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

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Amino Acid Sequence, Animals, Apoptosis, Calcium Signaling, Cell Line, Tumor, Cytoprotection, Doxorubicin, Female, GTP-Binding Proteins, Humans, Intracellular Signaling Peptides and Proteins, Lipoylation, Lysophospholipids, Mice, Molecular Sequence Data, Mutation, Ovarian Neoplasms, Phosphoproteins, Protein Binding, Receptors, Lysophosphatidic Acid, Sodium-Hydrogen Antiporter, Transcription Factors
J. Biol. Chem.
Date: May. 22, 2009
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