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.
