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Gene Review

Csk  -  c-src tyrosine kinase

Rattus norvegicus

Synonyms: C-Src kinase, Tyrosine-protein kinase CSK
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Disease relevance of Csk


High impact information on Csk

  • The activity of Src-PTKs in cells of different types is negatively controlled by Csk, which specifically phosphorylates a conserved regulatory tyrosine residue at the carboxy-terminal tail of the Src-PTKs [5].
  • Transient overexpression of a dominant interfering mutant of Pyk2 or the protein tyrosine kinase Csk reduces LPA- or bradykinin-induced activation of MAP kinase [6].
  • In addition, pyk2(K457A) blocked acid activation of c-Src kinase, which is also required for acid regulation of NHE3 [7].
  • Overexpression of C-terminal Src kinase (Csk), which inactivates Src family tyrosine kinases, suppressed the activation of transfected ERK in cardiac fibroblasts [8].
  • Overexpression of Csk or the dominant-negative mutant of Ras had no effects on Ang II-induced ERK activation in cardiac myocytes [8].

Chemical compound and disease context of Csk

  • The broad band of semi-purified p130 became sharp at an elevated position in the gel upon treatment with orthovanadate in vivo or with c-Src kinase produced using a baculovirus vector in vitro, whereas it shifted at a lower position upon treatment with alkaline phosphatase in vitro [9].

Biological context of Csk

  • The function of SFK is regulated by phosphorylation at the C-terminal regulatory site mediated by Csk [10].
  • Mechanism of Csk-mediated down-regulation of Src family tyrosine kinases in epidermal growth factor signaling [10].
  • Upon SFK activation induced by epidermal growth factor stimulation, fluorescent resonance energy transfer (FRET) response was detected transiently at membrane ruffles in COS1 cells co-expressing CFP-Csk and Cbp-YFP and in cells expressing a single-molecule FRET indicator consisting of CskSH2 and Cbp [10].
  • In striking contrast, Csk is highly expressed throughout embryonic development and remains high in the CNS until birth [11].
  • We report herein that prior to occurrence of neoplastic lesions in the azoxymethane-rat model of colon carcinogenesis; the tumor suppressor gene C-terminal Src kinase (Csk) was down-regulated with a concomitant increase in Src activity [3].

Anatomical context of Csk

  • The Csk homologous kinase associates with TrkA receptors and is involved in neurite outgrowth of PC12 cells [12].
  • When adult rats were treated with 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364), a compound known to induce germ cell loss from the seminiferous epithelium, in particular elongating/elongate and round spermatids, by disrupting Sertoli-germ cell AJs, an induction of c-Src and Csk, but not CK2, was detected [2].
  • In short, the data reported herein have shown that c-Src, Csk, and CK2 are novel protein kinases in AJ dynamics in the testis [2].
  • An induction in c-Src, Csk, and CK2 were detected during Sertoli-germ cell AJ assembly in vitro but not when Sertoli cells were cultured alone [2].
  • To investigate the roles of BatK and Csk, both of which are expressed in the brain, we compared their temporal expression patterns during development of the central nervous system (CNS) in rats [11].

Associations of Csk with chemical compounds

  • The onsets of the series of events including tyrosyl phosphorylation of Syk, mitogen-activated protein (MAP) kinase activation, elevation of intracellular calcium concentration ([Ca2+]i), and histamine release were all stepwisely delayed in Csk-expressing cells and in mCsk-expressing cells [13].
  • Once phosphorylated at Tyr-511 and down-regulated by CSK, c-Fgr is no more susceptible to polylysine stimulation [14].
  • Rats treated with azaserine showed a 7-fold-higher c-Src tyrosine kinase activity in their pancreas [15].
  • Both omeprazole- and TCDD-dependent AhR signalling was attenuated by inhibition of c-src kinase, either by using pyrazolopyrimidine 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4 ]pyrimidine (PP1) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) inhibitors or by expression of dominant-negative c-src [16].
  • The effect was also abrogated by chelating intracellular calcium with BAPTA-AM or TMB-8 by depleting intracellular calcium stores with a 30-min pretreatment with EGTA and by pretreatment with herbimycin A and PP1, two c-Src tyrosine kinase inhibitors [17].

