Time-Variant SRC Kinase Activation Determines Endothelial Permeability Response

Jennifer E. Klomp, Mark Shaaya, Jacob Matsche, Rima Rebiai, Jesse S. Aaron, Kerrie B. Collins, Vincent Huyot, Annette M. Gonzalez, William A. Muller, Teng Leong Chew, Asrar B. Malik, Andrei V. Karginov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

In the current model of endothelial barrier regulation, the tyrosine kinase SRC is purported to induce disassembly of endothelial adherens junctions (AJs) via phosphorylation of VE cadherin, and thereby increase junctional permeability. Here, using a chemical biology approach to temporally control SRC activation, we show that SRC exerts distinct time-variant effects on the endothelial barrier. We discovered that the immediate effect of SRC activation was to transiently enhance endothelial barrier function as the result of accumulation of VE cadherin at AJs and formation of morphologically distinct reticular AJs. Endothelial barrier enhancement via SRC required phosphorylation of VE cadherin at Y731. In contrast, prolonged SRC activation induced VE cadherin phosphorylation at Y685, resulting in increased endothelial permeability. Thus, time-variant SRC activation differentially phosphorylates VE cadherin and shapes AJs to fine-tune endothelial barrier function. Our work demonstrates important advantages of synthetic biology tools in dissecting complex signaling systems.

Original languageEnglish (US)
Pages (from-to)1081-1094.e6
JournalCell Chemical Biology
Volume26
Issue number8
DOIs
StatePublished - Aug 15 2019

Keywords

  • Kinase
  • LYN
  • SRC
  • VE cadherin
  • adherens junctions
  • cell migration
  • endothelial barrier function
  • endothelial cells
  • inducible kinase
  • reticular junctions

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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