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Cell Chem Biol. 2019 Apr 25. pii: S2451-9456(19)30121-7. doi: 10.1016/j.chembiol.2019.04.007. [Epub ahead of print]

Time-Variant SRC Kinase Activation Determines Endothelial Permeability Response.

Author information

1
Department of Pharmacology, The University of Illinois College of Medicine, 835 S. Wolcott Avenue, Chicago, IL 60612, USA.
2
Advanced Imaging Center at Janelia Research Campus, 19700 Helix Drive, Ashburn, VA 20147, USA.
3
Department of Pathology, The Feinberg School of Medicine at Northwestern University, Chicago, IL 60611, USA.
4
Department of Pharmacology, The University of Illinois College of Medicine, 835 S. Wolcott Avenue, Chicago, IL 60612, USA. Electronic address: karginov@uic.edu.

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.

KEYWORDS:

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

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