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Gene Review

Csk  -  c-src tyrosine kinase

Mus musculus

Synonyms: AW212630, C-Src kinase, Protein-tyrosine kinase MPK-2, Tyrosine-protein kinase CSK, p50CSK
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Disease relevance of Csk

  • Functional analysis of Csk and CHK kinases in breast cancer cells [1].
  • The recombinant adenovirus vector carrying csk cDNA induced Csk expression in mouse osteoclast-like cells formed in vitro and clearly reduced c-Src kinase activity in a dose-dependent manner [2].
  • Src/Csk transfectants developed normally in the initial stages of neural differentiation, but exhibited an apparent defect in cell-to-cell interaction, i.e. neurite fasciculation and aggregation of cell bodies, in the latter stages [3].
  • Of these candidates, Csk is the strongest for NC dermatitis, since its map position was most tightly linked to the derm1 locus [4].
  • Importantly, Csk overexpression in NL-17 cells resulted in significant suppression of in vivo metastasis, without affecting its tumorgenicity [5].

High impact information on Csk

  • These results demonstrate that Src family kinase activity is critically dependent on phosphorylation by Csk and suggest that the regulation of kinase activity may be essential during embryogenesis [6].
  • To analyze the significance of this regulation during development, we have generated mice deficient in Csk, a kinase that phosphorylates this tyrosine, by gene targeting in embryonic stem cells [6].
  • This provides evidence for the involvement of Csk in the regulation of T-cell activation [7].
  • Hyperphosphorylation of key signaling proteins such as Syk and Paxillin in mutant granulocytes further supported breakdown of the activation threshold set by Csk [8].
  • Csk-deficient granulocytes showed enhanced spontaneous and ligand-induced degranulation with hyperinduction of integrins [8].

Chemical compound and disease context of Csk


Biological context of Csk

  • The function of Csk as a repressor of Lck and Fyn activity suggests activation of these PTKs is solely responsible for the phenotype observed in csk-deficient T lineage cells [11].
  • These findings suggest that Cbp could serve as a sensor of SFK activity in early stages of cell adhesion signaling, and that Csk-mediated down-regulation of SFK is essential to allow dynamic cellular events involved in the regulation of cell spreading and migration [12].
  • Our studies showed that PAG tyrosine phosphorylation and association with Csk are suppressed in response to activation of normal mouse T cells [13].
  • In reconstitution experiments, we first showed that expression in the RAW 264.7 cell line of C-terminal Src kinase (Csk) inhibited and that of a membrane-anchored, gain-of-function Csk abolished the Fc gamma R-mediated signaling that leads to phagocytosis in a kinase-dependent manner [14].
  • These findings imply that Csk is involved in the regulation of Src family kinases that play roles in cell-to-cell interaction mediated by cell adhesion molecules [3].

Anatomical context of Csk

  • It remains unclear whether activation of Lck and Fyn in the absence of Csk uncouples alpha/beta T cell development entirely from engagement of surface-expressed receptors [11].
  • Cbp, a C-terminal Src kinase (Csk)-binding protein, is a transmembrane phosphoprotein that has been implicated in the regulation of the Src family kinase (SFK) through recruiting Csk, a negative regulator of SFK, to a membrane microdomain of lipid rafts [12].
  • They also show a role for Csk in P. aeruginosa invasion, while providing further evidence that actin cytoskeleton disruption contributes to ExsA-regulated P. aeruginosa cytotoxicity and invasion inhibition [15].
  • Both p130Cas and c-Cbl have been reported to play critical roles in osteoclast function as downstream targets of c-Src kinase [16].
  • We measured c-Src kinase activity in cell lysates from proliferating, growth-arrested and differentiating 3T3-L1 cells [17].

