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J. Biol. Chem., Vol. 280, Issue 2, 1543-1551, January 14, 2005
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Molecular Basis for a Direct Interaction between the Syk Protein-tyrosine Kinase and Phosphoinositide 3-Kinase*
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From the
Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907 and the ¶Department of Pediatrics, AFLAC Cancer Center, Emory University School of Medicine, Atlanta, Georgia 30322
After engagement of the B cell receptor for antigen, the Syk protein-tyrosine kinase becomes phosphorylated on multiple tyrosines, some of which serve as docking sites for downstream effectors with SH2 or other phosphotyrosine binding domains. The most frequently identified binding partner for catalytically active Syk identified in a yeast two-hybrid screen was the p85 regulatory subunit of phosphoinositide 3-kinase. The C-terminal SH2 domain of p85 was sufficient for mediating an interaction with tyrosine-phosphorylated Syk. Interestingly, this domain interacted with Syk at phosphotyrosine 317, a site phosphorylated in trans by the Src family kinase, Lyn, and identified previously as a binding site for c-Cbl. This site interacted preferentially with the p85 C-terminal SH2 domain compared with the c-Cbl tyrosine kinase binding domain. Molecular modeling studies showed a good fit between the p85 SH2 domain and a peptide containing phosphotyrosine 317. Tyr-317 was found to be essential for Syk to support phagocytosis mediated by Fc
RIIA receptors expressed in a heterologous system. These studies establish a new type of p85 binding site that can exist on proteins that serve as substrates for Src family kinases and provide a molecular explanation for observations on direct interactions between Syk and phosphoinositide 3-kinase.
Received for publication, July 12, 2004 , and in revised form, October 12, 2004.
The atomic coordinates and structure factors (code 1H90) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
* This work was supported by National Institutes of Health Grants CA37372 (to R. L. G. and M. L. H.), GM39478 (to C. B. P.), and CA94233 (to D. L. D.) and by the Georgia Cancer Coalition (to D. L. D.). 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.
Present address: National Institutes of Health, Bldg. 10, 9000 Rockville Pike, Bethesda, MD 20892.
|| To whom correspondence should be addressed: Dept. of Medicinal Chemistry and Molecular Pharmacology, Purdue University, Hansen Life Sciences Research Bldg., 201 S. University St., West Lafayette, IN 47907-2064. E-mail: geahlen{at}purdue.edu.
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