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J. Biol. Chem., Vol. 279, Issue 47, 48495-48504, November 19, 2004

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Phosphorylation of IQGAP1 Modulates Its Binding to Cdc42, Revealing a New Type of Rho-GTPase Regulator^*

Katarina Grohmanova, Dominik Schlaepfer, Daniel Hess, Peter Gutierrez, Matthias Beck, and Ruth Kroschewski¶

From the ETH-Zürich, Institute of Biochemistry, Schafmattstrasse 18, Zürich 8093, Switzerland and Friedrich Miescher Institute, Basel 4002, Switzerland

The Rho-GTPase Cdc42 is important for the establishment and maintenance of epithelial polarity. Signaling from Cdc42 is propagated via its effector molecules that specifically bind to Cdc42 in the GTP-bound form. The cell-cell contact regulator and actin-binding protein IQGAP1 is described as effector of Cdc42 and Rac. Unexpectedly, we show in this study that IQGAP1 bound also directly nucleotide-depleted Cdc42 (Cdc42-ND). This interaction was enhanced in the presence of phosphatase inhibitors and in epithelial cells without cell-cell contacts. Tandem mass spectrometry analysis and immunoprecipitation experiments revealed that IQGAP1 was Ser¹⁴⁴³-phosphorylated in vivo, potentially by protein kinase C and upon loss of cell-cell contacts. In addition, we identified two independent domains of the IQGAP1 C terminus that bound exclusively Cdc42-ND. These domains interacted with each other, favoring the binding to Cdc42-GTP. Moreover, phosphorylation on Ser¹⁴⁴³ strongly inhibited this intramolecular interaction. Thus, we unraveled a molecular mechanism that reveals a novel type of Rho-GTPase regulator. We propose that, depending on its phosphorylation state, IQGAP1 might serve as an effector or sequester nucleotide-free Cdc42 to prevent signaling.

Received for publication, July 19, 2004 , and in revised form, August 31, 2004.

^* This work was supported by the Swiss National Science Foundation (to K. G.), the Schwyzer Foundation (to D. S.), the Novartis Foundation (to M. B.), and the Roche Research Foundation (to P. G.). 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.

^¶ To whom correspondence should be addressed. Tel.: 41-1-632-6346; Fax: 41-1-632-1591; E-mail: kroschewski{at}bc.biol.ethz.ch.

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