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J. Biol. Chem., Vol. 281, Issue 40, 29501-29512, October 6, 2006

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Phospholipase C Suppresses Integrin Activation^*

Yatish Lad¹, Brian McHugh¹², Philip S. Hodkinson¹³, Alison C. MacKinnon, Christopher Haslett, Mark H. Ginsberg, and Tariq Sethi⁴

From the Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4SA, Scotland, United Kingdom and the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0726

Phospholipase C (PLC) is a newly described effector of the small GTP-binding protein H-Ras. Utilizing H-Ras effector mutants, we show that mutants H-Ras(G12V/E37G) and H-Ras(G12V/D38N) suppressed integrin activation in an ERK-independent manner. H-Ras(G12V/D38N) specifically activated the PLC effector pathway and suppressed integrin activation. Inhibition of PLC activation with a kinase-dead PLC mutant prevented H-Ras(G12V/D38N) from suppressing integrin activation, and low level expression of H-Ras(G12V/D38N) could synergize with wild-type PLC to suppress integrins. In addition, knockdown of endogenous PLC with small interfering RNA blocked H-Ras(G12V/D38N)-mediated integrin suppression. Suppressing integrin function with the H-Ras(G12V/D38N) mutant reduced cell adhesion to von Willebrand factor and fibronectin; this reduction in cell adhesion was blocked by coexpression of the kinase-dead PLC mutant. These results show that H-Ras suppresses integrin affinity via independent Raf and PLC signaling pathways and demonstrate a new physiological function for PLC in the regulation of integrin activation.

Received for publication, December 19, 2005 , and in revised form, August 7, 2006.

^* This work was supported in part by a Scottish Health Research and Education Trust project grant (to Y. L.). 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 These authors contributed equally to this work.

² Supported by a British Heart Foundation junior fellowship.

³ Supported by a Medical Research Council Clinical Research Training Fellowship.

⁴ Supported by a Wellcome Trust leave fellowship. To whom correspondence should be addressed. Tel.: 44-131-242-6550; Fax: 44-131-242-6578; E-mail: t.sethi{at}ed.ac.uk.

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