Lysophosphatidic acid 2 receptor-mediated supramolecular complex formation regulates its antiapoptotic effect

E. Shuyu, Yun Ju Lai, Ryoko Tsukahara, Chen Shan Chen, Yuko Fujiwara, Junming Yue, Jei Hwa Yu, Huazhang Guo, Akio Kihara, Gábor Tigyi, Fang Tsyr Lin

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52 Citations (Scopus)

Abstract

The G protein-coupled lysophosphatidic acid 2 (LPA2) 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 LPA2. LPA2 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 LPA2 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 LPA2-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 LPA2. Together, these results suggest that in addition to G protein-activated signals, the cooperation embedded in the LPA2-TRIP6-NHERF2 ternary complex provides a novel ligand-dependent signal amplification mechanism that is required for LPA2-mediated full activation of antiapoptotic signaling.

Original languageEnglish
Pages (from-to)14558-14571
Number of pages14
JournalJournal of Biological Chemistry
Volume284
Issue number21
DOIs
Publication statusPublished - 2009 May 22

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Shuyu, E., Lai, Y. J., Tsukahara, R., Chen, C. S., Fujiwara, Y., Yue, J., Yu, J. H., Guo, H., Kihara, A., Tigyi, G., & Lin, F. T. (2009). Lysophosphatidic acid 2 receptor-mediated supramolecular complex formation regulates its antiapoptotic effect. Journal of Biological Chemistry, 284(21), 14558-14571. https://doi.org/10.1074/jbc.M900185200