Enzymatic interactions of Csk

  • Csk and phosphorylated Cbp were co-purified as a large protein complex consisting of at least four Csk.Cbp units [18].
  • BatK is a second member of the Csk family of regulatory kinases that phosphorylate a key inhibitory tyrosine on Src family kinases, leading to down-regulation [11].
  • The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk [19].

Regulatory relationships of Csk


Other interactions of Csk

  • The Cbp-mediated relocation of Csk to the membrane may play a role in turning off the signaling events initiated by SFKs [18].
  • Structure of the carboxyl-terminal Src kinase, Csk [21].
  • In rat basophilic leukemia (RBL)-2H3 cells, the levels of tyrosine phosphorylation of Cbp/PAG and its association with Csk, a negative regulator for Lyn, significantly elevate immediately after aggregation of FcepsilonRI [22].
  • In Csk(-/-) fibroblasts, suppression of SFK results in prolonged EGF-induced activation of Erk1/2, with concomitant suppression of EGFR degradation [23].
  • In conclusion, altered regulation of Ang II type 1 receptor-activated c-Src by Csk may be an important upstream modulator of abnormal ERK1/2 signaling in VSMCs from SHR [24].

Analytical, diagnostic and therapeutic context of Csk

  • In human tumorous tissues, Western blot revealed a 53-kd immunoreactive band, which was slightly larger than the usual 50-kd band of Csk [1].
  • We investigated the role of Csk in hepatocarcinogenesis by analyzing the location, amount of Csk, and its kinase activity levels in nontumorous cirrhotic and tumorous sections of HCC of patients and an animal model of LEC rats [1].
  • We used the whole cell patch-clamp technique in calf pulmonary endothelial (CPAE) cells to investigate the effect of wild-type and mutant c-Src tyrosine kinase on I(Cl,swell), the swelling-induced Cl- current through volume-regulated anion channels (VRAC) [25].


