VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN

Daniel E. Conway, Brian G. Coon, Madhusuthan Budatha, Paul T. Arsenovic, Fabrizio Orsenigo, Florian Wessel, Jiasheng Zhang, Zhenwu Zhuang, Elisabetta Dejana, Dietmar Vestweber, Martin A. Schwartz

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Fluid shear stress due to blood flow on the vascular endothelium regulates blood vessel development, remodeling, physiology, and pathology [1, 2]. A complex consisting of PECAM-1, VE-cadherin, and vascular endothelial growth factor receptors (VEGFRs) that resides at endothelial cell-cell junctions transduces signals important for flow-dependent vasodilation, blood vessel remodeling, and atherosclerosis. PECAM-1 transduces forces to activate src family kinases (SFKs), which phosphorylate and transactivate VEGFRs [3–5]. By contrast, VE-cadherin functions as an adaptor that interacts with VEGFRs through their respective cytoplasmic domains and promotes VEGFR activation in flow [6]. Indeed, shear stress triggers rapid increases in force across PECAM-1 but decreases the force across VE-cadherin, in close association with downstream signaling [5]. Interestingly, VE-cadherin cytoplasmic tyrosine Y658 can be phosphorylated by SFKs [7], which is maximally induced by low shear stress in vitro and in vivo [8]. These considerations prompted us to address the involvement of VE-cadherin cytoplasmic tyrosines in flow sensing. We found that phosphorylation of a small pool of VE-cadherin on Y658 is essential for flow sensing through the junctional complex. Y658 phosphorylation induces dissociation of p120ctn, which allows binding of the polarity protein LGN. LGN is then required for multiple flow responses in vitro and in vivo, including activation of inflammatory signaling at regions of disturbed flow, and flow-dependent vascular remodeling. Thus, endothelial flow mechanotransduction through the junctional complex is mediated by a specific pool of VE-cadherin that is phosphorylated on Y658 and bound to LGN.

Original languageEnglish (US)
Pages (from-to)2219-2225.e5
JournalCurrent Biology
Volume27
Issue number14
DOIs
StatePublished - Jul 24 2017
Externally publishedYes

Keywords

  • flow signaling
  • mechanotransduction
  • p120 catenin
  • vascular biology
  • VEGF receptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Conway, D. E., Coon, B. G., Budatha, M., Arsenovic, P. T., Orsenigo, F., Wessel, F., Zhang, J., Zhuang, Z., Dejana, E., Vestweber, D., & Schwartz, M. A. (2017). VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. Current Biology, 27(14), 2219-2225.e5. https://doi.org/10.1016/j.cub.2017.06.020