Note | Src can be phosphorylated on Tyr-530 by CSK (c-Src kinase). The phosphorylated form is termed pp60c-src. Phosphorylation of this tyrosine allows facilitates interaction between the C-terminal tail and the SH2 domain, maintaining Src in an inactive formation. Protein Translation: MGSNKSKPKDASQRRRSLEPAENVHGAGGGAFPASQTPSKPASADGHRGPSAAFAPAAAEPKLFGGFNSSDTVTSPQRA GPLAGGVTTFVALYDYESRTETDLSFKKGERLQIVNNTEGDWWLAHSLSTGQTGYIPSNYVAPSDSIQAEEWYFGKITRRE GQGCFGEVWMGTWNGTTRVAIKTLKPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEYMSKGSLLDFLKGET GKYLRLPQLVDMAAQIASGMAYVERMNYVHRDLRAANILVGENLVCKVADFGLARLIEDNEYTARQGAKFPIKWTAPEAAL YGRFTIKSDVWSFGILLTELTTKGRVPYPGMVNREVLDQVERGYRMPCPPECPESLHDLMCQCWRKEPEERPTFEYLQA FLEDYFTSTEPQYQPGENL Note: This variant (isoform 1) represents the longer Src transcript although both isoforms 1 and 2 encode the same protein as the difference is in the 5' UTR. |
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| Linear representation of the protein structure of human Src family members, showing the six distinct domains. N and C denote N- and C-termini respectively. Location of major regulatory phosphorylation sites and the myristolation signal sequence are shown. |
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Description | Size: 536 amino acids; 59.835 KDa. Src is 59.6KDa in size and has a domain structure comprised of six distinct functional regions (see figure above). These include an N-terminal SH4 domain that contains a lipid-modification sequence allowing targeting of Src to cellular membranes, and an adjacent, poorly-conserved region thus being unique to each Src family member. SH3 and SH2 domains adjacent to the N-terminus facilitate protein-protein interactions between Src and its interacting proteins whilst the SH1 domain allows ATP and substrate binding and has tyrosine kinase activity; autophosphorylation of Y419 within this domain is required for the maximum kinase activity of Src. The negative regulatory tail of Src contains a tyrosine at 530, the phosphorylation of which promotes a conformational change to produce an inactive Src molecule. Sequences within the C-terminus of Src have been recently identified to facilitate protein-protein interactions have been shown to regulate Src function in addition to its kinase activity. |
Expression | Ubiquitously expressed but with particularly high levels in brain tissue, osteoclasts and platelets. |
Localisation | Predominantly cytoplasmic and/or plasma membrane, the latter due to myristolation of the N-terminus. Activated Src has also been reported in the cell nucleus in some tumour tissues. |
Function | Src can interact with a diverse array of cellular factors allowing it to regulate a variety of normal and oncogenic processes that ultimately result in cell proliferation, differentiation, survival, adhesion, motility, invasion and angiogenesis (Thomas and Brugge, 1997; Summy and Gallick, 2003). Such interacting partners include receptor tyrosine kinases (e.g. the EGF receptor family (Biscardi et al., 1998)), integrins (Galliher and Schiemann, 2006; Huveneers et al., 2007), cell-cell adhesion molecules (Giehl and Menke, 2008), in addition to STATs (Silva, 2004), FAK (Brunton and Frame, 2008), the adaptor protein p130Cas (Chang et al., 2008) and GPCRs (McGarrigle and Huang, 2007). Importantly, Src can also interact with the oestrogen receptor (Weatherman, 2008), where it has been shown to be pivotal in both non-genomic ER activation of signalling pathways and gene transcription events. The ability of Src to function as both an effector and regulator of receptor-induced signalling allows it to mediate cross-talk between normally distinct signalling pathways and thus regulate a wide variety of both normal and oncogenic processes, including proliferation, differentiation, survival, adhesion, motility, invasion and angiogenesis. |
