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

Research output: Contribution to journalArticle

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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

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Lysophosphatidic Acid Receptors
GTP-Binding Proteins
Apoptosis
Macromolecular Substances
Zinc Fingers
lysophosphatidic acid
Scaffolds
Amplification
Zinc
Ligands
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lysophosphatidic acid 2 receptor-mediated supramolecular complex formation regulates its antiapoptotic effect. / Shuyu, E.; Lai, Yun-Ju; Tsukahara, Ryoko; Chen, Chen Shan; Fujiwara, Yuko; Yue, Junming; Yu, Jei Hwa; Guo, Huazhang; Kihara, Akio; Tigyi, Gábor; Lin, Fang Tsyr.

In: Journal of Biological Chemistry, Vol. 284, No. 21, 22.05.2009, p. 14558-14571.

Research output: Contribution to journalArticle

Shuyu, E, Lai, Y-J, Tsukahara, R, Chen, CS, Fujiwara, Y, Yue, J, Yu, JH, Guo, H, Kihara, A, Tigyi, G & Lin, FT 2009, 'Lysophosphatidic acid 2 receptor-mediated supramolecular complex formation regulates its antiapoptotic effect', Journal of Biological Chemistry, vol. 284, no. 21, pp. 14558-14571. https://doi.org/10.1074/jbc.M900185200
Shuyu, E. ; Lai, Yun-Ju ; Tsukahara, Ryoko ; Chen, Chen Shan ; Fujiwara, Yuko ; Yue, Junming ; Yu, Jei Hwa ; Guo, Huazhang ; Kihara, Akio ; Tigyi, Gábor ; Lin, Fang Tsyr. / Lysophosphatidic acid 2 receptor-mediated supramolecular complex formation regulates its antiapoptotic effect. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 21. pp. 14558-14571.
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