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Transcriptional Regulation of S1PR1 Through FAK and KLF2 is Required for Maintaining Endothelial Barrier Integrity
Author(s) -
Yazbeck Pascal,
Schmidt Tracy,
Tauseef Mohammad,
Mehta Dolly
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.980.15
Subject(s) - s1pr1 , adherens junction , microbiology and biotechnology , tight junction , focal adhesion , barrier function , biology , endothelium , signal transduction , chemistry , cancer research , vascular endothelial growth factor a , cadherin , vascular endothelial growth factor , endocrinology , biochemistry , cell , vegf receptors
Formation of leaky blood vessels remains a persistent pathology in several diseases including acute lung injury. Sphingosine‐1‐phosphate (S1P) is a lipid mediator well known for its ability to induce endothelial barrier function. Formed through metabolism of sphingomyelin, S1P regulates endothelial barrier function by binding to S1P receptor 1 (previously known as endothelial differentiation gene (Edg1). However, mechanisms upregulating S1PR1 expression enabling formation of endothelial barrier function remain unclear. Focal adhesion kinase (FAK), a non‐receptor tyrosine kinase, regulates focal adhesion formation. We recently showed that loss of FAK impairs barrier formation leading to spontaneous vascular leak in mice lung vasculature. Here we found that FAK forms endothelial barrier by maintaining S1PR1 expression. We showed that FAK depletion significantly reduced the expression of S1PR1 both at mRNA and protein level without changing the expression of other S1PRs. Consistently, FAK depleted ECs failed to anneal adherens junctions as determined by VE‐cadherin immunostaining of the barrier. Additionally, loss of FAK impaired basal endothelial barrier function (as determined by measuring transendothelial electrical resistance (TEER)) under basal conditions and these cells could not strengthen endothelial barrier even after S1P application. Rescuing S1PR1 expression restored barrier function in FAK null ECs indicating S1PR1 function downstream of FAK. We identified KLF2 (Krüppel‐like transcription factor 2) as the transcription of S1PR1 which regulate S1PR1 transcription downstream of FAK. Our data provide a new insight of FAK regulation of S1PR1 expression and signaling through KLF2 to restore the formation of stable endothelial barrier.