Homology | c-Src is the prototypic member of a family of nine non-receptor tyrosine kinases which share the same domain structure (Src, Fyn, Yes, Lyn, Lck, Hck, Blk, Fgr and Frk) (Erpel and Courtneidge, 1995) and are expressed in vertebrates. All Src family members have the same basic structure of an N-terminal, unique domain containing a myristylation site and frequently a palmitoylation site; regulatory SH3 and SH2 domains; a catalytic domain that has its active site wedged between the two lobes of the molecule, and a C-terminal regulatory tail that contains the hallmark regulatory tyrosine residue (Tyr527 in Src). The activity of Src family kinases is suppressed upon phosphorylation of Tyr527, allowing binding of the C-terminal domain to the SH2 domain. The SH2 and SH3 domains bind phosphotyrosine and proline-rich peptides, respectively; through these interactions, they participate in intra- and intermolecular regulation of kinase activity, as well as localization and substrate recognition. Differences in the SH2 linker sequences within Src family kinases correlate with the division of the Src kinase family into two separate subfamilies: Group A: Src, Fyn, Yes, Fgr and Group B: Lyn, Hck, Lck and Blk. Frk forms a separate but linked subfamily but with homologues also found in invertebrates. Src family members, with the exception of Src, Fyn and Yes, exhibit tissue-restricted distribution, being found primarily in cells of a haematopoietic nature. Below is a table constructed from Src homology analysis performed by CluSTr: Src family member | % identity* | % similarity** | Fyn | 75 | 10 | Yes | 73 | 9 | Fgr | 66 | 11 | Lck | 60 | 17 | Lyn | 60 | 17 | Hck | 57 | 17 | Blk | 62 | 13 |
*Percent identity between Src and protein; defined as: (Same AAs/Length of Protein 1) X100% **Percent similarity between Src and protein; defined as: (Sim. AAs/Length of Protein 1) X100% |
Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. |
Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE. |
Cancer. 2002 Jan 15;94(2):344-51. |
PMID 11900220 |
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Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. |
Arpino G, Wiechmann L, Osborne CK, Schiff R. |
Endocr Rev. 2008 Apr;29(2):217-33. Epub 2008 Jan 23. (REVIEW) |
PMID 18216219 |
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Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. |
Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ. |
Breast Cancer Res. 2000;2(3):203-10. Epub 2000 Mar 7. (REVIEW) |
PMID 11250711 |
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Src and focal adhesion kinase as therapeutic targets in cancer. |
Brunton VG, Frame MC. |
Curr Opin Pharmacol. 2008 Aug;8(4):427-32. Epub 2008 Jul 22. (REVIEW) |
PMID 18625340 |
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Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. |
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. |
J Biol Chem. 2001 Mar 30;276(13):9817-24. Epub 2001 Jan 3. |
PMID 11139588 |
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Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis. |
Cartwright CA, Coad CA, Egbert BM. |
J Clin Invest. 1994 Feb;93(2):509-15. |
PMID 7509341 |
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PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. |
Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone MV, Auricchio F. |
EMBO J. 2001 Nov 1;20(21):6050-9. |
PMID 11689445 |
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Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530. |
Chang YM, Bai L, Liu S, Yang JC, Kung HJ, Evans CP. |
Oncogene. 2008 Oct 23;27(49):6365-75. Epub 2008 Aug 4. |
PMID 18679417 |
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Analysis of pp60c-src tyrosine kinase activity and phosphotyrosyl phosphatase activity in human colon carcinoma and normal human colon mucosal cells. |
DeSeau V, Rosen N, Bolen JB. |
J Cell Biochem. 1987 Oct;35(2):113-28. |
PMID 2448318 |
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Src family protein tyrosine kinases and cellular signal transduction pathways. |
Erpel T, Courtneidge SA. |
Curr Opin Cell Biol. 1995 Apr;7(2):176-82. (REVIEW) |
PMID 7612268 |
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Potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK through a serine 118-independent pathway. |
Feng W, Webb P, Nguyen P, Liu X, Li J, Karin M, Kushner PJ. |
Mol Endocrinol. 2001 Jan;15(1):32-45. |
PMID 11145737 |
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Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. |
Galliher AJ, Schiemann WP. |
Breast Cancer Res. 2006;8(4):R42. |
PMID 16859511 |
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Microenvironmental regulation of E-cadherin-mediated adherens junctions. |
Giehl K, Menke A. |
Front Biosci. 2008 May 1;13:3975-85. (REVIEW) |
PMID 18508491 |
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Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells. |
Hiscox S, Jordan NJ, Smith C, James M, Morgan L, Taylor KM, Green TP, Nicholson RI. |
