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Originally published In Press as doi:10.1074/jbc.M308405200 on February 17, 2004

J. Biol. Chem., Vol. 279, Issue 17, 17329-17337, April 23, 2004
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IQGAP1 Binds ERK2 and Modulates Its Activity*

Monideepa Roy, Zhigang Li, and David B. Sacks{ddagger}

From the Department of Pathology, Brigham, and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

IQGAP1 binds several proteins including actin, calmodulin, E-cadherin, {beta}-catenin, Cdc42, Rac1, and CLIP-170. The interaction with these targets enables IQGAP1 to participate in many cellular functions varying from regulation of the cytoskeleton to gene transcription. Here we show that extracellular signal-regulated kinase (ERK) 2 binds to IQGAP1. In vitro analysis with purified proteins demonstrated a direct interaction between ERK2 and IQGAP1. Moreover, binding occurred in cells as endogenous ERK2 co-immunoprecipitated with IQGAP1 from human breast epithelial cell lysates. The association between ERK2 and IQGAP1 was independent of epidermal growth factor. The in vivo interaction has functional significance. Manipulation of intracellular IQGAP1 levels significantly reduced growth factor-stimulated ERK1 and ERK2 activity. Similarly, stimulation of ERK1 and ERK2 activity by insulin-like growth factor I was reduced when IQGAP1 levels were changed. In contrast, overexpression of an IQGAP1 construct lacking the ERK2 binding region did not interfere with activation of ERK1 and ERK2 by epidermal growth factor. Our data disclose a previously unidentified communication between IQGAP1 and the ERK pathway and imply that IQGAP1 modulates the Ras/mitogen-activated protein kinase signaling cascade.

Received for publication, July 31, 2003 , and in revised form, February 7, 2004.

* This study was supported in part by grants from the National Institutes of Health (to D. B. S.) and United States Army Fellowship Grant DAMD17-02-1-0304 (to M. R.). 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.

{ddagger} To whom should be addressed: Brigham and Women's Hospital, Thorn 530, 75 Francis St., Boston, MA 02115. Tel.: 617-732-6627; Fax: 617-278-6921; E-mail: dsacks{at}rics.bwh.harvard.edu.


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