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Gene Review

Src  -  Rous sarcoma oncogene

Mus musculus

Synonyms: AW259666, Neuronal proto-oncogene tyrosine-protein kinase Src, Proto-oncogene c-Src, p60-Src, pp60c-src
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Disease relevance of Src


Psychiatry related information on Src

  • Infection of newborn or 2-week-old Src-negative mice with a retrovirus encoding middle T led to the induction of visceral hemangiomas that were indistinguishable from tumors in wild-type mice with respect to their morphology, frequency or latency period [6].

High impact information on Src


Chemical compound and disease context of Src


Biological context of Src


Anatomical context of Src

  • Lck is the major Src family member required for thymopoiesis, since there is a severe deficit of CD4+CD8+ thymocytes and mature T cells in its absence [20].
  • Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development [21].
  • Translocation of Src kinase to the cell periphery is mediated by the actin cytoskeleton under the control of the Rho family of small G proteins [22].
  • Thus, we conclude that translocation of Src from its site of synthesis to its site of action at the cell membrane requires an intact cytoskeletal network and that the small G proteins of the Rho family may specify the peripheral localization in focal adhesions or along the membrane, mediated by their effects on the cytoskeleton [22].
  • Stable transfection of selected SH3 domain mutants into NIH-3T3 cells showed that despite elevated levels of phosphotyrosine, the cells were morphologically normal, indicating that the SH3 domain was required for efficient transformation of NIH-3T3 cells by Src [23].

Associations of Src with chemical compounds


Physical interactions of Src

  • The c-cbl protooncogene product (c-Cbl) is a 120-kDa protein that has been shown to bind to the Src homology 3 domains of various proteins, suggesting its involvement in signal transduction pathways [28].
  • Furthermore, we show that this interaction is direct and that Grb2 binds to phospho-AbetaPP via its Src homology 2 region [29].
  • Eliminating the Src-binding site on Pyk2 (Pyk2(Y402F)) markedly inhibited bone resorption by osteoclast-like cells, whereas kinase-dead Pyk2 had little effect [30].
  • Autophosphorylation of PDGF receptors upon ligand stimulation provides binding sites for Src homology 2 domains of intracellular signaling molecules, which thereby become activated [31].
  • Furthermore, this tyrosine phosphorylated protein was not detected in c-Src complexes derived from fibroblasts transformed by either Neu or PyV middle T [32].

Enzymatic interactions of Src

  • This heteromolecular complex is coordinated by proline-rich and Src family-dependent phosphorylated regions of M2 [33].
  • In contrast, expression of a cortactin mutant lacking tyrosine residues phosphorylated by Src did not restore podosome formation [34].
  • In summary, we show that CN-induced chemical anoxia activates c-Src and induces its translocation to cell-cell junctions where it binds to and phosphorylates beta-catenin and p120 [35].
  • Sam68 is the major tyrosine-phosphorylated and Src-associated protein in mitotic cells [36].
  • Src phosphorylates the insulin-like growth factor type I receptor on the autophosphorylation sites. Requirement for transformation by src [37].

Co-localisations of Src


Regulatory relationships of Src

  • Tr-kit-induced resumption of the cell cycle in mouse eggs requires activation of a Src-like kinase [39].
  • We also measured the levels of Src kinase activity in cell lines expressing isoforms of the Ret receptor activated by different mutations [40].
  • We next tested reconstruction of the signaling in the membrane-anchored, gain-of-function Csk-expressing cells by introducing Src family kinases the C-terminal negative regulatory sequence of which was replaced with a c-myc epitope [41].
  • Epidermal growth factor-induced DNA synthesis. Key role for Src phosphorylation of the docking protein Gab2 [42].
  • In addition, we demonstrated that the Src-induced response was down-regulated by Gab2-associated SHP2 [42].

