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A more recent version of this article appeared on September 1, 2005
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Submitted on February 16, 2005
Revised on June 7, 2005
Accepted on June 29, 2005
*Department of Cell and Developmental Biology, College of Medicine, State University of New York Upstate Medical University, Syracuse, NY 13210; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
Monitoring Editor: Clare Waterman-Storer
The ArfGAP, PKL/GIT2 has been implicated in regulating cell spreading and motility through its transient recruitment of the p21-activated kinase (PAK) to focal adhesions. The Nck-PAK-PIX-PKL protein complex is recruited to focal adhesions by paxillin upon integrin engagement and Rac activation. In this report we identify tyrosine phosphorylated PKL as a protein that associates with the SH3-SH2 adaptor Nck, in a Src-dependent manner, following cell adhesion to fibronectin. Both cell adhesion and Rac activation stimulated PKL tyrosine phosphorylation. PKL is phosphorylated on tyrosine residues 286/392/592 by Src and/FAK and these sites are required for PKL localization to focal adhesions and for paxillin binding. The absence of either FAK or Src-family kinases prevents PKL phosphorylation and suppresses localization of PKL but not GIT1 to focal adhesions following Rac activation. Expression of an activated FAK mutant in the absence of Src-family kinases partially restores PKL localization suggesting that Src activation of FAK is required for PKL phosphorylation and localization. Overexpression of the nonphosphorylated GFP-PKL Triple YF mutant stimulates cell spreading and protrusiveness, similar to overexpression of a paxillin mutant that does not bind PKL, suggesting that failure to recruit PKL to focal adhesions interferes with normal cell spreading and motility.
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