  1. Reduced C-terminal Src kinase (Csk) activities in hepatocellular carcinoma. Masaki, T., Okada, M., Tokuda, M., Shiratori, Y., Hatase, O., Shirai, M., Nishioka, M., Omata, M. Hepatology (1999) [Pubmed]
  2. Protein kinases and adherens junction dynamics in the seminiferous epithelium of the rat testis. Lee, N.P., Cheng, C.Y. J. Cell. Physiol. (2005) [Pubmed]
  3. Down-regulation of the tumor suppressor gene C-terminal Src kinase: an early event during premalignant colonic epithelial hyperproliferation. Kunte, D.P., Wali, R.K., Koetsier, J.L., Hart, J., Kostjukova, M.N., Kilimnik, A.Y., Pyatkin, I.G., Strelnikova, S.R., Roy, H.K. FEBS Lett. (2005) [Pubmed]
  4. Inherited hydrocephalus in Csk: Wistar-Imamichi rats; Hyd strain: a new disease model for hydrocephalus. Koto, M., Miwa, M., Shimizu, A., Tsuji, K., Okamoto, M., Adachi, J. Jikken Dobutsu (1987) [Pubmed]
  5. 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]
  6. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Dikic, I., Tokiwa, G., Lev, S., Courtneidge, S.A., Schlessinger, J. Nature (1996) [Pubmed]
  7. Pyk2 activation is integral to acid stimulation of sodium/hydrogen exchanger 3. Li, S., Sato, S., Yang, X., Preisig, P.A., Alpern, R.J. J. Clin. Invest. (2004) [Pubmed]
  8. Cell type-specific angiotensin II-evoked signal transduction pathways: critical roles of Gbetagamma subunit, Src family, and Ras in cardiac fibroblasts. Zou, Y., Komuro, I., Yamazaki, T., Kudoh, S., Aikawa, R., Zhu, W., Shiojima, I., Hiroi, Y., Tobe, K., Kadowaki, T., Yazaki, Y. Circ. Res. (1998) [Pubmed]
  9. Characterization, partial purification, and peptide sequencing of p130,the main phosphoprotein associated with v-Crk oncoprotein. Sakai, R., Iwamatsu, A., Hirano, N., Ogawa, S., Tanaka, T., Nishida, J., Yazaki, Y., Hirai, H. J. Biol. Chem. (1994) [Pubmed]
  10. Mechanism of Csk-mediated down-regulation of Src family tyrosine kinases in epidermal growth factor signaling. Matsuoka, H., Nada, S., Okada, M. J. Biol. Chem. (2004) [Pubmed]
  11. Csk and BatK show opposite temporal expression in the rat CNS: consistent with its late expression in development, BatK induces differentiation of PC12 cells. Kuo, S.S., Armanini, M.P., Phillips, H.S., Caras, I.W. Eur. J. Neurosci. (1997) [Pubmed]
  12. The Csk homologous kinase associates with TrkA receptors and is involved in neurite outgrowth of PC12 cells. Yamashita, H., Avraham, S., Jiang, S., Dikic, I., Avraham, H. J. Biol. Chem. (1999) [Pubmed]
  13. Roles of C-terminal Src kinase in the initiation and the termination of the high affinity IgE receptor-mediated signaling. Honda, Z., Suzuki, T., Hirose, N., Aihara, M., Shimizu, T., Nada, S., Okada, M., Ra, C., Morita, Y., Ito, K. J. Biol. Chem. (1997) [Pubmed]
  14. Regulation of c-Fgr protein kinase by c-Src kinase (CSK) and by polycationic effectors. Ruzzene, M., James, P., Brunati, A.M., Donella-Deana, A., Pinna, L.A. J. Biol. Chem. (1994) [Pubmed]
  15. Increased immunoreactivity and protein tyrosine kinase activity of the protooncogene pp60c-src in preneoplastic lesions in rat pancreas. Visser, C.J., Rijksen, G., Woutersen, R.A., De Weger, R.A. Lab. Invest. (1996) [Pubmed]
  16. Regulation of aryl hydrocarbon receptor signal transduction by protein tyrosine kinases. Backlund, M., Ingelman-Sundberg, M. Cell. Signal. (2005) [Pubmed]
  17. Angiotensin II phosphorylation of extracellular signal-regulated kinases in rat anterior pituitary cells. Suárez, C., Díaz-Torga, G., Gonzalez-Iglesias, A., Vela, J., Mladovan, A., Baldi, A., Becu-Villalobos, D. Am. J. Physiol. Endocrinol. Metab. (2003) [Pubmed]
  18. Transmembrane phosphoprotein Cbp positively regulates the activity of the carboxyl-terminal Src kinase, Csk. Takeuchi, S., Takayama, Y., Ogawa, A., Tamura, K., Okada, M. J. Biol. Chem. (2000) [Pubmed]
  19. Phosphorylation of Hic-5 at tyrosine 60 by CAKbeta and Fyn. Ishino, M., Aoto, H., Sasaski, H., Suzuki, R., Sasaki, T. FEBS Lett. (2000) [Pubmed]
  20. Transforming growth factor-alpha prevents detachment-induced inhibition of c-Src kinase activity, Bcl-XL down-regulation, and apoptosis of intestinal epithelial cells. Rosen, K., Coll, M.L., Li, A., Filmus, J. J. Biol. Chem. (2001) [Pubmed]
  21. Structure of the carboxyl-terminal Src kinase, Csk. Ogawa, A., Takayama, Y., Sakai, H., Chong, K.T., Takeuchi, S., Nakagawa, A., Nada, S., Okada, M., Tsukihara, T. J. Biol. Chem. (2002) [Pubmed]
  22. Cutting Edge: Transmembrane phosphoprotein Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains as a negative feedback regulator of mast cell signaling through the FcepsilonRI. Ohtake, H., Ichikawa, N., Okada, M., Yamashita, T. J. Immunol. (2002) [Pubmed]
  23. Role of Src family tyrosine kinases in the down-regulation of epidermal growth factor signaling in PC12 cells. Kasai, A., Shima, T., Okada, M. Genes Cells (2005) [Pubmed]
  24. Increased angiotensin II-mediated Src signaling via epidermal growth factor receptor transactivation is associated with decreased C-terminal Src kinase activity in vascular smooth muscle cells from spontaneously hypertensive rats. Touyz, R.M., Wu, X.H., He, G., Salomon, S., Schiffrin, E.L. Hypertension (2002) [Pubmed]
  25. Inhibition of VRAC by c-Src tyrosine kinase targeted to caveolae is mediated by the Src homology domains. Trouet, D., Carton, I., Hermans, D., Droogmans, G., Nilius, B., Eggermont, J. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
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