Associations of Csk with chemical compounds

  • Further study revealed that the Src kinase was activated by HgCl2 at least in part independent of the known Csk kinase-linked or Y527-phosphorylation/dephosphorylation-mediated control [18].
  • Since SH2 domains recognize phosphotyrosine, it is possible that these two non-catalytic domains associate, and thereby repress c-Src kinase activity [19].
  • Further analyses revealed that this interaction was mediated by the Csk SH3 domain and by a proline-rich region (PPPLPERTP) in the non-catalytic C-terminal portion of PEP [20].
  • This phosphorylation induces the binding of Dok-3 to at least two inhibitory molecules, the 5' inositol phosphatase SHIP and the protein tyrosine kinase Csk [21].
  • In Y567F, Lyn activation on SCF stimulation decreased and C-terminal Src kinase (Csk) suppressed KIT-mediated Ca(2+) influx and cell migration, suggesting that Y567-mediated Src family kinase (SFK) activation leads to Ca(2+) influx and migration [22].

Physical interactions of Csk

  • CD45-D2 bound similarly to Src family kinases but bound Csk to a lesser extent and did not bind significantly to the less related kinase, Erk1 [23].
  • In addition, tyrosine-phosphorylated PSD-93 was able to bind to Csk, a negative regulator of Src family kinases, in vitro as well as in a brain lysate [24].
  • In this report, we have tested the possibility that Csk also interacts with PTP-PEST, a ubiquitous PTP sharing structural homology with PEP [25].

Enzymatic interactions of Csk

  • Firm evidence that Ntk is a Csk-related enzyme was provided by the observation that it phosphorylated a Src-related polypeptide on the inhibitory carboxyl-terminal tyrosine [26].
  • Paxillin was also tyrosine-phosphorylated in Csk-overexpressing cells, indicating that it can serve as a substrate of Csk [27].
  • Csk binds specifically to the phosphorylated caveolin-1 and attenuates its stress-induced phosphorylation [28].

Regulatory relationships of Csk


Other interactions of Csk

  • These data suggest a differential involvement of the Csk-mediated regulation of Src family PTKs in positive and negative selection of developing thymocytes [11].
  • In resting T cells, Csk is constitutively localized in lipid rafts by virtue of interaction with a phosphorylated adaptor protein, Csk-binding protein (Cbp)/phosphoprotein associated with glycolipid-enriched microdomains, and sets an activation threshold in TCR signaling [29].
  • Interestingly, there was a concomitant increase in the phosphorylation of Fyn on its Csk (C-terminal Src kinase) site, indicating feedback inhibition [33].
  • Upon cell adhesion onto fibronectin, Cbp becomes transiently phosphorylated (consistent with SFK activation) and recruits Csk to lipid rafts [12].
  • Csk expression and kinase activity were abundant in normal human breast tissues, breast carcinomas, and breast cancer cell lines, whereas CHK expression was negative in normal breast tissues and low in some breast tumors and in the MCF-7 breast cancer cell line [1].

