TY - JOUR
T1 - Cellular characterization of a novel focal adhesion kinase inhibitor
AU - Slack-Davis, Jill K.
AU - Martin, Karen H.
AU - Tilghman, Robert W.
AU - Iwanicki, Marcin
AU - Ung, Ethan J.
AU - Autry, Christopher
AU - Luzzio, Michael J.
AU - Cooper, Beth
AU - Kath, John C.
AU - Roberts, W. Gregory
AU - Parsons, J. Thomas
PY - 2007/5/18
Y1 - 2007/5/18
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M606695200
DO - 10.1074/jbc.M606695200
M3 - Article
C2 - 17395594
AN - SCOPUS:34447538483
SN - 0021-9258
VL - 282
SP - 14845
EP - 14852
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -