Cellular characterization of a novel focal adhesion kinase inhibitor
Cellular characterization of a novel focal adhesion kinase inhibitor
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DOI：
10.1074/jbc.m606695200
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发表时间：
2007-05-18
影响因子：
4.8
通讯作者：
Parsons, J. Thomas
中科院分区：
文献类型：
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作者：
Slack-Davis, Jill K.;Martin, Karen H.;Parsons, J. Thomas
粘着斑激酶（FAK）是一个非受体蛋白酪氨酸激酶家族的成员，调节与细胞迁移、增殖和存活有关的整合素和生长因子信号通路。FAK表达在许多癌症中增加，包括乳腺癌和前列腺癌。在这里，我们描述了干扰粘附介导的信号与FAK抑制剂，PF-573，228。在体外，该化合物抑制纯化的FAK重组催化片段，IC 50为4 nM。在培养的细胞中，PF-573，228抑制Tyr（397）上的FAK磷酸化，IC 50为30-100 nM。用显著降低FAK Tyr（397）磷酸化的PF-573，228浓度处理细胞，未能抑制细胞生长或诱导细胞凋亡。相比之下，PF-573，228处理抑制了趋化性和趋触性迁移，同时抑制了粘着斑转换。这些研究表明，PF-573，228可作为一种有用的工具来剖析FAK在正常和癌细胞中的整合素依赖性信号通路中的功能，并为产生适合临床前和患者试验的化合物奠定了基础。
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 Tyr(397) with an IC50 of 30-100 nM. Treatment of cells with concentrations of PF-573,228 that significantly decreased FAK Tyr(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.