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M606695200v1
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Papers In Press, published online ahead of print March 28, 2007
J. Biol. Chem, 10.1074/jbc.M606695200
Submitted on July 14, 2006
Revised on March 13, 2007
Accepted on March 28, 2007

Cellular characterization of a novel focal adhesion kinase inhibitor

Jill K. Slack-Davis, Karen H. Martin, Robert W. Tilghman, Marcin Iwanicki, Ethan J. Ung, Christopher Autry, Michael J. Luzzio, Beth Cooper, John C. Kath, W. Gregory Roberts, and J. Thomas Parsons

Department of Microbiology, University of Virginia, University of Virginia Health System, Charlottesville, VA 22908

Corresponding Author: jtp{at}virginia.edu

Focal adhesion kinase (FAK) is a member of a family of non-receptor protein tyrosine kinases that regulates integrin and growth factor signaling pathways involved in cell migration, proliferation and survival. FAK expression is increased in many cancers, including breast and prostate cancer. Here we describe perturbation of adhesion-mediated signaling with a FAK inhibitor, PF-573,228. In vitro, this compound inhibited purified recombinant catalytic fragment of FAK with an IC50 of 4 nM. In cultured cells, PF-573,228 inhibited FAK phosphorylation on tyrosine 397 with an IC50 of 30-100 nM. Treatment of cells with concentrations of PF-573,228 that significantly decreased FAK tyrosine 397 phosphorylation failed to inhibit cell growth or induce apoptosis. In contrast, treatment with PF-573,228 inhibited both chemotactic and haptotactic migration concomitant with the inhibition of focal adhesion turnover. These studies show that PF-573,228 serves as a useful tool to dissect the functions of FAK in integrin-dependent signaling pathways in normal and cancer cells and forms the basis for the generation of compounds amenable for preclinical and patient trials.


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