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Gene Review

Src  -  SRC proto-oncogene, non-receptor tyrosine...

Rattus norvegicus

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


Psychiatry related information on Src

  • Lateral hypothalamic signaling mechanisms underlying feeding stimulation: differential contributions of Src family tyrosine kinases to feeding triggered either by NMDA injection or by food deprivation [6].

High impact information on Src

  • The G betagamma-responsive ERK activation induced by H2O2 is independent of ligands binding to Gi-coupled receptors, but requires phosphatidylinositol-3-kinase and Src activation [7].
  • Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases [8].
  • NMDA-receptor-mediated whole-cell currents and NMDA-receptor single-channel activity were increased by raising [Na+]i and channel activity decreased upon lowering [Na+]i; therefore, the activity of NMDA channels tracks changes in [Na+]i. We found that the sensitivity of the channel to Na+ was set by a Src kinase that is associated with the channel [9].
  • It achieves this, at least in part, by binding and activating one of the non-receptor tyrosine kinases, pp60c-src, pp62c-yes or pp59c-fyn (reviewed in refs 2 and 3) [10].
  • Thus, Src activation is necessary and sufficient for inducing LTP and may function by up-regulating NMDA receptors [11].

Chemical compound and disease context of Src

  • In the cells treated with CGS21680, PI3K activation was prevented either by inhibiting adenylate cyclase and PKA with, respectively, 2,5-dideoxyadenosine and H89 or by blocking Galphai-protein and Src tyrosine kinase with, respectively, pertussis toxin and PP2 [12].
  • The large (130kDa), multi-domain Cas molecule contains an SH3 domain, a Src-binding domain, a serine-rich protein interaction region, and a C-terminal region that participates in protein interactions implicated in antiestrogen resistance in breast cancer [13].
  • Langendorff rat heart preparations were exposed to 50 microM ouabain to produce positive inotropy without toxicity, and assayed for Src kinase, protein kinase C, and extracellular signal-regulated kinases 1 and 2 (ERK(1/2)) [14].
  • Upregulation of c-Src signaling may be important in the profibrotic and proinflammatory actions of aldosterone in this genetic model of hypertension [15].
  • Here, we describe a novel class of Src inhibitors, substituted 5,7-diphenyl-pyrrolo[2,3-d]pyrimidines, and characterize one of them, CGP77675, in vitro and in models of bone resorption in vivo [16].

Biological context of Src


Anatomical context of Src


Associations of Src with chemical compounds


Physical interactions of Src

  • DPP IV coimmunoprecipitated with the cellular tyrosine kinase Src (c-Src) with maximal association also observed after 2 min following insulin injection [31].
  • Indeed, the formation of p-FAK/c-Src protein complex, but not their association with beta1-integrin, was stimulated during T suppression-induced germ cell loss [32].
  • Infection of cardiomyocytes with an adenovirus expressing a mutant Pyk2 which lacked its kinase domain or its ability to bind to c-Src, eliminated ET-1- and PE-induced hypertrophic responses [33].
  • The purified caveolin-1 binds c-Src, suppressing its autophosphorylation [34].
  • Coimmunoprecipitation studies revealed decreased binding of ZO-1 and increased binding of c-Src to Cx43 at low pHi [35].

Enzymatic interactions of Src

  • In the present investigation, we report that tamalin possesses a typical immunoreceptor tyrosine-based activation motif (ITAM), which enables Syk kinase to be recruited and phosphorylated by the Src family kinases [36].
  • Tyr(124) is phosphorylated by Src in vitro; in whole cells, Y124F Kv2.1 is significantly less phosphorylated by Src and loses most of its ability to bind the D245A substrate-trapping mutant of cyt-PTPepsilon [37].
  • Also, addition of c-Src and [(32)P]ATP phosphorylated the synthesized peptide corresponding to amino acid sequence 333-362 of the COOH terminus of ROMK1 [38].
  • Upon E2 treatment, Src kinase is tyrosine phosphorylated, which, in turn, stimulates Src kinase to phosphorylate caveolin-1 [39].
  • Src family kinases have been shown to phosphorylate PLC-gamma 1 and to be activated by G protein-coupled receptors [40].

