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Vinculin modulation of paxillin–FAK interactions regulates ERK to control survival and motility

¹ Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
² The Burnham Institute, La Jolla Cancer Research Center, La Jolla, CA 92037
³ Department of Cell and Developmental Biology, State University of New York, Upstate Medical University, Syracuse, NY 13210

Address correspondence to K.M. Hahn at his present address Dept. of Pharmacology, Mary Ellen Jones Bldg., Rm. 1141, CB 7365, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365. Tel.: (919) 966-1307. email: khahn{at}med.unc.edu

Cells lacking vinculin are highly metastatic and motile. The reasons for this finding have remained unclear. Both enhanced survival and motility are critical to metastasis. Here, we show that vinculin null (vin^–/–) cells and cells expressing a vinculin Y822F mutant have increased survival due to up-regulated activity of extracellular signal–regulated kinase (ERK). This increase is shown to result from vinculin's modulation of paxillin–FAK interactions. A vinculin fragment (amino acids 811–1066) containing the paxillin binding site restored apoptosis and suppressed ERK activity in vin^–/– cells. Both vinY822F and vin^–/– cells exhibit increased interaction between paxillin and focal adhesion kinase (FAK) and increased paxillin and FAK phosphorylation. Transfection with paxillin Y31FY118F dominant-negative mutant in these cells inhibits ERK activation and restores apoptosis. The enhanced motility of vin^–/– and vinY822F cells is also shown to be due to a similar mechanism. Thus, vinculin regulates survival and motility via ERK by controlling the accessibility of paxillin for FAK interaction.

Key Words: apoptosis; extracellular signal–regulated kinase; anoikis; MAPK; migration

Abbreviations used in this paper: talin bs, deleted talin binding sites; Ab, antibody; DEVD-AMC, N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin; ERK, extracellular signal–regulated kinase; FAT, focal adhesion targeting; FRNK, FAK-related nonkinase; MEK, MAPK kinase; mRFP, monomeric red fluorescent protein; PI-3K, phosphatidylinositol-3 kinase.

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