FAK regulates tension transmission to the nucleus and endothelial transcriptome independent of kinase activity
Md Zahid Akhter,
Pascal Yazbeck,
Mohammad Tauseef,
Mumtaz Anwar,
Faruk Hossen,
Sayanti Datta,
Vigneshwaran Vellingiri,
Jagdish Chandra Joshi,
Peter T. Toth,
Nityanand Srivastava,
Stephen Lenzini,
Guangjin Zhou,
James Lee,
Mukesh K. Jain,
Jae-Won Shin,
Dolly Mehta
Affiliations
Md Zahid Akhter
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA
Pascal Yazbeck
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA
Mohammad Tauseef
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA
Mumtaz Anwar
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA
Faruk Hossen
Department of Biomedical Engineering, Chicago, IL, USA
Sayanti Datta
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA
Vigneshwaran Vellingiri
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA
Jagdish Chandra Joshi
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA
Peter T. Toth
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA; Research Resources Center, University of Illinois, Chicago, IL, USA
Nityanand Srivastava
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA
Stephen Lenzini
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA
Guangjin Zhou
Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
James Lee
Department of Biomedical Engineering, Chicago, IL, USA
Mukesh K. Jain
Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, RI, USA
Jae-Won Shin
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA; Department of Biomedical Engineering, Chicago, IL, USA
Dolly Mehta
Department of Pharmacology & Regenerative Medicine and Center for Lung and Vascular Biology, Chicago, IL, USA; Corresponding author
Summary: 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.