Regulatory relationships of Src

  • These data indicate that Ang II induces Ca2+-dependent transactivation of the EGF receptor which serves as a scaffold for pre-activated c-Src and for downstream adaptors, leading to MAPK activation in VSMC [41].
  • At the mechanistic level, Ca(2+) chelator (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester)), phosphatidylinositol-phospholipase C inhibitor (U73122), or Src inhibitor (PP2) attenuated the PGE(2)-induced Fn expression [42].
  • The involvement of Src-tyrosine kinase activity was demonstrated by detection of increased c-Src phosphorylation in response to E(2) and by blockade of E(2)-induced ERK1/2 activation by inhibition of Src-family tyrosine kinase activity [43].
  • Together our results suggest that PSD-95 may be important for localizing and/or regulating multiple Src protein tyrosine kinases at the NMDA receptor multiprotein complex [44].
  • The c-Src inhibitor PP2 inhibited DPP IV phosphorylation [31].
  • Using a thermoactivatable mutant of v-Src, we show that at the permissive temperature, annexin 2 becomes phosphorylated and colocalizes with activated v-Src and focal adhesion kinase both at the plasma membrane and in a Rab11-positive compartment of the endosomal pathway [45].

Other interactions of Src


Analytical, diagnostic and therapeutic context of Src

  • Activated MAPK, Pyk2, and c-Src amounts were measured by Western blot analysis [48].
  • By immunoelectron microscopy, we demonstrate that, unlike Src, the Src-related kinases are associated with electron-dense cytoplasmic domains and plasma membrane domains that correspond in size and frequency to endocytotic vesicles and coated pits [49].
  • Co-immunoprecipitation identified an association between the channel protein and Src [50].
  • Immunoblot using clone 28, a monoclonal antibody specific for the active form of Src kinases, demonstrated increased active Src expression in the injured rat kidney 6 hours after reperfusion with peak activation at 12 hours [51].
  • Immunohistochemistry using clone 28 demonstrated that active Src was preferentially expressed in the S3 segment of the proximal tubule in reperfused kidney, where it is not normally expressed [51].


