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J. Biol. Chem., Vol. 279, Issue 20, 20752-20766, May 14, 2004

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A Novel Non-catalytic Mechanism Employed by the C-terminal Src-homologous Kinase to Inhibit Src-family Kinase Activity^*

Yuh-Ping Chong, Terrence D. Mulhern, Hong-Jian Zhu¶, Donald J. Fujita||, Jeffrey D. Bjorge||, John-Paul Tantiongco, Nikolaos Sotirellis, Daisy Sio Seng Lio, Glen Scholz**, and Heung-Chin Cheng

From the Department of Biochemistry and Molecular Biology and ^**Department of Medicine, University of Melbourne, Parkville, Victoria 3010, Australia, ^||Department of Biochemistry and Molecular Biology, University of Calgary Health Sciences Center, Calgary, Alberta, T2N 2N1, Canada, and the ^¶Ludwig Institute of Cancer Research, Royal Melbourne Hospital, Victoria 3052, Australia

Although C-terminal Src kinase (CSK)-homologous kinase (CHK) is generally believed to inactivate Src-family tyrosine kinases (SFKs) by phosphorylating their consensus C-terminal regulatory tyrosine (Tyr_T), exactly how CHK inactivates SFKs is not fully understood. Herein, we report that in addition to phosphorylating Tyr_T, CHK can inhibit SFKs by a novel non-catalytic mechanism. First, CHK directly binds to the SFK members Hck, Lyn, and Src to form stable protein complexes. The complex formation is mediated by a non-catalytic Tyr_T-independent mechanism because it occurs even in the absence of ATP or when Tyr_T of Hck is replaced by phenylalanine. Second, the non-catalytic CHK-SFK interaction alone is sufficient to inactivate SFKs by inhibiting the catalytic activity of autophosphorylated SFKs. Third, CHK and Src co-localize to specific plasma membrane microdomains of rat brain cells, suggesting that CHK is in close proximity to Src such that it can effectively inactivate Src in vivo. Fourth, native CHK·Src complex exists in rat brain, and recombinant CHK·Hck complex exists in transfected HEK293T cells, implying that CHK forms stable complexes with SFKs in vivo. Taken together, our findings suggest that CHK inactivates SFKs (i) by phosphorylating their Tyr_T and (ii) by this novel Tyr_T-independent mechanism involving direct binding of CHK to SFKs. It has been documented that autophosphorylated SFKs can still be active, in some cases even when their Tyr_T is phosphorylated. Thus, the ability of the Tyr_T-independent mechanism to suppress the activity of both non-phosphorylated and autophosphorylated SFKs represents a fail-safe measure employed by CHK to down-regulate SFK signaling under all circumstances.

Received for publication, September 5, 2003 , and in revised form, January 30, 2004.

^* This work was supported by grants from the National Health and Medical Research Council of Australia (to H.-C. C. and G. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Fig. 1.

Both authors contributed equally.

To whom correspondence should be addressed. Tel.: 61-3-83445947; Fax: 61-3-93477730; E-mail: h.cheng{at}biochemistry.unimelb.edu.au.

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