Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development.
Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development.
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DOI：
10.1083/jcb.200912094
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发表时间：
2010-06-14
期刊：
影响因子：
--
通讯作者：
Guan JL
中科院分区：
文献类型：
--
作者：
Zhao X;Peng X;Sun S;Park AY;Guan JL
小鼠血管发育在E13.5之前只需要FAK的激酶独立功能，但完成胚胎发生需要激酶活性。局灶黏附激酶（FAK）对血管发育至关重要，因为内皮细胞（EC）特异性敲除FAK（条件性FAK敲除[CFKO]小鼠）会导致胚胎死亡。在这项研究中，我们通过创建和分析ec特异性FAK激酶缺陷（KD）突变敲入（条件FAK敲入[CFKI]）小鼠模型，报告了FAK在血管发育中的激酶独立和激酶依赖的差异功能。CFKI胚胎在胚胎日(E) 13.5时发育正常，而大部分CFKO胚胎在胚胎日(E) 13.5时死亡。在胚胎和体外，通过抑制上调的p21，在FAK缺失的情况下，KD - FAK的表达逆转了EC细胞凋亡的增加。然而，CFKI胚胎没有恢复CFKO胚胎的血管扩张和血管生成缺陷。无FAK或表达KD FAK的ECs通透性增加，血管内皮钙粘蛋白（VE-cadherin）分布异常，VE-cadherin Y658磷酸化降低。总之，我们的数据表明FAK的激酶独立功能可以通过E13.5支持EC在血管发育中的存活，但不足以维持EC功能以完成胚胎发生。
Vascular development in mice only requires kinase-independent functions of FAK until E13.5, but kinase activity is needed for embryogenesis to complete. Focal adhesion kinase (FAK) is essential for vascular development as endothelial cell (EC)–specific knockout of FAK (conditional FAK knockout [CFKO] mice) leads to embryonic lethality. In this study, we report the differential kinase-independent and -dependent functions of FAK in vascular development by creating and analyzing an EC-specific FAK kinase-defective (KD) mutant knockin (conditional FAK knockin [CFKI]) mouse model. CFKI embryos showed apparently normal development through embryonic day (E) 13.5, whereas the majority of CFKO embryos died at the same stage. Expression of KD FAK reversed increased EC apoptosis observed with FAK deletion in embryos and in vitro through suppression of up-regulated p21. However, vessel dilation and defective angiogenesis of CFKO embryos were not rescued in CFKI embryos. ECs without FAK or expressing KD FAK showed increased permeability, abnormal distribution of vascular endothelial cadherin (VE-cadherin), and reduced VE-cadherin Y658 phosphorylation. Together, our data suggest that kinase-independent functions of FAK can support EC survival in vascular development through E13.5 but are insufficient for maintaining EC function to allow for completion of embryogenesis.
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