  1. Herbal formulation, Yukmi-jihang-tang-Jahage, regulates bone resorption by inhibition of phosphorylation mediated by tyrosine kinase Src and cyclooxygenase expression. Jin, U.H., Kim, D.I., Lee, T.K., Lee, D.N., Kim, J.K., Lee, I.S., Kim, C.H. Journal of ethnopharmacology. (2006) [Pubmed]
  2. Pressure activates colon cancer cell adhesion by inside-out focal adhesion complex and actin cytoskeletal signaling. Thamilselvan, V., Basson, M.D. Gastroenterology (2004) [Pubmed]
  3. Focal adhesion kinase and p130Cas mediate both sarcomeric organization and activation of genes associated with cardiac myocyte hypertrophy. Kovacic-Milivojević, B., Roediger, F., Almeida, E.A., Damsky, C.H., Gardner, D.G., Ilić, D. Mol. Biol. Cell (2001) [Pubmed]
  4. Src homology 3 binding sites in the P2Y2 nucleotide receptor interact with Src and regulate activities of Src, proline-rich tyrosine kinase 2, and growth factor receptors. Liu, J., Liao, Z., Camden, J., Griffin, K.D., Garrad, R.C., Santiago-Pérez, L.I., González, F.A., Seye, C.I., Weisman, G.A., Erb, L. J. Biol. Chem. (2004) [Pubmed]
  5. Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP. Pei, L., Teves, R.L., Wallace, M.C., Gurd, J.W. J. Cereb. Blood Flow Metab. (2001) [Pubmed]
  6. Lateral hypothalamic signaling mechanisms underlying feeding stimulation: differential contributions of Src family tyrosine kinases to feeding triggered either by NMDA injection or by food deprivation. Khan, A.M., Cheung, H.H., Gillard, E.R., Palarca, J.A., Welsbie, D.S., Gurd, J.W., Stanley, B.G. J. Neurosci. (2004) [Pubmed]
  7. G alpha(i) and G alpha(o) are target proteins of reactive oxygen species. Nishida, M., Maruyama, Y., Tanaka, R., Kontani, K., Nagao, T., Kurose, H. Nature (2000) [Pubmed]
  8. Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Kawabuchi, M., Satomi, Y., Takao, T., Shimonishi, Y., Nada, S., Nagai, K., Tarakhovsky, A., Okada, M. Nature (2000) [Pubmed]
  9. Gain control of NMDA-receptor currents by intracellular sodium. Yu, X.M., Salter, M.W. Nature (1998) [Pubmed]
  10. Transformation by polyoma virus middle T-antigen involves the binding and tyrosine phosphorylation of Shc. Dilworth, S.M., Brewster, C.E., Jones, M.D., Lanfrancone, L., Pelicci, G., Pelicci, P.G. Nature (1994) [Pubmed]
  11. Src activation in the induction of long-term potentiation in CA1 hippocampal neurons. Lu, Y.M., Roder, J.C., Davidow, J., Salter, M.W. Science (1998) [Pubmed]
  12. Role of phosphatidylinositol 3-kinase in the development of hepatocyte preconditioning. Carini, R., Grazia De Cesaris, M., Splendore, R., Baldanzi, G., Nitti, M.P., Alchera, E., Filigheddu, N., Domenicotti, C., Pronzato, M.A., Graziani, A., Albano, E. Gastroenterology (2004) [Pubmed]
  13. Organization of functional domains in the docking protein p130Cas. Nasertorabi, F., Garcia-Guzman, M., Briknarová, K., Larsen, E., Havert, M.L., Vuori, K., Ely, K.R. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  14. Positive inotropic effect of ouabain on isolated heart is accompanied by activation of signal pathways that link Na+/K+-ATPase to ERK1/2. Mohammadi, K., Liu, L., Tian, J., Kometiani, P., Xie, Z., Askari, A. J. Cardiovasc. Pharmacol. (2003) [Pubmed]
  15. c-Src-dependent nongenomic signaling responses to aldosterone are increased in vascular myocytes from spontaneously hypertensive rats. Callera, G.E., Montezano, A.C., Yogi, A., Tostes, R.C., He, Y., Schiffrin, E.L., Touyz, R.M. Hypertension (2005) [Pubmed]
  16. A novel inhibitor of the tyrosine kinase Src suppresses phosphorylation of its major cellular substrates and reduces bone resorption in vitro and in rodent models in vivo. Missbach, M., Jeschke, M., Feyen, J., Müller, K., Glatt, M., Green, J., Susa, M. Bone (1999) [Pubmed]
  17. Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis. Häussinger, D., Kurz, A.K., Wettstein, M., Graf, D., Vom Dahl, S., Schliess, F. Gastroenterology (2003) [Pubmed]
