization of major ligands for Src homology 2 domains derived from protein tyrosine kinases, from the adaptor protein SHC and from GTPase-activating protein in Ramos B cells. Baumann, G., Maier, D., Freuler, F., Tschopp, C., Baudisch, K., Wienands, J. Eur. J. Immunol. (1994) [Pubmed]
  35. SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor. Marchetto, S., Fournier, E., Beslu, N., Aurran-Schleinitz, T., Dubreuil, P., Borg, J.P., Birnbaum, D., Rosnet, O. Leukemia (1999) [Pubmed]
  36. Heregulin-stimulated acetylcholine receptor gene expression in muscle: requirement for MAP kinase and evidence for a parallel inhibitory pathway independent of electrical activity. Altiok, N., Altiok, S., Changeux, J.P. EMBO J. (1997) [Pubmed]
  37. Elevated levels of p66 Shc are found in breast cancer cell lines and primary tumors with high metastatic potential. Jackson, J.G., Yoneda, T., Clark, G.M., Yee, D. Clin. Cancer Res. (2000) [Pubmed]
  38. Tamoxifen interferes with the insulin-like growth factor I receptor (IGF-IR) signaling pathway in breast cancer cells. Guvakova, M.A., Surmacz, E. Cancer Res. (1997) [Pubmed]
  39. Constitutive activation of the prolactin receptor results in the induction of growth factor-independent proliferation and constitutive activation of signaling molecules. Lee, R.C., Walters, J.A., Reyland, M.E., Anderson, S.M. J. Biol. Chem. (1999) [Pubmed]
  40. Characterization of human SHC p66 cDNA and its processed pseudogene mapping to Xq12-q13.1. Harun, R.B., Smith, K.K., Leek, J.P., Markham, A.F., Norris, A., Morrison, J.F. Genomics (1997) [Pubmed]
  41. Jaks and Stats in signaling by the cytokine receptor superfamily. Ihle, J.N., Kerr, I.M. Trends Genet. (1995) [Pubmed]
  42. Identification of SHC as a substrate of the insulin receptor kinase distinct from the GAP-associated 62 kDa tyrosine phosphoprotein. Kovacina, K.S., Roth, R.A. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
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