Analytical, diagnostic and therapeutic context of Csk


  1. Functional analysis of Csk and CHK kinases in breast cancer cells. Bougeret, C., Jiang, S., Keydar, I., Avraham, H. J. Biol. Chem. (2001) [Pubmed]
  2. In vitro and in vivo suppression of osteoclast function by adenovirus vector-induced csk gene. Miyazaki, T., Takayanagi, H., Isshiki, M., Takahashi, T., Okada, M., Fukui, Y., Oda, H., Nakamura, K., Hirai, H., Kurokawa, T., Tanaka, S. J. Bone Miner. Res. (2000) [Pubmed]
  3. Role of Csk in neural differentiation of the embryonic carcinoma cell line P19. Takayama, Y., Nada, S., Nagai, K., Okada, M. FEBS Lett. (1997) [Pubmed]
  4. A major determinant quantitative-trait locus responsible for atopic dermatitis-like skin lesions in NC/Nga mice is located on Chromosome 9. Kohara, Y., Tanabe, K., Matsuoka, K., Kanda, N., Matsuda, H., Karasuyama, H., Yonekawa, H. Immunogenetics (2001) [Pubmed]
  5. Overexpression of the csk gene suppresses tumor metastasis in vivo. Nakagawa, T., Tanaka, S., Suzuki, H., Takayanagi, H., Miyazaki, T., Nakamura, K., Tsuruo, T. Int. J. Cancer (2000) [Pubmed]
  6. Disruption of the csk gene, encoding a negative regulator of Src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice. Imamoto, A., Soriano, P. Cell (1993) [Pubmed]
  7. Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50csk. Chow, L.M., Fournel, M., Davidson, D., Veillette, A. Nature (1993) [Pubmed]
  8. C-terminal SRC kinase controls acute inflammation and granulocyte adhesion. Thomas, R.M., Schmedt, C., Novelli, M., Choi, B.K., Skok, J., Tarakhovsky, A., Roes, J. Immunity (2004) [Pubmed]
  9. Use of c-Src and c-Fos knockout mice for the studies on the role of c-Src kinase signaling in the expression of toxicity of TCDD. Enan, E., Dunlap, D.Y., Matsumura, F. J. Biochem. Mol. Toxicol. (1998) [Pubmed]
  10. Mechanisms of gender-specific TCDD-induced toxicity in guinea pig adipose tissue. Enan, E., El-Sabeawy, F., Overstreet, J., Matsumura, F., Lasley, B. Reprod. Toxicol. (1998) [Pubmed]
  11. Autonomous maturation of alpha/beta T lineage cells in the absence of COOH-terminal Src kinase (Csk). Schmedt, C., Tarakhovsky, A. J. Exp. Med. (2001) [Pubmed]
  12. Transmembrane phosphoprotein Cbp senses cell adhesion signaling mediated by Src family kinase in lipid rafts. Shima, T., Nada, S., Okada, M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  13. Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor. Davidson, D., Bakinowski, M., Thomas, M.L., Horejsi, V., Veillette, A. Mol. Cell. Biol. (2003) [Pubmed]
  14. 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]
  15. Mutation of csk, encoding the C-terminal Src kinase, reduces Pseudomonas aeruginosa internalization by mammalian cells and enhances bacterial cytotoxicity. Evans, D.J., Kuo, T.C., Kwong, M., Van, R., Fleiszig, S.M. Microb. Pathog. (2002) [Pubmed]
  16. Distinct roles of p130Cas and c-Cbl in adhesion-induced or macrophage colony-stimulating factor-mediated signaling pathways in prefusion osteoclasts. Nakamura, I., Rodan, G.A., Duong, l.e. .T. Endocrinology (2003) [Pubmed]
  17. 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]
  18. Mercuric chloride mediates a protein sulfhydryl modification-based pathway of signal transduction for activating Src kinase which is independent of the phosphorylation/dephosphorylation of a carboxyl terminal tyrosine. Pu, M.Y., Akhand, A.A., Kato, M., Koike, T., Hamaguchi, M., Suzuki, H., Nakashima, I. J. Cell. Biochem. (1996) [Pubmed]
  19. Regulation of c-Src tyrosine kinase activity by the Src SH2 domain. Liu, X., Brodeur, S.R., Gish, G., Songyang, Z., Cantley, L.C., Laudano, A.P., Pawson, T. Oncogene (1993) [Pubmed]