Other interactions of Src


Analytical, diagnostic and therapeutic context of Src


  1. PYK2 in osteoclasts is an adhesion kinase, localized in the sealing zone, activated by ligation of alpha(v)beta3 integrin, and phosphorylated by src kinase. Duong, L.T., Lakkakorpi, P.T., Nakamura, I., Machwate, M., Nagy, R.M., Rodan, G.A. J. Clin. Invest. (1998) [Pubmed]
  2. Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis. Lowell, C.A., Niwa, M., Soriano, P., Varmus, H.E. Blood (1996) [Pubmed]
  3. Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells. Proietti, C., Salatino, M., Rosemblit, C., Carnevale, R., Pecci, A., Kornblihtt, A.R., Molinolo, A.A., Frahm, I., Charreau, E.H., Schillaci, R., Elizalde, P.V. Mol. Cell. Biol. (2005) [Pubmed]
  4. 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]
  5. Hypoxic activation of nuclear factor-kappa B is mediated by a Ras and Raf signaling pathway and does not involve MAP kinase (ERK1 or ERK2). Koong, A.C., Chen, E.Y., Mivechi, N.F., Denko, N.C., Stambrook, P., Giaccia, A.J. Cancer Res. (1994) [Pubmed]
  6. Induction of tumor formation and cell transformation by polyoma middle T antigen in the absence of Src. Thomas, J.E., Aguzzi, A., Soriano, P., Wagner, E.F., Brugge, J.S. Oncogene (1993) [Pubmed]
  7. B cell signaling and tumorigenesis. Jumaa, H., Hendriks, R.W., Reth, M. Annu. Rev. Immunol. (2005) [Pubmed]
  8. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Hu, Y., Liu, Y., Pelletier, S., Buchdunger, E., Warmuth, M., Fabbro, D., Hallek, M., Van Etten, R.A., Li, S. Nat. Genet. (2004) [Pubmed]
  9. Src kinases in Ph+ lymphoblastic leukemia. Deininger, M. Nat. Genet. (2004) [Pubmed]
  10. Src tyrosine kinase is a novel direct effector of G proteins. Ma, Y.C., Huang, J., Ali, S., Lowry, W., Huang, X.Y. Cell (2000) [Pubmed]
  11. Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F. Zaleskas, V.M., Krause, D.S., Lazarides, K., Patel, N., Hu, Y., Li, S., Van Etten, R.A. PLoS ONE (2006) [Pubmed]
  12. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Golas, J.M., Arndt, K., Etienne, C., Lucas, J., Nardin, D., Gibbons, J., Frost, P., Ye, F., Boschelli, D.H., Boschelli, F. Cancer Res. (2003) [Pubmed]
  13. Involvement of G(i) proteins and Src tyrosine kinase in TNFalpha production induced by lipopolysaccharide, group B Streptococci and Staphylococcus aureus. Fan, H., Teti, G., Ashton, S., Guyton, K., Tempel, G.E., Halushka, P.V., Cook, J.A. Cytokine (2003) [Pubmed]
  14. The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation. He, H., Hirokawa, Y., Gazit, A., Yamashita, Y., Mano, H., Kawakami, Y., Kawakami, n.u.l.l., Hsieh, C.Y., Kung, H.J., Lessene, G., Baell, J., Levitzki, A., Maruta, H. Cancer Biol. Ther. (2004) [Pubmed]
  15. Abnormal localisation and hyperclustering of (alpha)(V)(beta)(3) integrins and associated proteins in Src-deficient or tyrphostin A9-treated osteoclasts. Lakkakorpi, P.T., Nakamura, I., Young, M., Lipfert, L., Rodan, G.A., Duong, L.T. J. Cell. Sci. (2001) [Pubmed]
  16. A target for Src in mitosis. Fumagalli, S., Totty, N.F., Hsuan, J.J., Courtneidge, S.A. Nature (1994) [Pubmed]
  17. c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption. Tanaka, S., Amling, M., Neff, L., Peyman, A., Uhlmann, E., Levy, J.B., Baron, R. Nature (1996) [Pubmed]