Breast Cancer Res Treat. 2009 May;115(1):57-67. Epub 2008 May 21. |
PMID 18493848 |
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Src as a therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer. |
Hiscox S, Morgan L, Green T, Nicholson RI. |
Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S53-9. (REVIEW) |
PMID 17259559 |
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Integrin alpha v beta 3 controls activity and oncogenic potential of primed c-Src. |
Huveneers S, van den Bout I, Sonneveld P, Sancho A, Sonnenberg A, Danen EH. |
Cancer Res. 2007 Mar 15;67(6):2693-700. |
PMID 17363590 |
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Activating SRC mutation in a subset of advanced human colon cancers. |
Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, Karl R, Fujita DJ, Jove R, Yeatman TJ. |
Nat Genet. 1999 Feb;21(2):187-90. |
PMID 9988270 |
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Role of Src expression and activation in human cancer. |
Irby RB, Yeatman TJ. |
Oncogene. 2000 Nov 20;19(49):5636-42. (REVIEW) |
PMID 11114744 |
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Elevated c-Src is linked to altered cell-matrix adhesion rather than proliferation in KM12C human colorectal cancer cells. |
Jones RJ, Avizienyte E, Wyke AW, Owens DW, Brunton VG, Frame MC. |
Br J Cancer. 2002 Nov 4;87(10):1128-35. |
PMID 12402152 |
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Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. |
Li S. |
Leuk Lymphoma. 2008 Jan;49(1):19-26. (REVIEW) |
PMID 18203007 |
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Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. |
Massarweh S, Schiff R. |
Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S15-24. (REVIEW) |
PMID 17259554 |
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GPCRs signaling directly through Src-family kinases. |
McGarrigle D, Huang XY. |
Sci STKE. 2007 Jun 26;2007(392):pe35. (REVIEW) |
PMID 17595221 |
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Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. |
Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F. |
EMBO J. 2000 Oct 16;19(20):5406-17. |
PMID 11032808 |
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The Src kinase pathway promotes tamoxifen agonist action in Ishikawa endometrial cells through phosphorylation-dependent stabilization of estrogen receptor (alpha) promoter interaction and elevated steroid receptor coactivator 1 activity. |
Shah YM, Rowan BG. |
Mol Endocrinol. 2005 Mar;19(3):732-48. Epub 2004 Nov 4. |
PMID 15528270 |
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Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. |
Silva CM. |
Oncogene. 2004 Oct 18;23(48):8017-23. (REVIEW) |
PMID 15489919 |
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Src family kinases in tumor progression and metastasis. |
Summy JM, Gallick GE. |
Cancer Metastasis Rev. 2003 Dec;22(4):337-58. (REVIEW) |
PMID 12884910 |
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ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer metastasis. |
Tan M, Li P, Klos KS, Lu J, Lan KH, Nagata Y, Fang D, Jing T, Yu D. |
Cancer Res. 2005 Mar 1;65(5):1858-67. |
PMID 15753384 |
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Cellular functions regulated by Src family kinases. |
Thomas SM, Brugge JS. |
Annu Rev Cell Dev Biol. 1997;13:513-609. (REVIEW) |
PMID 9442882 |
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Heregulin and HER2 signaling selectively activates c-Src phosphorylation at tyrosine 215. |
Vadlamudi RK, Sahin AA, Adam L, Wang RA, Kumar R. |
FEBS Lett. 2003 May 22;543(1-3):76-80. |
PMID 12753909 |
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c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. |
Verbeek BS, Vroom TM, Adriaansen-Slot SS, Ottenhoff-Kalff AE, Geertzema JG, Hennipman A, Rijksen G. |
J Pathol. 1996 Dec;180(4):383-8. |
PMID 9014858 |
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Sensing estrogen's many pathways. |
Weatherman RV. |
ACS Chem Biol. 2008 Jun 20;3(6):338-40. |
PMID 18570353 |
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Identification of estrogen receptor ligands leading to activation of non-genomic signaling pathways while exhibiting only weak transcriptional activity. |
Wessler S, Otto C, Wilck N, Stangl V, Fritzemeier KH. |
J Steroid Biochem Mol Biol. 2006 Jan;98(1):25-35. Epub 2005 Oct 3. |
PMID 16203130 |
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