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.
E
Shuyu
S
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Lai
Yun-Ju
YJ
Tsukahara
Ryoko
R
Chen
Chen-Shan
CS
Fujiwara
Yuko
Y
Yue
Junming
J
Yu
Jei-Hwa
JH
Guo
Huazhang
H
Kihara
Akio
A
Tigyi
Gábor
G
Lin
Fang-Tsyr
FT
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D060588:LIM Domain Proteins; D054878:Lipoylation / Q000187:drug effects; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010051:Ovarian Neoplasms / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding / Q000187:drug effects; D049368:Receptors, Lysophosphatidic Acid / Q000737:chemistry / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008246:Lysophospholipids; C092282:PSMC5 protein, human; D010750:Phosphoproteins; D049368:Receptors, Lysophosphatidic Acid; D017923:Sodium-Hydrogen Exchangers; D014157:Transcription Factors; C093376:sodium-hydrogen exchanger regulatory factor; D004317:Doxorubicin; D046988:Proteasome Endopeptidase Complex; D019204:GTP-Binding Proteins; D000074183:ATPases Associated with Diverse Cellular Activities; C032881:lysophosphatidic acid