FAK regulates tension transmission to the nucleus and endothelial transcriptome independent of kinase activity

The mechanical environment generated through the adhesive interaction of endothelial cells (ECs) with the matrix controls nuclear tension, preventing aberrant gene synthesis and the transition from restrictive to leaky endothelium, a hallmark of acute lung injury (ALI). However, the mechanisms controlling tension transmission to the nucleus and EC-restrictive fate remain elusive. Here, we demonstrate that, in a kinase-independent manner, focal adhesion kinase (FAK) safeguards tension transmission to the nucleus to maintain EC-restrictive fate. In FAK-depleted ECs, robust activation of the RhoA-Rho-kinase pathway increased EC tension and phosphorylation of the nuclear envelope protein, emerin, activating DNMT3a. Activated DNMT3a methylates the KLF2 promoter, impairing the synthesis of KLF2 and its target S1PR1 to induce the leaky EC transcriptome. Repleting FAK (wild type or kinase dead) or inhibiting RhoA-emerin-DNMT3a activities in damaged lung ECs restored KLF2 transcription of the restrictive EC transcriptome. Thus, FAK sensing and control of tension transmission to the nucleus govern restrictive endothelium to maintain lung homeostasis. [Display omitted] •FAK, in a kinase-independent manner, safeguards tension transmission to the nucleus•Loss of endothelial FAK induces RhoA pathway activating nuclear emerin and DNMT3a•Suppression of KLF2 by DNMT3a subverts EC transcriptome to leaky phenotype•Restoring FAK or inhibiting DNMT3a rescues KLF2 transcription of restricted EC The adhesive interaction between endothelial cells (ECs) and the matrix generates restrictive endothelium but the mechanism remains unclear. Akhter et al. show that, in a kinase-independent manner, FAK suppression of the RhoA pathway safeguards tension transmission to the nucleus, limiting emerin-DNMT3a activities and enabling KLF2 transcription of the restricted ECs for vascular homeostasis.