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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATPases Associated with Diverse Cellular Activities
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Adaptor Proteins, Signal Transducing*
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Animals
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Cell Line, Tumor
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Cell Movement
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Cytoskeletal Proteins / chemistry
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Cytoskeletal Proteins / metabolism
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Disease Progression
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Glutathione Transferase / metabolism
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Green Fluorescent Proteins
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Humans
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LIM Domain Proteins
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Luminescent Proteins / metabolism
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Lysophospholipids / metabolism*
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Mice
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Microscopy, Fluorescence
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Mutation
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NIH 3T3 Cells
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Paxillin
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Phosphoproteins / chemistry
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Phosphoproteins / metabolism
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Plasmids / metabolism
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Precipitin Tests
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Proteasome Endopeptidase Complex
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Protein Binding
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Protein Structure, Tertiary
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Protein-Tyrosine Kinases / chemistry
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RNA, Small Interfering / metabolism
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Receptors, G-Protein-Coupled / chemistry
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Receptors, G-Protein-Coupled / metabolism*
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Receptors, Lysophosphatidic Acid
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Two-Hybrid System Techniques
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rho GTP-Binding Proteins / metabolism
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src-Family Kinases / chemistry
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cytoskeletal Proteins
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LIM Domain Proteins
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Luminescent Proteins
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Lysophospholipids
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PSMC5 protein, human
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PXN protein, human
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Paxillin
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Phosphoproteins
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Pxn protein, mouse
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RNA, Small Interfering
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Receptors, G-Protein-Coupled
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Receptors, Lysophosphatidic Acid
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Transcription Factors
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Green Fluorescent Proteins
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Glutathione Transferase
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Protein-Tyrosine Kinases
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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PTK2 protein, human
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Ptk2 protein, mouse
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src-Family Kinases
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Proteasome Endopeptidase Complex
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ATPases Associated with Diverse Cellular Activities
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rho GTP-Binding Proteins