Focal adhesion kinase is a phospho-regulated repressor of Rac and proliferation in human endothelial cells.
Focal adhesion kinase is a phospho-regulated repressor of Rac and proliferation in human endothelial cells.
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DOI：
10.1242/bio.20121008
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发表时间：
2012-08-15
期刊：
影响因子：
2.4
通讯作者：
Pumiglia KM
中科院分区：
文献类型：
--
作者：
Bryant PW;Zheng Q;Pumiglia KM
粘着斑激酶(FAK)在整合细胞外基质和细胞黏附信号方面起着至关重要的作用。它对正常的血管发育是必不可少的，并参与了广泛的细胞功能，包括调节细胞的增殖、迁移、分化和生存。目前正在积极使用不同的治疗方法进行靶向治疗。我们使用人内皮细胞作为模型系统，比较了几种不同的方法抑制FAK的效果，包括显性阴性、激酶抑制剂和shRNA。我们发现，操纵FAK信号导致抑制FAK 397的磷酸化，抑制了细胞的增殖和迁移。然而，使用稳定(ShRNA)或瞬时(SiRNA)方法取消FAK表达并不干扰这些细胞功能。通过FAK调控细胞增殖的能力与Rac的激活状态有关，Rac是调控细胞周期蛋白依赖性激酶抑制剂的重要信号。FAK的敲除虽然不影响细胞的增殖或迁移，但极大地干扰了血管的形态形成和存活，反映了体内的研究结果。我们提出了一种新的FAK信号模型，在该模型中，FAK作为信号蛋白的多功能之一包括作为RAC激活的磷酸调节抑制因子的FAK，这对解释研究实验和治疗开发具有重要意义。
Focal adhesion kinase (FAK) is critically positioned to integrate signals from the extracellular matrix and cellular adhesion. It is essential for normal vascular development and has been implicated in a wide range of cellular functions including the regulation of cell proliferation, migration, differentiation, and survival. It is currently being actively targeted therapeutically using different approaches. We have used human endothelial cells as a model system to compare the effects of inhibiting FAK through several different approaches including dominant negatives, kinase inhibitors and shRNA. We find that manipulations of FAK signaling that result in inhibition of FAK 397 phosphorylation inhibit proliferation and migration. However, abolition of FAK expression using stable (shRNA) or transient (siRNA) approaches does not interfere with these cellular functions. The ability to regulate cell proliferation by FAK manipulation is correlated with the activation status of Rac, an essential signal for the regulation of cyclin-dependent kinase inhibitors. The knockdown of FAK, while not affecting cellular proliferation or migration, dramatically interferes with vascular morphogenesis and survival, mirroring in vivo findings. We propose a novel model of FAK signaling whereby one of the multifunctional roles of FAK as a signaling protein includes FAK as a phospho-regulated repressor of Rac activation, with important implications on interpretation of research experiments and therapeutic development.
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影响因子：
4.8
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