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, J. Thomas Parsons

Research output: Contribution to journalArticlepeer-review

415 Scopus citations

Abstract

Focal adhesion kinase (FAK) is a member of a family of nonreceptor 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 Tyr397 with an IC50 of 30-100 nM. Treatment of cells with concentrations of PF-573,228 that significantly decreased FAK Tyr397 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.

Original languageEnglish
Pages (from-to)14845-14852
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number20
DOIs
StatePublished - 18 May 2007

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