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Gene Review

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

Homo sapiens

Synonyms: ASV, Proto-oncogene c-Src, Proto-oncogene tyrosine-protein kinase Src, SRC1, c-SRC, ...
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Disease relevance of SRC


Psychiatry related information on SRC


High impact information on SRC

  • Autoinhibited c-Abl forms an assembly that is strikingly similar to that of inactive Src kinases but with specific differences that explain the differential ability of the drug STI-571/Gleevec/imatinib (STI-571) to inhibit the catalytic activity of Abl, but not that of c-Src [7].
  • EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake [8].
  • We report here the identification of a truncating mutation in SRC at codon 531 in 12% of cases of advanced human colon cancer tested and demonstrate that the mutation is activating, transforming, tumorigenic and promotes metastasis [9].
  • Activating SRC mutation in a subset of advanced human colon cancers [9].
  • The discovery of Rous sarcoma virus (RSV) led to the identification of cellular Src (c-Src), a non-receptor tyrosine kinase, which has since been implicated in the development of numerous human cancers. c-Src has been found to be highly activated in colon cancers, particularly in those metastatic to the liver [9].

Chemical compound and disease context of SRC


Biological context of SRC


Anatomical context of SRC

  • Activation of SRC tyrosine kinases in response to ICAM-1 ligation in pulmonary microvascular endothelial cells [18].
  • PP1, an inhibitor of SRC family kinases, blunted both the A(2A)-receptor- and the forskolin-induced MAP kinase stimulation (IC(50) = 50 nm); this was also seen in PC12 cells, which express the A(2A)-receptor endogenously, and in NIH3T3 fibroblasts, in which cAMP causes MAP kinase stimulation [19].
  • The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells [4].
  • SRC kinase and mitogen-activated protein kinases in the progression from normal to malignant endometrium [20].
  • To address this problem, we transfected MCF-7 cells to express the noncatalytic carboxylterminal domain of focal adhesion kinase (FAK), FAK(Y397F), kinase-defective c-Src, or Shc FFF, all of which express dominant-negative activity [21].

Associations of SRC with chemical compounds

  • Taken together, these data support a role for the SRC family of transcriptional coactivators in TCDD-dependent gene regulation [22].
  • Cross-linking ICAM-1 on tumor necrosis factor-alpha-pretreated ECs induced an increase in the activity of SRC tyrosine kinases [18].
  • Phenylarsine oxide, a tyrosine phosphatase inhibitor, reduced the base-line activity of SRC as well as the increase in SRC activity induced by ICAM-1 cross-linking [18].
  • Furthermore, phosphorylation of p52Shc by c-Src is essential for its recruitment to EphB1 signaling complexes through its phosphotyrosine binding domain [23].
  • Here, we examined the effects that different ERalpha ligands have on coactivator protein steady-state levels and demonstrate that the selective ER modulators (SERMs) 4-hydroxytamoxifen (4HT) and raloxifene are able to elevate SRC-1 and SRC-3 protein levels [24].
  • During decidualization, STAT5 was phosphorylated on tyrosine 694, a well-known SRC phosphorylation site [25].

Physical interactions of SRC


Enzymatic interactions of SRC

  • Under these in vitro conditions, E381G c-Src was found to be phosphorylated by CSK to wild-type levels, while E527K c-Src was not detectably phosphorylated [31].
  • In coimmunoprecipitation experiments, IKKalpha/beta was found to be associated with c-Src and to be phosphorylated on its tyrosine residues after TNF-alpha or TPA treatment [32].
  • The C-terminal autophosphorylation domain of EGFR was extensively phosphorylated by c-src and EGFR kinase activities in vitro as determined by electrospay ionization mass spectrometry [33].
  • Our results support a model in which activated c-Src phosphorylates the COOH-terminal tail of Cx43 on residue Tyr(265), resulting in a stable interaction between both proteins leading to inhibition of gap junctional communication [34].
  • We demonstrate that c-Src can directly phosphorylate GRK2 on tyrosine residues, as shown by in vitro experiments with purified proteins [35].

Co-localisations of SRC

  • Experiments in c-Src depleted cells reveal that AT1R remained mostly colocalized with AP-2 at the plasma membrane after Ang II stimulation, consistent with the observed delay in receptor internalization [30].

Regulatory relationships of SRC


Other interactions of SRC

  • Our results provide an insight into hypoxia-triggered intracellular signalling, define VEGF as a new downstream target for c-SRC, and suggest a role for c-SRc in promoting angiogenesis [10].
  • Expression of dominant-negative c-Src significantly reduced EphB1-dependent ERK1/2 activation and chemotaxis [23].
  • In particular, we found that EGF receptors, but not beta(2)-adrenergic receptors, activated c-Src by a Ral-GTPase-dependent mechanism [40].
  • Furthermore, we identify two tyrosine residues that are subject to phosphorylation in response to muscarinic signaling and show that this phosphorylation induces two cytosolic proteins, c-Src and Grb2, to bind to PYK2 [41].
  • Dok-R mediates attenuation of epidermal growth factor-dependent mitogen-activated protein kinase and Akt activation through processive recruitment of c-Src and Csk [42].

Analytical, diagnostic and therapeutic context of SRC


  1. 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]
  2. SRC family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck cancer cells. Zhang, Q., Thomas, S.M., Xi, S., Smithgall, T.E., Siegfried, J.M., Kamens, J., Gooding, W.E., Grandis, J.R. Cancer Res. (2004) [Pubmed]
  3. Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Trevino, J.G., Summy, J.M., Lesslie, D.P., Parikh, N.U., Hong, D.S., Lee, F.Y., Donato, N.J., Abbruzzese, J.L., Baker, C.H., Gallick, G.E. Am. J. Pathol. (2006) [Pubmed]
  4. The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells. Sprangers, M., Feldhahn, N., Herzog, S., Hansmann, M.L., Reppel, M., Hescheler, J., Jumaa, H., Siebert, R., Müschen, M. Oncogene (2006) [Pubmed]
  5. The SRC-induced mesenchymal state in late-stage colon cancer cells. Avizienyte, E., Brunton, V.G., Fincham, V.J., Frame, M.C. Cells Tissues Organs (Print) (2005) [Pubmed]
  6. Nonreceptor tyrosine protein kinase pp60c-src in spatial learning: synapse-specific changes in its gene expression, tyrosine phosphorylation, and protein-protein interactions. Zhao, W., Cavallaro, S., Gusev, P., Alkon, D.L. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  7. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Nagar, B., Hantschel, O., Young, M.A., Scheffzek, K., Veach, D., Bornmann, W., Clarkson, B., Superti-Furga, G., Kuriyan, J. Cell (2003) [Pubmed]
  8. EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake. Wilde, A., Beattie, E.C., Lem, L., Riethof, D.A., Liu, S.H., Mobley, W.C., Soriano, P., Brodsky, F.M. Cell (1999) [Pubmed]
  9. Activating SRC mutation in a subset of advanced human colon cancers. Irby, R.B., Mao, W., Coppola, D., Kang, J., Loubeau, J.M., Trudeau, W., Karl, R., Fujita, D.J., Jove, R., Yeatman, T.J. Nat. Genet. (1999) [Pubmed]
  10. Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Mukhopadhyay, D., Tsiokas, L., Zhou, X.M., Foster, D., Brugge, J.S., Sukhatme, V.P. Nature (1995) [Pubmed]
  11. Role of beta-arrestin 1 in the metastatic progression of colorectal cancer. Buchanan, F.G., Gorden, D.L., Matta, P., Shi, Q., Matrisian, L.M., DuBois, R.N. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  12. Physical and functional interactions between Cas and c-Src induce tamoxifen resistance of breast cancer cells through pathways involving epidermal growth factor receptor and signal transducer and activator of transcription 5b. Riggins, R.B., Thomas, K.S., Ta, H.Q., Wen, J., Davis, R.J., Schuh, N.R., Donelan, S.S., Owen, K.A., Gibson, M.A., Shupnik, M.A., Silva, C.M., Parsons, S.J., Clarke, R., Bouton, A.H. Cancer Res. (2006) [Pubmed]