  20. Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. Cloutier, J.F., Veillette, A. EMBO J. (1996) [Pubmed]
  21. Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling. Lemay, S., Davidson, D., Latour, S., Veillette, A. Mol. Cell. Biol. (2000) [Pubmed]
  22. Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration. Ueda, S., Mizuki, M., Ikeda, H., Tsujimura, T., Matsumura, I., Nakano, K., Daino, H., Honda Zi, Z., Sonoyama, J., Shibayama, H., Sugahara, H., Machii, T., Kanakura, Y. Blood (2002) [Pubmed]
  23. Subdomain X of the kinase domain of Lck binds CD45 and facilitates dephosphorylation. Felberg, J., Lefebvre, D.C., Lam, M., Wang, Y., Ng, D.H., Birkenhead, D., Cross, J.L., Johnson, P. J. Biol. Chem. (2004) [Pubmed]
  24. Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn. Nada, S., Shima, T., Yanai, H., Husi, H., Grant, S.G., Okada, M., Akiyama, T. J. Biol. Chem. (2003) [Pubmed]
  25. Inhibitory tyrosine protein kinase p50csk is associated with protein-tyrosine phosphatase PTP-PEST in hemopoietic and non-hemopoietic cells. Davidson, D., Cloutier, J.F., Gregorieff, A., Veillette, A. J. Biol. Chem. (1997) [Pubmed]
  26. Ntk: a Csk-related protein-tyrosine kinase expressed in brain and T lymphocytes. Chow, L.M., Jarvis, C., Hu, Q., Nye, S.H., Gervais, F.G., Veillette, A., Matis, L.A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  27. Adenovirus-mediated overexpression of C-terminal Src kinase (Csk) in type I astrocytes interferes with cell spreading and attachment to fibronectin. Correlation with tyrosine phosphorylations of paxillin and FAK. Takayama, Y., Tanaka, S., Nagai, K., Okada, M. J. Biol. Chem. (1999) [Pubmed]
  28. Oxidative stress activates both Src-kinases and their negative regulator Csk and induces phosphorylation of two targeting proteins for Csk: caveolin-1 and paxillin. Cao, H., Sanguinetti, A.R., Mastick, C.C. Exp. Cell Res. (2004) [Pubmed]
  29. Cutting edge: Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells. Yasuda, K., Nagafuku, M., Shima, T., Okada, M., Yagi, T., Yamada, T., Minaki, Y., Kato, A., Tani-Ichi, S., Hamaoka, T., Kosugi, A. J. Immunol. (2002) [Pubmed]
  30. Direct and specific interaction of c-Src with Neu is involved in signaling by the epidermal growth factor receptor. Muthuswamy, S.K., Muller, W.J. Oncogene (1995) [Pubmed]
  31. Cellular stress induces the tyrosine phosphorylation of caveolin-1 (Tyr(14)) via activation of p38 mitogen-activated protein kinase and c-Src kinase. Evidence for caveolae, the actin cytoskeleton, and focal adhesions as mechanical sensors of osmotic stress. Volonté, D., Galbiati, F., Pestell, R.G., Lisanti, M.P. J. Biol. Chem. (2001) [Pubmed]
  32. RACK1 inhibits the serum- and anchorage-independent growth of v-Src transformed cells. Mamidipudi, V., Chang, B.Y., Harte, R.A., Lee, K.C., Cartwright, C.A. FEBS Lett. (2004) [Pubmed]
  33. Fyn is required for oxidative- and hyperosmotic-stress-induced tyrosine phosphorylation of caveolin-1. Sanguinetti, A.R., Cao, H., Corley Mastick, C. Biochem. J. (2003) [Pubmed]
  34. Ctk: a protein-tyrosine kinase related to Csk that defines an enzyme family. Klages, S., Adam, D., Class, K., Fargnoli, J., Bolen, J.B., Penhallow, R.C. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  35. Expression of p50 C-terminal Src kinase (Csk) in mouse testis. Gye, M.C., Choi, J.K., Ahn, H.S., Kim, Y.S. Arch. Androl. (2004) [Pubmed]
  36. Nitric oxide controls src kinase activity through a sulfhydryl group modification-mediated Tyr-527-independent and Tyr-416-linked mechanism. Akhand, A.A., Pu, M., Senga, T., Kato, M., Suzuki, H., Miyata, T., Hamaguchi, M., Nakashima, I. J. Biol. Chem. (1999) [Pubmed]
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