May 23, 2019 (Updated June 12, 2019) | Jola Glotzer
Endothelial barrier—tight then leaky
Three CBC affiliates — Andrei Karginov and Asrar B. Malik (UIC), and Teng-Leong Chew (Janelia) — contribute to a new study in Cell Chemical Biology about the endothelial barrier regulation
Congratulations to Andrei Karginov, UIC, on a recent publication in Cell Chemical Biology, “Time-Variant SRC Kinase Activation Determines Endothelial Permeability Response.” The authors used a chemically inducible kinase system and physiological stimuli to demonstrate that SRC kinase regulates the endothelial barrier in a temporally dependent manner. SRC activity initially enhances barrier function via the adherens junction protein VE cadherin, while prolonged activity leads to endothelial barrier disruption. The two seemingly opposing effects are achieved by phosphorylation of different tyrosines in VE cadherin.
The authors acknowledge CBC funding as contributing to the published work — specifically, a CBC Catalyst Award to Karginov that he received in 2013. Karginov is senior author on the publication. Two other co-authors on the paper have links to the CBC: Teng-Leong Chew and Asrar B. Malik. Chew, who works at the Advanced Imaging Center at Janelia Research Campus, was an invited speaker at the CBC Tech Day (2014). Two of Malik’s postdocs received CBC Postdoctoral Research Awards (2014 and 2016). Malik also participated both as an organizer and a speaker in a CBC Exploratory Workshop dedicated to the field of vascular biology. The CBC congratulates all authors on the published study.
Publication attributed to CBC funding*:
Klomp JE, Shaaya M, Jacob M, Rebiai R, Aaron JS, Collins KB, Huyot V, Gonzalez AM, Muller WA, Chew TL, Malik AB, Karginov AV. Time-Variant SRC Kinase Activation Determines Endothelial Permeability Response. Cell Chemical Biology 26, 1–14, August 15, 2019. [Epub ahead of print] (www.cell.com)
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.
We extend our appreciation to Dr. John O’Bryan, Dr. Maulik Patel, and Dr. Anne-Marie Ray for helpful insights during the pursuit of this project; as well as to Dr. Jeffrey A. Klomp for assistance with statistical analysis. We would also like to thank Aaron Taylor and Satya Khuon at Janelia Research Campus for assistance with live-cell SIM and technical support, respectively. iPALM imaging was performed in collaboration with the Advanced Imaging Center at Janelia Research Campus, supported by the Gordon and Betty Moore Foundation and the Howard Hughes Medical Institute. We are grateful to NIH, the Chicago Biomedical Consortium, and University of Illinois at Chicago Center for Clinical and Translational Science for funding (R21CA159179 from NCI, CBC Catalyst Award, and R01 grant R01GM118582 from NIGMS to A.V.K., NIH T32 HL007829-22 and P01 HL060678 to A.B.M., UIC CCTS grant UL1TR000050 to J.E.K.).
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