  13. Underexpressed Coactivators PGC1{alpha} AND SRC1 Impair Hepatocyte Nuclear Factor 4{alpha} Function and Promote Dedifferentiation in Human Hepatoma Cells. Mart??nez-Jim??nez, C.P., G??mez-Lech??n, M.J., Castell, J.V., Jover, R. J. Biol. Chem. (2006) [Pubmed]
  14. Phorbol 12-myristate 13-acetate induces epidermal growth factor receptor transactivation via protein kinase Cdelta/c-Src pathways in glioblastoma cells. Amos, S., Martin, P.M., Polar, G.A., Parsons, S.J., Hussaini, I.M. J. Biol. Chem. (2005) [Pubmed]
  15. Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines. Torigoe, T., O'Connor, R., Santoli, D., Reed, J.C. Blood (1992) [Pubmed]
  16. Phenotypic changes induced by interleukin-2 (IL-2) and IL-3 in an immature T-lymphocytic leukemia are associated with regulated expression of IL-2 receptor beta chain and of protein tyrosine kinases LCK and LYN. O'Connor, R., Torigoe, T., Reed, J.C., Santoli, D. Blood (1992) [Pubmed]
  17. Mutual antagonism of estrogen receptors alpha and beta and their preferred interactions with steroid receptor coactivators in human osteoblastic cell lines. Monroe, D.G., Johnsen, S.A., Subramaniam, M., Getz, B.J., Khosla, S., Riggs, B.L., Spelsberg, T.C. J. Endocrinol. (2003) [Pubmed]
  18. Activation of SRC tyrosine kinases in response to ICAM-1 ligation in pulmonary microvascular endothelial cells. Wang, Q., Pfeiffer, G.R., Gaarde, W.A. J. Biol. Chem. (2003) [Pubmed]
  19. MAP kinase stimulation by cAMP does not require RAP1 but SRC family kinases. Klinger, M., Kudlacek, O., Seidel, M.G., Freissmuth, M., Sexl, V. J. Biol. Chem. (2002) [Pubmed]
  20. SRC kinase and mitogen-activated protein kinases in the progression from normal to malignant endometrium. Desouki, M.M., Rowan, B.G. Clin. Cancer Res. (2004) [Pubmed]
  21. Urokinase-type plasminogen activator stimulates the Ras/Extracellular signal-regulated kinase (ERK) signaling pathway and MCF-7 cell migration by a mechanism that requires focal adhesion kinase, Src, and Shc. Rapid dissociation of GRB2/Sps-Shc complex is associated with the transient phosphorylation of ERK in urokinase-treated cells. Nguyen, D.H., Webb, D.J., Catling, A.D., Song, Q., Dhakephalkar, A., Weber, M.J., Ravichandran, K.S., Gonias, S.L. J. Biol. Chem. (2000) [Pubmed]
  22. Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex. Beischlag, T.V., Wang, S., Rose, D.W., Torchia, J., Reisz-Porszasz, S., Muhammad, K., Nelson, W.E., Probst, M.R., Rosenfeld, M.G., Hankinson, O. Mol. Cell. Biol. (2002) [Pubmed]
  23. EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. Vindis, C., Cerretti, D.P., Daniel, T.O., Huynh-Do, U. J. Cell Biol. (2003) [Pubmed]
  24. Selective estrogen receptor modulators 4-hydroxytamoxifen and raloxifene impact the stability and function of SRC-1 and SRC-3 coactivator proteins. Lonard, D.M., Tsai, S.Y., O'Malley, B.W. Mol. Cell. Biol. (2004) [Pubmed]
  25. Activation of SRC kinase and phosphorylation of signal transducer and activator of transcription-5 are required for decidual transformation of human endometrial stromal cells. Nagashima, T., Maruyama, T., Uchida, H., Kajitani, T., Arase, T., Ono, M., Oda, H., Kagami, M., Masuda, H., Nishikawa, S., Asada, H., Yoshimura, Y. Endocrinology (2008) [Pubmed]
  26. Wiskott-Aldrich syndrome protein (WASp) is a binding partner for c-Src family protein-tyrosine kinases. Banin, S., Truong, O., Katz, D.R., Waterfield, M.D., Brickell, P.M., Gout, I. Curr. Biol. (1996) [Pubmed]
  27. The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin. Li, Y., Kuwahara, H., Ren, J., Wen, G., Kufe, D. J. Biol. Chem. (2001) [Pubmed]
  28. Involvement of PYK2 in angiotensin II signaling of vascular smooth muscle cells. Eguchi, S., Iwasaki, H., Inagami, T., Numaguchi, K., Yamakawa, T., Motley, E.D., Owada, K.M., Marumo, F., Hirata, Y. Hypertension (1999) [Pubmed]
