Abstract
Lysophosphatidic acid (LPA) induces actin rearrangement, focal adhesion assembly, and cell migration through the activation of small G protein Rho and its downstream effectors. These diverse cellular responses are mediated by its associated G protein-coupled receptors. However, the mechanisms and specificity by which these LPA receptors mediate LPA actions are still poorly understood. Here we show that LPA stimulation promotes the interaction of the LPA(2) receptor with a focal adhesion molecule, TRIP6 (thyroid receptor interacting protein 6)/ZRP-1 (zyxin-related protein 1). TRIP6 directly binds to the carboxyl-terminal tail of the LPA(2) receptor through its LIM domains. LPA-dependent recruitment of TRIP6 to the plasma membrane promotes its targeting to focal adhesions and co-localization with actin stress fibers. In addition, TRIP6 associates with the components of focal complexes including paxillin, focal adhesion kinase, c-Src, and p130(cas) in an agonist-dependent manner. Overexpression of TRIP6 augments LPA-induced cell migration; in contrast, suppression of endogenous TRIP6 expression by a TRIP6-specific small interfering RNA reduces it in SKOV3 ovarian cancer cells. Strikingly, the association with TRIP6 is specific to the LPA(2) receptor but not LPA(1) or LPA(3) receptor, indicating a specific role for TRIP6 in regulating LPA(2) receptor-mediated signaling. Taken together, our results suggest that TRIP6 functions at a point of convergence between the activated LPA(2) receptor and downstream signals involved in cell adhesion and migration.
Highlights
Lysophosphatidic acid (LPA)1 is a bioactive growth factorlike phospholipid, which mediates diverse biological responses such as mitogenesis, differentiation, cell survival, angiogenesis, inflammation, and cell migration [1]
Our results suggest that TRIP6 functions at a point of convergence between the activated LPA2 receptor and downstream signals involved in cell adhesion and migration
We further examined the ability of the carboxylterminal tails of LPA1 and LPA3 receptors to bind to TRIP6
Summary
Lysophosphatidic acid (LPA)1 is a bioactive growth factorlike phospholipid, which mediates diverse biological responses such as mitogenesis, differentiation, cell survival, angiogenesis, inflammation, and cell migration [1]. Immunocytochemistry—To examine LPA-induced co-localization of TRIP6 with the LPA2 receptor, SKOV3 cells were transiently co-transfected with the plasmids expressing HcRed1-TRIP6 and GFP-LPA2R.
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