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J. Biol. Chem., Vol. 283, Issue 34, 22972-22982, August 22, 2008

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IQGAP1 Integrates Ca²⁺/Calmodulin and B-Raf Signaling^*

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

Ca²⁺ and calmodulin modulate numerous cellular functions, ranging from muscle contraction to the cell cycle. Accumulating evidence indicates that Ca²⁺ and calmodulin regulate the MAPK signaling pathway at multiple positions in the cascade, but the molecular mechanism underlying these observations is poorly defined. We previously documented that IQGAP1 is a scaffold in the MAPK cascade. IQGAP1 binds to and regulates the activities of ERK, MEK, and B-Raf. Here we demonstrate that IQGAP1 integrates Ca²⁺ and calmodulin with B-Raf signaling. In vitro analysis reveals that Ca²⁺ promotes the direct binding of IQGAP1 to B-Raf. This interaction is inhibited by calmodulin in a Ca²⁺-regulated manner. Epidermal growth factor (EGF) is unable to stimulate B-Raf activity in fibroblasts treated with the Ca²⁺ ionophore A23187. [GenBank] In contrast, chelation of intracellular free Ca²⁺ concentrations ([Ca²⁺]_i) significantly enhances EGF-stimulated B-Raf activity, an effect that is dependent on IQGAP1. Incubation of cells with EGF augments the association of B-Raf with IQGAP1. Moreover, Ca²⁺ regulates the association of B-Raf with IQGAP1 in cells. Increasing [Ca²⁺]_i with Ca²⁺ ionophores significantly reduces co-immunoprecipitation of B-Raf and IQGAP1, whereas chelation of Ca²⁺ enhances the interaction. Consistent with these findings, increasing and decreasing [Ca²⁺]_i increase and decrease, respectively, co-immunoprecipitation of calmodulin with IQGAP1. Collectively, our data identify a previously unrecognized mechanism in which the scaffold protein IQGAP1 couples Ca²⁺ and calmodulin signaling to B-Raf function.

Received for publication, June 17, 2008

^* 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.

¹ To whom correspondence 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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				M. D. Brown, L. Bry, Z. Li, and D. B. Sacks Actin Pedestal Formation by Enteropathogenic Escherichia coli Is Regulated by IQGAP1, Calcium, and Calmodulin J. Biol. Chem., December 12, 2008; 283(50): 35212 - 35222. [Abstract] [Full Text] [PDF]