  29. Bone morphogenetic protein receptor type II C-terminus interacts with c-Src: implication for a role in pulmonary arterial hypertension. Wong, W.K., Knowles, J.A., Morse, J.H. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  30. c-Src regulates clathrin adapter protein 2 interaction with beta-arrestin and the angiotensin II type 1 receptor during clathrin- mediated internalization. Fessart, D., Simaan, M., Laporte, S.A. Mol. Endocrinol. (2005) [Pubmed]
  31. Characterization of two activated mutants of human pp60c-src that escape c-Src kinase regulation by distinct mechanisms. Bjorge, J.D., Bellagamba, C., Cheng, H.C., Tanaka, A., Wang, J.H., Fujita, D.J. J. Biol. Chem. (1995) [Pubmed]
  32. Tyrosine phosphorylation of I-kappa B kinase alpha/beta by protein kinase C-dependent c-Src activation is involved in TNF-alpha-induced cyclooxygenase-2 expression. Huang, W.C., Chen, J.J., Inoue, H., Chen, C.C. J. Immunol. (2003) [Pubmed]
  33. In vitro phosphorylation of the epidermal growth factor receptor autophosphorylation domain by c-src: identification of phosphorylation sites and c-src SH2 domain binding sites. Lombardo, C.R., Consler, T.G., Kassel, D.B. Biochemistry (1995) [Pubmed]
  34. Interaction of c-Src with gap junction protein connexin-43. Role in the regulation of cell-cell communication. Giepmans, B.N., Hengeveld, T., Postma, F.R., Moolenaar, W.H. J. Biol. Chem. (2001) [Pubmed]
  35. Agonist-dependent phosphorylation of the G protein-coupled receptor kinase 2 (GRK2) by Src tyrosine kinase. Sarnago, S., Elorza, A., Mayor, F. J. Biol. Chem. (1999) [Pubmed]
  36. Pyk2 amplifies epidermal growth factor and c-Src-induced Stat3 activation. Shi, C.S., Kehrl, J.H. J. Biol. Chem. (2004) [Pubmed]
  37. Transactivation of fetal liver kinase-1/kinase-insert domain-containing receptor by lysophosphatidylcholine induces vascular endothelial cell proliferation. Fujita, Y., Yoshizumi, M., Izawa, Y., Ali, N., Ohnishi, H., Kanematsu, Y., Ishizawa, K., Tsuchiya, K., Tamaki, T. Endocrinology (2006) [Pubmed]
  38. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Luttrell, L.M., Ferguson, S.S., Daaka, Y., Miller, W.E., Maudsley, S., Della Rocca, G.J., Lin, F., Kawakatsu, H., Owada, K., Luttrell, D.K., Caron, M.G., Lefkowitz, R.J. Science (1999) [Pubmed]
  39. CSK controls retinoic acid receptor (RAR) signaling: a RAR-c-SRC signaling axis is required for neuritogenic differentiation. Dey, N., De, P.K., Wang, M., Zhang, H., Dobrota, E.A., Robertson, K.A., Durden, D.L. Mol. Cell. Biol. (2007) [Pubmed]
  40. An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity. Goi, T., Shipitsin, M., Lu, Z., Foster, D.A., Klinz, S.G., Feig, L.A. EMBO J. (2000) [Pubmed]
  41. Activation of protein tyrosine kinase PYK2 by the m1 muscarinic acetylcholine receptor. Felsch, J.S., Cachero, T.G., Peralta, E.G. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  42. Dok-R mediates attenuation of epidermal growth factor-dependent mitogen-activated protein kinase and Akt activation through processive recruitment of c-Src and Csk. Van Slyke, P., Coll, M.L., Master, Z., Kim, H., Filmus, J., Dumont, D.J. Mol. Cell. Biol. (2005) [Pubmed]
  43. Expression of androgen receptor coregulators in prostate cancer. Linja, M.J., Porkka, K.P., Kang, Z., Savinainen, K.J., Jänne, O.A., Tammela, T.L., Vessella, R.L., Palvimo, J.J., Visakorpi, T. Clin. Cancer Res. (2004) [Pubmed]
  44. Endometrial nuclear receptor co-factors SRC-1 and N-CoR are increased in human endometrium during menstruation. Wieser, F., Schneeberger, C., Hudelist, G., Singer, C., Kurz, C., Nagele, F., Gruber, C., Huber, J.C., Tschugguel, W. Mol. Hum. Reprod. (2002) [Pubmed]
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