Tyrosine phosphorylation of beta2-chimaerin by Src-family kinase negatively regulates its Rac-specific GAP activity.

Abstract	beta2-Chimaerin, an intracellular receptor for the second messenger diacylglycerol and phorbol esters, is a GTPase-activating protein (GAP) specific for Rac. beta2-Chimaerin negatively controls many Rac-dependent pathophysiological events including tumor development. However, the regulatory mechanism of beta2-chimaerin remains largely unknown. Here we report that beta2-chimaerin is tyrosine-phosphorylated by Src-family kinases (SFKs) upon cell stimulation with epidermal growth factor (EGF). Mutational analysis identified Tyr-21 in the N-terminal regulatory region as a major phosphorylation site. Intriguingly, the addition of SFK inhibitor and the replacement of Tyr-21 with Phe (Y21F) markedly enhanced Rac-GAP activity of beta2-chimaerin in EGF-treated cells. Moreover, the Y21F mutant inhibited integrin-dependent cell spreading, in which Rac1 plays a critical role, more strongly than wild-type beta2-chimaerin. These results suggest Tyr-21 phosphorylation as a novel, SFK-dependent mechanism that negatively regulates beta2-chimaerin Rac-GAP activity.
Authors	Masahiro Kai, Satoshi Yasuda, Shin-Ichi Imai, Hideo Kanoh, Fumio Sakane
Journal	Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1773 Issue 9 Pg. 1407-15 (Sep 2007) ISSN: 0006-3002 [Print] Netherlands
PMID	17560670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Neoplasm Proteins beta-chimaerin Green Fluorescent Proteins Tyrosine Phenylalanine Epidermal Growth Factor src-Family Kinases rac GTP-Binding Proteins
Topics	Amino Acid Substitution Animals COS Cells Cell Adhesion (genetics) Chlorocebus aethiops DNA Mutational Analysis Epidermal Growth Factor (pharmacology) Gene Expression Regulation, Enzymologic Green Fluorescent Proteins (metabolism) Mutation Neoplasm Proteins (genetics, metabolism) Phenylalanine (metabolism) Phosphorylation Transfection Tyrosine (metabolism) rac GTP-Binding Proteins (genetics, metabolism) src-Family Kinases (analysis, metabolism)

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