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J. Biol. Chem., Vol. 282, Issue 52, 37759-37769, December 28, 2007

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The Lysophosphatidic Acid 2 Receptor Mediates Down-regulation of Siva-1 to Promote Cell Survival^*

Fang-Tsyr Lin¹, Yun-Ju Lai², Natalia Makarova, Gabor Tigyi, and Weei-Chin Lin^¶

From the Department of Cell Biology and the ^¶Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 and the Department of Physiology, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163

Lysophosphatidic acid (LPA) promotes cell survival through the activation of G protein-coupled LPA receptors. However, whether different LPA receptors activate distinct anti-apoptotic signaling pathways is not yet clear. Here we report a novel mechanism by which the LPA₂ receptor targets the proapoptotic Siva-1 protein for LPA-dependent degradation, thereby attenuating Siva-1 function in DNA damage response. The carboxyl-terminal tail of the LPA₂ receptor, but not LPA₁ or LPA₃ receptor, specifically associates with the carboxyl cysteine-rich domain of Siva-1. Prolonged LPA stimulation promotes the association of Siva-1 with the LPA₂ receptor and targets both proteins for ubiquitination and degradation. As a result, adriamycin-induced Siva-1 protein stabilization is attenuated by LPA in an LPA₂-dependent manner, and the function of Siva-1 in promoting DNA damage-induced apoptosis is inhibited by LPA pretreatment. Consistent with this result, inhibition of the LPA₂ receptor expression increases Siva-1 protein levels and augments adriamycin-induced caspase-3 cleavage and apoptosis. Together, these findings reveal a critical and specific role for the LPA₂ receptor through which LPA directly inactivates a critical component of the death machinery to promote cell survival.

Received for publication, June 19, 2007 , and in revised form, October 4, 2007.

^* This work was supported by National Institutes of Health Grant CA100848 (to F.-T. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

² Recipient of an American Heart Association predoctoral fellowship.

¹ To whom correspondence should be addressed: Dept. of Cell Biology, The University of Alabama at Birmingham, MCLM 360A, 1918 University Blvd., Birmingham, AL 35294-0005. Tel.: 205-975-5060; Fax: 205-975-5648; E-mail: flin{at}uab.edu.

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