PLCepsilon  suppresses integrin activation

doi:10.1074/jbc.M513471200

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Papers In Press, published online ahead of print August 8, 2006
J. Biol. Chem, 10.1074/jbc.M513471200
Submitted on December 19, 2005
Revised on August 7, 2006
Accepted on August 8, 2006

PLC $epsilon$ suppresses integrin activation

Yatish Lad, Brian McHugh, Philip S. Hodkinson, Alison MacKinnon, Christopher Haslett, Mark H. Ginsberg, and Tariq Sethi

Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4SA

Corresponding Author: pshodkinson{at}hotmail.com

PLC $epsilon$ is a newly described effector of the small GTP-binding protein H-Ras. Utilizing H-Ras effector mutants, we show that the mutants H-Ras(G12V/E37G) and H-Ras(G12V/D38N) suppress integrin activation in an ERK-independent manner. H-Ras(G12V/D38N) specifically activates the PLC $epsilon$ effector pathway and suppresses integrin activation. Inhibition of PLC $epsilon$ activation with a kinase dead PLC $epsilon$ mutant prevented H-Ras(G12V/D38N) from suppressing integrin activation and low-level expression of H-Ras(G12V/D38N) can synergize with wild type PLC $epsilon$ to suppress integrins. In addition knockdown of endogenous PLC $epsilon$ with siRNA blocked H-Ras(G12V/D38N) mediated integrin suppression. Importantly, 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 co-expression of the kinase dead PLC $epsilon$ mutant. These results show that H-Ras suppresses integrin affinity via independent Raf and PLC $epsilon$ signaling pathways, and demonstrate a new physiological function for PLC $epsilon$ in the regulation of integrin activation.

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PLC suppresses integrin activation

PLC $epsilon$ suppresses integrin activation