Lysophosphatidic Acid 2 Receptor-mediated Supramolecular Complex Formation Regulates Its Antiapoptotic Effect

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2009 Mar 19

PMID 19293149

Citations 45

Authors

Shuyu E

Yun-Ju Lai

Ryoko Tsukahara

Chen-Shan Chen

Yuko Fujiwara

Junming Yue

Jei-Hwa Yu

Huazhang Guo

Akio Kihara

Gabor Tigyi

Fang-Tsyr Lin

Affiliations

Soon will be listed here.

Abstract

The G protein-coupled lysophosphatidic acid 2 (LPA(2)) receptor elicits prosurvival responses to prevent and rescue cells from apoptosis. However, G protein-coupled signals are not sufficient for the full protective effect of LPA(2). LPA(2) differs from other LPA receptor subtypes in the C-terminal tail, where it contains a zinc finger-binding motif for the interactions with LIM domain-containing TRIP6 and proapoptotic Siva-1, and a PDZ-binding motif through which it complexes with the NHERF2 scaffold protein. In this report, we identify a unique CXXC motif of LPA(2) responsible for the binding to TRIP6 and Siva-1, and demonstrate that disruption of these macromolecular complexes or knockdown of TRIP6 or NHERF2 expression attenuates LPA(2)-mediated protection from chemotherapeutic agent-induced apoptosis. In contrast, knockdown of Siva-1 expression enhances this effect. Furthermore, a PDZ-mediated direct interaction between TRIP6 and NHERF2 facilitates their interaction with LPA(2). Together, these results suggest that in addition to G protein-activated signals, the cooperation embedded in the LPA(2)-TRIP6-NHERF2 ternary complex provides a novel ligand-dependent signal amplification mechanism that is required for LPA(2)-mediated full activation of antiapoptotic signaling.

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