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J. Biol. Chem., Vol. 281, Issue 12, 8183-8189, March 24, 2006

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Docking-based Substrate Recognition by the Catalytic Domain of a Protein Tyrosine Kinase, C-terminal Src Kinase (Csk)^*

Sungsoo Lee¹, Marina K. Ayrapetov, David J. Kemble, Keykavous Parang, and Gongqin Sun²

From the Departments of Cell and Molecular Biology and Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881

Protein tyrosine kinases are key enzymes of mammalian signal transduction. Substrate specificity is a fundamental property that determines the specificity and fidelity of signaling by protein tyrosine kinases. However, how protein tyrosine kinases recognize the protein substrates is not well understood. C-terminal Src kinase (Csk) specifically phosphorylates Src family kinases on a C-terminal Tyr residue, which down-regulates their activities. We have previously determined that Csk recognizes Src using a substrate-docking site away from the active site. In the current study, we identified the docking determinants in Src recognized by the Csk substrate-docking site and demonstrated an interaction between the docking determinants of Src and the Csk substrate-docking site for this recognition. A similar mechanism was confirmed for Csk recognition of another Src family kinase, Yes. Although both Csk and MAP kinases used docking sites for substrate recognition, their docking sites consisted of different substructures in the catalytic domain. These results helped establish a docking-based substrate recognition mechanism for Csk. This model may provide a framework for understanding substrate recognition and specificity of other protein tyrosine kinases.

Received for publication, July 25, 2005 , and in revised form, January 23, 2006.

^* This work was supported by American Cancer Society Grant RSG-04-247-01-CDD and National Institutes of Health Grants 1RO1CA111687 and 1 P20 RR16457. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

² To whom correspondence should be addressed: Dept. of Cell and Molecular Biology, 117 Morrill Science Bldg., 45 Lower College Rd., University of Rhode Island, Kingston, RI 02881. Tel.: 401-874-5937; Fax: 401-874-2202; E-mail: gsun{at}uri.edu.

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