  18. Mapping of atypical protein kinase C within the nerve growth factor signaling cascade: relationship to differentiation and survival of PC12 cells. Wooten, M.W., Seibenhener, M.L., Neidigh, K.B., Vandenplas, M.L. Mol. Cell. Biol. (2000) [Pubmed]
  19. Dependence of peroxisome proliferator-activated receptor ligand-induced mitogen-activated protein kinase signaling on epidermal growth factor receptor transactivation. Gardner, O.S., Dewar, B.J., Earp, H.S., Samet, J.M., Graves, L.M. J. Biol. Chem. (2003) [Pubmed]
  20. Role of Src-induced dynamin-2 phosphorylation in caveolae-mediated endocytosis in endothelial cells. Shajahan, A.N., Timblin, B.K., Sandoval, R., Tiruppathi, C., Malik, A.B., Minshall, R.D. J. Biol. Chem. (2004) [Pubmed]
  21. Essential roles of Lyn in fibronectin-mediated filamentous actin assembly and cell motility in mast cells. Suzuki, T., Shoji, S., Yamamoto, K., Nada, S., Okada, M., Yamamoto, T., Honda, Z. J. Immunol. (1998) [Pubmed]
  22. Inhibition of AT1 receptor internalization by concanavalin A blocks angiotensin II-induced ERK activation in vascular smooth muscle cells. Involvement of epidermal growth factor receptor proteolysis but not AT1 receptor internalization. Tang, H., Nishishita, T., Fitzgerald, T., Landon, E.J., Inagami, T. J. Biol. Chem. (2000) [Pubmed]
  23. Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade. Oldham, S.M., Cox, A.D., Reynolds, E.R., Sizemore, N.S., Coffey, R.J., Der, C.J. Oncogene (1998) [Pubmed]
  24. Src and Cas are essentially but differentially involved in angiotensin II-stimulated migration of vascular smooth muscle cells via extracellular signal-regulated kinase 1/2 and c-Jun NH2-terminal kinase activation. Kyaw, M., Yoshizumi, M., Tsuchiya, K., Kagami, S., Izawa, Y., Fujita, Y., Ali, N., Kanematsu, Y., Toida, K., Ishimura, K., Tamaki, T. Mol. Pharmacol. (2004) [Pubmed]
  25. Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat. Alvaro, D., Onori, P., Metalli, V.D., Svegliati-Baroni, G., Folli, F., Franchitto, A., Alpini, G., Mancino, M.G., Attili, A.F., Gaudio, E. Hepatology (2002) [Pubmed]
  26. Regulation of the L-type calcium channel by alpha 5beta 1 integrin requires signaling between focal adhesion proteins. Wu, X., Davis, G.E., Meininger, G.A., Wilson, E., Davis, M.J. J. Biol. Chem. (2001) [Pubmed]
  27. GIT1 mediates Src-dependent activation of phospholipase Cgamma by angiotensin II and epidermal growth factor. Haendeler, J., Yin, G., Hojo, Y., Saito, Y., Melaragno, M., Yan, C., Sharma, V.K., Heller, M., Aebersold, R., Berk, B.C. J. Biol. Chem. (2003) [Pubmed]
  28. Cell adhesion-dependent cofilin serine 3 phosphorylation by the integrin-linked kinase.c-Src complex. Kim, Y.B., Choi, S., Choi, M.C., Oh, M.A., Lee, S.A., Cho, M., Mizuno, K., Kim, S.H., Lee, J.W. J. Biol. Chem. (2008) [Pubmed]
  29. Neuroprotection of GluR5-containing kainate receptor activation against ischemic brain injury through decreasing tyrosine phosphorylation of N-methyl-D-aspartate receptors mediated by Src kinase. Xu, J., Liu, Y., Zhang, G.Y. J. Biol. Chem. (2008) [Pubmed]
  30. Localization of PTP-1B, SHP-2, and Src exclusively in rat brain mitochondria and functional consequences. Arachiche, A., Augereau, O., Decossas, M., Pertuiset, C., Gontier, E., Letellier, T., Dachary-Prigent, J. J. Biol. Chem. (2008) [Pubmed]
  31. Insulin-dependent phosphorylation of DPP IV in liver. Evidence for a role of compartmentalized c-Src. Bilodeau, N., Fiset, A., Poirier, G.G., Fortier, S., Gingras, M.C., Lavoie, J.N., Faure, R.L. FEBS J. (2006) [Pubmed]
  32. Regulation of ectoplasmic specialization dynamics in the seminiferous epithelium by focal adhesion-associated proteins in testosterone-suppressed rat testes. Wong, C.H., Xia, W., Lee, N.P., Mruk, D.D., Lee, W.M., Cheng, C.Y. Endocrinology (2005) [Pubmed]
  33. Ca(2+)-sensitive tyrosine kinase Pyk2/CAK beta-dependent signaling is essential for G-protein-coupled receptor agonist-induced hypertrophy. Hirotani, S., Higuchi, Y., Nishida, K., Nakayama, H., Yamaguchi, O., Hikoso, S., Takeda, T., Kashiwase, K., Watanabe, T., Asahi, M., Taniike, M., Tsujimoto, I., Matsumura, Y., Sasaki, T., Hori, M., Otsu, K. J. Mol. Cell. Cardiol. (2004) [Pubmed]
