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Originally published as MBoC in Press, 10.1091/mbc.E09-07-0548 on September 23, 2009

Vol. 20, Issue 22, 4706-4719, November 15, 2009

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Paxillin-Kinase-Linker Tyrosine Phosphorylation Regulates Directional Cell Migration

Jianxin A. Yu, Nicholas O. Deakin, and Christopher E. Turner

Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210

Submitted July 6, 2009; Revised August 14, 2009; Accepted September 15, 2009
Monitoring Editor: Josephine C. Adams

Directed cell migration requires the coordination of growth factor and cell adhesion signaling and is of fundamental importance during embryonic development, wound repair, and pathological conditions such as tumor metastasis. Herein, we demonstrate that the ArfGAP, paxillin-kinase-linker (PKL/GIT2), is tyrosine phosphorylated in response to platelet-derived growth factor (PDGF) stimulation, in an adhesion dependent manner and is necessary for directed cell migration. Using a combination of pharmacological inhibitors, knockout cells and kinase mutants, FAK, and Src family kinases were shown to mediate PDGF-dependent PKL tyrosine phosphorylation. In fibroblasts, expression of a PKL mutant lacking the principal tyrosine phosphorylation sites resulted in loss of wound-induced cell polarization as well as directional migration. PKL phosphorylation was necessary for PDGF-stimulated PKL binding to the focal adhesion protein paxillin and expression of paxillin or PKL mutants defective in their respective binding motifs recapitulated the polarization defects. RNA interference or expression of phosphorylation mutants of PKL resulted in disregulation of PDGF-stimulated Rac1 and PAK activities, reduction of Cdc42 and Erk signaling, as well as mislocalization of βPIX. Together these studies position PKL as an integral component of growth factor and cell adhesion cross-talk signaling, controlling the development of front–rear cell polarity and directional cell migration.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E09-07-0548) on September 23, 2009.

Address correspondence to: Christopher E. Turner (turnerce{at}upstate.edu)

Abbreviations used: FAK, focal adhesion kinase; PAK, p21-activated kinase; PIX, PAK-interacting exchange factor; PKL, paxillin-kinase-linker; pTyr, tyrosine phosphorylation; SFK, Src family kinase.




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