c-Src-mediated phosphorylation of TRIP6 regulates its function in lysophosphatidic acid-induced cell migration.
TRIP6 (thyroid receptor-interacting protein 6), also known as ZRP-1 (zyxin-related protein 1), is a member of the zyxin family that has been implicated in cell motility. Previously we have shown that TRIP6 binds to the LPA2 receptor and associates with several components of focal complexes in an agonist-dependent manner and, thus, enhances lysophosphatidic acid (LPA)-induced cell migration. Here we further report that the function of TRIP6 in LPA signaling is regulated by c-Src-mediated phosphorylation of TRIP6 at the Tyr-55 residue. LPA stimulation induces tyrosine phosphorylation of endogenous TRIP6 in NIH 3T3 cells and c-Src-expressing fibroblasts, which is virtually eliminated in Src-null fibroblasts. Strikingly, both phosphotyrosine-55 and proline-58 residues of TRIP6 are required for Crk binding in vitro and in cells. Mutation of Tyr-55 to Phe does not alter the ability of TRIP6 to localize at focal adhesions or associate with actin. However, it abolishes the association of TRIP6 with Crk and p130cas in cells and significantly reduces the function of TRIP6 to promote LPA-induced ERK activation. Ultimately, these signaling events control TRIP6 function in promoting LPA-induced morphological changes and cell migration.
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
Yun-Ju
YJ
Lai
Chen-Shan
CS
Chen
Weei-Chin
WC
Lin
Fang-Tsyr
FT
Lin
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion; D002465:Cell Movement / Q000502:physiology*; D060588:LIM Domain Proteins; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases
D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; D008246:Lysophospholipids; C092282:PSMC5 protein, human; D014157:Transcription Factors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; C032881:lysophosphatidic acid