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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATPases Associated with Diverse Cellular Activities
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Apoptosis* / drug effects
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Calcium Signaling / drug effects
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Cell Line, Tumor
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Cytoprotection / drug effects
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Doxorubicin / pharmacology
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Female
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GTP-Binding Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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LIM Domain Proteins
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Lipoylation / drug effects
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Lysophospholipids / pharmacology
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Mice
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Molecular Sequence Data
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Mutation / genetics
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Ovarian Neoplasms / pathology
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Phosphoproteins / metabolism
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Proteasome Endopeptidase Complex
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Protein Binding / drug effects
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Receptors, Lysophosphatidic Acid / chemistry
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Receptors, Lysophosphatidic Acid / metabolism*
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Sodium-Hydrogen Exchangers / metabolism
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Transcription Factors / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Intracellular Signaling Peptides and Proteins
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LIM Domain Proteins
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Lysophospholipids
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PSMC5 protein, human
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Phosphoproteins
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Receptors, Lysophosphatidic Acid
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Sodium-Hydrogen Exchangers
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Transcription Factors
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sodium-hydrogen exchanger regulatory factor
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Doxorubicin
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Proteasome Endopeptidase Complex
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GTP-Binding Proteins
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ATPases Associated with Diverse Cellular Activities
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lysophosphatidic acid