Definition
C-terminal Src kinase (CSK) is an endogenous inhibitor of Src family of protoongogenic protein kinases. It phosphorylates these kinases at a specific Tyr-504 residue1.
Discovery
CSK activity was first described in 19912.
Classification
CSK belongs to the tyrosine kinase family of proteins1.
Structural Characteristics
CSK is a 50 Kda protein. Its structure consists of a small, N-terminal lobe made up of a beta-sheet, and a larger C-terminal lobe made up mostly of alpha-helices3. The structure reveals atomic details of interactions with staurosporine, which binds in a deep cleft between the lobes. Interactions between the N and C-terminal lobe are mediated by the bound staurosporine molecule and by hydrogen bonds3. In addition, there are several water molecules forming lobe-bridging hydrogen bonds, which may be important for maintaining catalytic integrity of the kinase. CSK all in all has three major domains, SH2, SH3 and kinase domains3.
Mode of action
CSK first binds to transmambrane proteins through its SH2, SH3 and kinase domains which facilitates its translocation to the plasma membrane4. It then binds to Src kinase and phosphorylates it at the Tyr-504 residue4. This phosphorylation results in conformational changes in Src kinase which lead to its inactivation4.
Functions
Csk catalyzes a tail phosphorylation reaction on Src and thereby restrains Src's activity and oncogenic potential5.
References
1. Book: Drug discovery handbook. By Shayne C. Gad, 1198-1199.
2. Okada M and Nakagawa H (1989). A protein-tyrosine kinase involved in regulation of pp60c-src function. J. Biol. Chem., 264, 20886–20893.
3. Lamers MBAC, Antson A, Scott RG, Hubbard RE and Williams DH (1999). Structure of the Protein Tyrosine Kinase Domain of C-terminal Src Kinase (CSK) in Complex with Staurosporine. J. Mol. Biol., 285 (2), 712-725.
4. Chong YP, Mulhern TD, Cheng HC (2005). C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK)--endogenous negative regulators of Src-family protein kinases. Growth Factors, 23(3), 233-44.
5. Cole PA, Shen K, Qiao Y, Wang D (2003). Protein tyrosine kinases Src and Csk: a tail's tale. Curr Opin Chem Biol., 7(5):580-5.