  34. Interaction of shrimp ras protein with mammalian caveolin-1. Chen, C.H., Wang, H.C., Chuang, N.N. J. Exp. Zool. (2000) [Pubmed]
  35. Regulation of connexin43 protein complexes by intracellular acidification. Duffy, H.S., Ashton, A.W., O'Donnell, P., Coombs, W., Taffet, S.M., Delmar, M., Spray, D.C. Circ. Res. (2004) [Pubmed]
  36. Phosphorylation and recruitment of Syk by immunoreceptor tyrosine-based activation motif-based phosphorylation of tamalin. Hirose, M., Kitano, J., Nakajima, Y., Moriyoshi, K., Yanagi, S., Yamamura, H., Muto, T., Jingami, H., Nakanishi, S. J. Biol. Chem. (2004) [Pubmed]
  37. Phosphorylation-dependent regulation of Kv2.1 Channel activity at tyrosine 124 by Src and by protein-tyrosine phosphatase epsilon. Tiran, Z., Peretz, A., Attali, B., Elson, A. J. Biol. Chem. (2003) [Pubmed]
  38. K depletion increases protein tyrosine kinase-mediated phosphorylation of ROMK. Lin, D.H., Sterling, H., Lerea, K.M., Welling, P., Jin, L., Giebisch, G., Wang, W.H. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  39. Oestrogen-mediated tyrosine phosphorylation of caveolin-1 and its effect on the oestrogen receptor localisation: an in vivo study. Kiss, A.L., Turi, A., Müllner, N., Kovács, E., Botos, E., Greger, A. Mol. Cell. Endocrinol. (2005) [Pubmed]
  40. Angiotensin II activates pp60c-src in vascular smooth muscle cells. Ishida, M., Marrero, M.B., Schieffer, B., Ishida, T., Bernstein, K.E., Berk, B.C. Circ. Res. (1995) [Pubmed]
  41. Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. Eguchi, S., Numaguchi, K., Iwasaki, H., Matsumoto, T., Yamakawa, T., Utsunomiya, H., Motley, E.D., Kawakatsu, H., Owada, K.M., Hirata, Y., Marumo, F., Inagami, T. J. Biol. Chem. (1998) [Pubmed]
  42. Prostaglandin E2 stimulates fibronectin expression through EP1 receptor, phospholipase C, protein kinase Calpha, and c-Src pathway in primary cultured rat osteoblasts. Tang, C.H., Yang, R.S., Fu, W.M. J. Biol. Chem. (2005) [Pubmed]
  43. Rapid estrogenic regulation of extracellular signal- regulated kinase 1/2 signaling in cerebellar granule cells involves a G protein- and protein kinase A-dependent mechanism and intracellular activation of protein phosphatase 2A. Belcher, S.M., Le, H.H., Spurling, L., Wong, J.K. Endocrinology (2005) [Pubmed]
  44. Interactions between Src family protein tyrosine kinases and PSD-95. Kalia, L.V., Salter, M.W. Neuropharmacology (2003) [Pubmed]
  45. Annexin 2 has a dual role as regulator and effector of v-Src in cell transformation. Hayes, M.J., Moss, S.E. J. Biol. Chem. (2009) [Pubmed]
  46. Sensitization of epidermal growth factor-induced signaling by bradykinin is mediated by c-Src. Implications for a role of lipid microdomains. Hur, E.M., Park, Y.S., Lee, B.D., Jang, I.H., Kim, H.S., Kim, T.D., Suh, P.G., Ryu, S.H., Kim, K.T. J. Biol. Chem. (2004) [Pubmed]
  47. Estrogen modulation of prolactin gene expression requires an intact mitogen-activated protein kinase signal transduction pathway in cultured rat pituitary cells. Watters, J.J., Chun, T.Y., Kim, Y.N., Bertics, P.J., Gorski, J. Mol. Endocrinol. (2000) [Pubmed]
  48. Roles of protein kinase C, Ca2+, Pyk2, and c-Src in agonist activation of rat lacrimal gland p42/p44 MAPK. Hodges, R.R., Rios, J.D., Vrouvlianis, J., Ota, I., Zoukhri, D., Dartt, D.A. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  49. The Src family kinases, Fgr, Fyn, Lck, and Lyn, colocalize with coated membranes in platelets. Stenberg, P.E., Pestina, T.I., Barrie, R.J., Jackson, C.W. Blood (1997) [Pubmed]
  50. Regulation of an ERG K+ current by Src tyrosine kinase. Cayabyab, F.S., Schlichter, L.C. J. Biol. Chem. (2002) [Pubmed]
  51. Activation of Src kinase in platelet-derived growth factor-B-dependent tubular regeneration after acute ischemic renal injury. Takikita-Suzuki, M., Haneda, M., Sasahara, M., Owada, M.K., Nakagawa, T., Isono, M., Takikita, S., Koya, D., Ogasawara, K., Kikkawa, R. Am. J. Pathol. (2003) [Pubmed]
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