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J. Biol. Chem., Vol. 280, Issue 23, 21933-21941, June 10, 2005

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Regulation of Phospholipase C-1 through Direct Interactions with the Small GTPase Ral and Calmodulin^*

Ranjinder S. Sidhu, Richard R. Clough, and Rajinder P. Bhullar¶||

From the Departments of Oral Biology and ^¶Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0W2, Canada

Second messengers generated from membrane lipids play a critical role in signaling and control diverse cellular processes. Despite being one of the most evolutionarily conserved of all the phosphoinositide-specific phospholipase C (PLC) isoforms, a family of enzymes responsible for hydrolysis of the membrane lipid phosphatidylinositol bisphosphate, the mechanism of PLC-1 activation is still poorly understood. Here we report a novel regulatory mechanism for PLC-1 activation that involves direct interaction of the small GTPase Ral and the universal calcium-signaling molecule calmodulin (CaM) with PLC-1. In addition, we have identified a novel IQ type CaM binding motif within the catalytic region of PLC-1 that is not found in other PLC isoforms. Binding of CaM at the IQ motif inhibits PLC-1 activity, while addition of Ral reverses the inhibition. The overexpression of various Ral mutants in cells potentiates PLC-1 activity. Thus, the Ral-CaM complex defines a multifaceted regulatory mechanism for PLC-1 activation.

Received for publication, November 16, 2004 , and in revised form, April 1, 2005.

^* This work was supported in part by grants (to R. P. B.) from the Canadian Institutes of Health Research and the University of Manitoba. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Table I.

Currently supported by a Doctoral Fellowship from the Heart and Stroke Foundation of Canada and previously by Manitoba Health Research Council Studentship and the University of Manitoba Graduate Fellowship.

^|| To whom correspondence should be addressed: Dept. of Oral Biology, Faculty of Dentistry, University of Manitoba, Winnipeg, MB R3E 0W2, Canada. Tel.: 204-789-3703; Fax: 204-789-3713; E-mail: bhullar{at}MS.Umanitoba.CA.

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