Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation
Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation
复制标题
DOI：
10.1016/j.molcel.2007.11.031
复制
发表时间：
2008-01-18
期刊：
影响因子：
16
通讯作者：
Llic, Dusko
中科院分区：
文献类型：
--
作者：
Lim, Ssang-Taek;Chen, Xiao Lei;Llic, Dusko
FAK是一种整合素和生长因子相关的酪氨酸激酶，可促进细胞运动。在这里，我们表明，在小鼠发育过程中，FAK失活导致p53和p21依赖的中胚层细胞生长停滞。原代FAK（-/-）p21（-/-）成纤维细胞的重建显示FAK以激酶非依赖性方式通过增强Mdm 2依赖性p53泛素化促进p53周转。FAK导致的p53失活需要FAK FERM F1叶与p53结合，FERM F2叶介导的核定位，以及FERM F3叶与Mdm 2的连接和蛋白酶体降解。星形孢菌素或细胞粘附的丧失增强了FERM依赖的FAK核积聚。在原代人细胞中，FAK敲低升高了p53-p21水平，减缓了细胞增殖，但不引起凋亡。值得注意的是，FAK敲低加顺铂触发p53依赖性细胞凋亡，这是由全长FAK或FAK FERM再表达拯救。这些研究定义了核FAK在细胞应激条件下通过增强p53降解促进细胞存活方面的支架作用。
FAK is known as an integrin- and growth factor-associated tyrosine kinase promoting cell motility. Here we show that, during mouse development, FAK inactivation results in p53- and p21-dependent mesodermal cell growth arrest. Reconstitution of primary FAK(-/-)p21(-/-) fibroblasts revealed that FAK, in a kinase-independent manner, facilitates p53 turnover via enhanced Mdm2-dependent p53 ubiquitination. p53 inactivation by FAK required FAK FERM F1 lobe binding to p53, FERM F2 lobe-mediated nuclear localization, and FERM F3 lobe for connections to Mdm2 and proteasomal degradation. Staurosporine or loss of cell adhesion enhanced FERM-dependent FAK nuclear accumulation. In primary human cells, FAK knockdown raised p53-p21 levels and slowed cell proliferation but did not cause apoptosis. Notably, FAK knockdown plus cisplatin triggered p53-dependent cell apoptosis, which was rescued by either full-length FAK or FAK FERM re-expression. These studies define a scaffolding role for nuclear FAK in facilitating cell survival through enhanced p53 degradation under conditions of cellular stress.