  18. Myc but not Fos rescue of PDGF signalling block caused by kinase-inactive Src. Barone, M.V., Courtneidge, S.A. Nature (1995) [Pubmed]
  19. Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division. Roche, S., Fumagalli, S., Courtneidge, S.A. Science (1995) [Pubmed]
  20. alpha beta T cell development is abolished in mice lacking both Lck and Fyn protein tyrosine kinases. van Oers, N.S., Lowin-Kropf, B., Finlay, D., Connolly, K., Weiss, A. Immunity (1996) [Pubmed]
  21. Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development. Saijo, K., Schmedt, C., Su, I.H., Karasuyama, H., Lowell, C.A., Reth, M., Adachi, T., Patke, A., Santana, A., Tarakhovsky, A. Nat. Immunol. (2003) [Pubmed]
  22. Translocation of Src kinase to the cell periphery is mediated by the actin cytoskeleton under the control of the Rho family of small G proteins. Fincham, V.J., Unlu, M., Brunton, V.G., Pitts, J.D., Wyke, J.A., Frame, M.C. J. Cell Biol. (1996) [Pubmed]
  23. Mutational analysis of the Src SH3 domain: the same residues of the ligand binding surface are important for intra- and intermolecular interactions. Erpel, T., Superti-Furga, G., Courtneidge, S.A. EMBO J. (1995) [Pubmed]
  24. Coordinate interactions of Csk, Src, and Syk kinases with [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton. Obergfell, A., Eto, K., Mocsai, A., Buensuceso, C., Moores, S.L., Brugge, J.S., Lowell, C.A., Shattil, S.J. J. Cell Biol. (2002) [Pubmed]
  25. Proline-rich sequences that bind to Src homology 3 domains with individual specificities. Alexandropoulos, K., Cheng, G., Baltimore, D. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  26. Perlecan proteolysis induces an alpha2beta1 integrin- and Src family kinase-dependent anti-apoptotic pathway in fibroblasts in the absence of focal adhesion kinase activation. Laplante, P., Raymond, M.A., Labelle, A., Abe, J., Iozzo, R.V., Hébert, M.J. J. Biol. Chem. (2006) [Pubmed]
  27. Regulation of c-Src activity in glutamate-induced neurodegeneration. Khanna, S., Roy, S., Park, H.A., Sen, C.K. J. Biol. Chem. (2007) [Pubmed]
  28. Tyrosine phosphorylation and translocation of the c-cbl protein after activation of tyrosine kinase signaling pathways. Tanaka, S., Neff, L., Baron, R., Levy, J.B. J. Biol. Chem. (1995) [Pubmed]
  29. Growth factor receptor-bound protein 2 interaction with the tyrosine-phosphorylated tail of amyloid beta precursor protein is mediated by its Src homology 2 domain. Zhou, D., Noviello, C., D'Ambrosio, C., Scaloni, A., D'Adamio, L. J. Biol. Chem. (2004) [Pubmed]
  30. Src kinase activity is essential for osteoclast function. Miyazaki, T., Sanjay, A., Neff, L., Tanaka, S., Horne, W.C., Baron, R. J. Biol. Chem. (2004) [Pubmed]
  31. Compartmentalization of autocrine signal transduction pathways in Sis-transformed NIH 3T3 cells. Valgeirsdóttir, S., Eriksson, A., Nistér, M., Heldin, C.H., Westermark, B., Claesson-Welsh, L. J. Biol. Chem. (1995) [Pubmed]
  32. Activation of Src family kinases in Neu-induced mammary tumors correlates with their association with distinct sets of tyrosine phosphorylated proteins in vivo. Muthuswamy, S.K., Muller, W.J. Oncogene (1995) [Pubmed]
  33. Activation of Vav by the gammaherpesvirus M2 protein contributes to the establishment of viral latency in B lymphocytes. Rodrigues, L., Pires de Miranda, M., Caloca, M.J., Bustelo, X.R., Simas, J.P. J. Virol. (2006) [Pubmed]
