Focal adhesion kinase (FAK) has multiple functions in endothelial cells, but only some of them require the protein's kinase activity, Zhao et al. report.

FAK promotes the migration and survival of many cell types, including endothelial cells. Mice lacking FAK in their vascular system die before birth due to defects in angiogenesis, but how FAK supports blood vessel development is unclear. In vitro experiments suggest that FAK sometimes acts as an adaptor for other kinases instead of phosphorylating target proteins itself. To investigate whether FAK's kinase activity is required for angiogenesis, Zhao et al. generated mice that only express a kinase-deficient version of the protein in their vasculature.

Although these mice still died before birth, they survived for a couple of days longer than animals without any FAK in their vascular system. Endothelial cells completely lacking FAK are prone to apoptosis, but kinase-dead FAK boosted cell survival by suppressing the cyclin-dependent kinase inhibitor p21. But other problems emerged as the embryos developed further: blood vessels were dilated and fewer in number. The researchers found that endothelial cell layers are more permeable in the absence of FAK due to mislocalization and reduced phosphorylation of the adhesion protein VE-cadherin. These defects weren't rescued by the kinase-deficient mutant.

FAK therefore has kinase-dependent and -independent functions in endothelial cells. The same may be true in cancer cells, says senior author Jun-Lin Guan, so drugs that only target FAK's kinase activity may not prevent the protein from promoting metastasis.

et al
J. Cell Biol.