Disease relevance of Src

• Taken together, these findings suggest that Src-dependent tyrosine phosphorylation of PYK2 is involved in the adhesion-induced formation of the sealing zone, required for osteoclastic bone resorption [1].
• Src-deficient mice exhibit functional abnormalities in only one myeloid cell type, the osteoclast, resulting in impaired bone remodeling and osteopetrosis, while hck-/- or fgr-/- mice have few and subtle myeloid cell deficiencies [2].
• Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells [3].
• Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras [4].
• We detected an increase in Src proto-oncogene activity within 15-30 min of cellular exposure to hypoxia [5].

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

• For example, the kinases Src and Abelson (Abl) were originally identified as oncogenes and were later characterized as important proteins for signal transduction in various cell types, including lymphocytes [7].
• The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl [8].
• Src kinases in Ph+ lymphoblastic leukemia [9].
• Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases [10].
• These data demonstrate that the Src family tyrosine kinases are direct effectors of G proteins [10].

Chemical compound and disease context of Src

• Polycythemia and reticulocytosis responded to treatment with imatinib or a JAK2 inhibitor, but were unresponsive to the Src inhibitor dasatinib [11].
• 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 [12].
• Involvement of G(i) proteins and Src tyrosine kinase in TNFalpha production induced by lipopolysaccharide, group B Streptococci and Staphylococcus aureus [13].
• AG 879, in combination of PP1 (an inhibitor specific for Src kinase family), suppresses almost completely the growth of RAS-induced sarcomas in nude mice [14].
• The objective of this study was to analyse the role of c-Src in the (alpha)(v)(beta)(3) integrin-dependent recruitment of signalling and cytoskeletal molecules in osteoclasts during bone resorption [15].

Biological context of Src

• A target for Src in mitosis [16].
• The activity of the c-Src protein is increased during cell-cycle stage G1 in fibroblasts stimulated with certain growth factors, and at the G2/M transition, but little is known about Src substrates in these circumstances [16].
• We report here that the proto-oncogene product c-Cbl is tyrosine-phosphorylated in a Src-dependent manner in osteoclasts, where the two proteins colocalize on some vesicular structures [17].
• Our data suggest that Src kinases control the transcriptional activation of Myc [18].
• Thus, Src family kinases and proteins associating with their SH2 domains are required for entry into mitosis [19].

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

• We compared the phosphotyrosine content of growing and mitotically arrested Src-transformed cells [16].
• Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division [19].
• We find here that Src associates constitutively with integrin alphaIIbbeta3 in platelets [24].
• Proline-rich sequences that bind to Src homology 3 domains with individual specificities [25].
• One clone that binds to both Src and Abl SH3 domains through a common site exhibits reversed binding orientation, in that an arginine indispensable for binding to all tested SH3 domains occurs at the C terminus [25].

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 [26].
• Furthermore, we show that this interaction is direct and that Grb2 binds to phospho-AbetaPP via its Src homology 2 region [27].
• Eliminating the Src-binding site on Pyk2 (Pyk2(Y402F)) markedly inhibited bone resorption by osteoclast-like cells, whereas kinase-dead Pyk2 had little effect [28].
• Autophosphorylation of PDGF receptors upon ligand stimulation provides binding sites for Src homology 2 domains of intracellular signaling molecules, which thereby become activated [29].
• Furthermore, this tyrosine phosphorylated protein was not detected in c-Src complexes derived from fibroblasts transformed by either Neu or PyV middle T [30].

Enzymatic interactions of Src

• This heteromolecular complex is coordinated by proline-rich and Src family-dependent phosphorylated regions of M2 [31].
• In contrast, expression of a cortactin mutant lacking tyrosine residues phosphorylated by Src did not restore podosome formation [32].
• 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 [33].
• Sam68 is the major tyrosine-phosphorylated and Src-associated protein in mitotic cells [34].
• Src phosphorylates the insulin-like growth factor type I receptor on the autophosphorylation sites. Requirement for transformation by src [35].

Co-localisations of Src

• Upon activation of PKC, RACK1 co-localizes with the Src tyrosine kinase at the plasma membrane and functions as a substrate, binding partner and inhibitor of Src (as measured in vitro), and a growth inhibitor in NIH 3T3 cells [36].

Regulatory relationships of Src

• Tr-kit-induced resumption of the cell cycle in mouse eggs requires activation of a Src-like kinase [37].
• We also measured the levels of Src kinase activity in cell lines expressing isoforms of the Ret receptor activated by different mutations [38].
• 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 [39].
• Epidermal growth factor-induced DNA synthesis. Key role for Src phosphorylation of the docking protein Gab2 [40].
• In addition, we demonstrated that the Src-induced response was down-regulated by Gab2-associated SHP2 [40].

Other interactions of Src

• The engagement of these receptors leads to the activation of Lck and Fyn, which are protein tyrosine kinases (PTKs) of the Src family [41].
• c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption [17].
• The p68 was physically associated with activated c-Src, and it bound to the SH3 domain of c-Src in vitro [16].
• Fyn and Yes, the other members of the Src family present in fibroblasts, were also found to be activated at mitosis [19].
• Two families of protein tyrosine kinases (PTKs), the Src and Syk/ZAP-70 families, are required for T cell development [20].

Analytical, diagnostic and therapeutic context of Src

• To assess the relevance of Src inhibition to angiogenesis, in vivo gelfoam assays were done [42].
• Based on coprecipitation analysis and two-color immunofluorescence, this heterologous Src family kinase was observed to physically associate with the B cell Ag receptor [43].
• We also compared the tyrosine-phosphorylation status of Lck and Fgr to other Src family members in resting platelets using immunoprecipitation and immunoblotting [44].
• Inhibition of Src kinases combined with CD40 ligand blockade prolongs murine cardiac allograft survival [45].
• An association between CSK and c-Src was detected by immunoprecipitation following IGF-I stimulation of differentiating but not proliferating 3T3-L1 cells [46].

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)
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)
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)
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)
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)
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)
7. B cell signaling and tumorigenesis. Jumaa, H., Hendriks, R.W., Reth, M. Annu. Rev. Immunol. (2005)
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)
9. Src kinases in Ph+ lymphoblastic leukemia. Deininger, M. Nat. Genet. (2004)
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)
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)
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)
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)
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)
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)
16. A target for Src in mitosis. Fumagalli, S., Totty, N.F., Hsuan, J.J., Courtneidge, S.A. Nature (1994)
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)
18. Myc but not Fos rescue of PDGF signalling block caused by kinase-inactive Src. Barone, M.V., Courtneidge, S.A. Nature (1995)
19. Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division. Roche, S., Fumagalli, S., Courtneidge, S.A. Science (1995)
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)
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)
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)
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)
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)
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)
26. 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)
27. 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)
28. 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)
29. 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)
30. 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)
31. 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)
32. 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)
33. 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)
34. Sam68 is a Ras-GAP-associated protein in mitosis. Guitard, E., Barlat, I., Maurier, F., Schweighoffer, F., Tocque, B. Biochem. Biophys. Res. Commun. (1998)
35. 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)
36. RACK1 regulates Src-mediated Sam68 and p190RhoGAP signaling. Miller, L.D., Lee, K.C., Mochly-Rosen, D., Cartwright, C.A. Oncogene (2004)
37. 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)
38. 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)
39. 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)
40. 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)
41. 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)
42. 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)
43. 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)
44. 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)
45. 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)
46. 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)