  34. Cortactin has an essential and specific role in osteoclast actin assembly. Tehrani, S., Faccio, R., Chandrasekar, I., Ross, F.P., Cooper, J.A. Mol. Biol. Cell (2006) [Pubmed]
  35. Chemical anoxia of tubular cells induces activation of c-Src and its translocation to the zonula adherens. Sinha, D., Wang, Z., Price, V.R., Schwartz, J.H., Lieberthal, W. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  36. Sam68 is a Ras-GAP-associated protein in mitosis. Guitard, E., Barlat, I., Maurier, F., Schweighoffer, F., Tocque, B. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  37. Src phosphorylates the insulin-like growth factor type I receptor on the autophosphorylation sites. Requirement for transformation by src. Peterson, J.E., Kulik, G., Jelinek, T., Reuter, C.W., Shannon, J.A., Weber, M.J. J. Biol. Chem. (1996) [Pubmed]
  38. RACK1 regulates Src-mediated Sam68 and p190RhoGAP signaling. Miller, L.D., Lee, K.C., Mochly-Rosen, D., Cartwright, C.A. Oncogene (2004) [Pubmed]
  39. Tr-kit-induced resumption of the cell cycle in mouse eggs requires activation of a Src-like kinase. Sette, C., Paronetto, M.P., Barchi, M., Bevilacqua, A., Geremia, R., Rossi, P. EMBO J. (2002) [Pubmed]
  40. Ret-mediated mitogenesis requires Src kinase activity. Melillo, R.M., Barone, M.V., Lupoli, G., Cirafici, A.M., Carlomagno, F., Visconti, R., Matoskova, B., Di Fiore, P.P., Vecchio, G., Fusco, A., Santoro, M. Cancer Res. (1999) [Pubmed]
  41. Differential involvement of Src family kinases in Fc gamma receptor-mediated phagocytosis. Suzuki, T., Kono, H., Hirose, N., Okada, M., Yamamoto, T., Yamamoto, K., Honda, Z. J. Immunol. (2000) [Pubmed]
  42. Epidermal growth factor-induced DNA synthesis. Key role for Src phosphorylation of the docking protein Gab2. Kong, M., Mounier, C., Dumas, V., Posner, B.I. J. Biol. Chem. (2003) [Pubmed]
  43. Csk controls antigen receptor-mediated development and selection of T-lineage cells. Schmedt, C., Saijo, K., Niidome, T., Kühn, R., Aizawa, S., Tarakhovsky, A. Nature (1998) [Pubmed]
  44. Expression and activity of SRC regulate interleukin-8 expression in pancreatic adenocarcinoma cells: implications for angiogenesis. Trevino, J.G., Summy, J.M., Gray, M.J., Nilsson, M.B., Lesslie, D.P., Baker, C.H., Gallick, G.E. Cancer Res. (2005) [Pubmed]
  45. Kinase-independent potentiation of B cell antigen receptor-mediated signal transduction by the protein tyrosine kinase Src. Lin, J., Tao, J., Dyer, R.B., Herzog, N.K., Justement, L.B. J. Immunol. (1997) [Pubmed]
  46. Identification of the Src family kinases, Lck and Fgr in platelets. Their tyrosine phosphorylation status and subcellular distribution compared with other Src family members. Pestina, T.I., Stenberg, P.E., Druker, B.J., Steward, S.A., Hutson, N.K., Barrie, R.J., Jackson, C.W. Arterioscler. Thromb. Vasc. Biol. (1997) [Pubmed]
  47. Inhibition of Src kinases combined with CD40 ligand blockade prolongs murine cardiac allograft survival. Zhang, Q., Fairchild, R.L., Reich, M.B., Miller, G.G. Transplantation (2005) [Pubmed]
  48. C-terminal Src kinase (CSK) modulates insulin-like growth factor-I signaling through Src in 3T3-L1 differentiation. Sekimoto, H., Boney, C.M. Endocrinology (2003) [Pubmed]
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