N-cadherin signaling via Trio assembles adherens junctions to restrict endothelial permeability

Kevin Kruse, Quinn S. Lee, Ying Sun, Jeff Klomp, Xiaoyan Yang, Fei Huang, Mitchell Y. Sun, Shuangping Zhao, Zhigang Hong, Stephen M. Vogel, J. W. Shin, Deborah E. Leckband, Leon M. Tai, Asrar B. Malik, Yulia A. Komarova

Research output: Contribution to journalArticle

Abstract

Vascular endothelial (VE)–cadherin forms homotypic adherens junctions (AJs) in the endothelium, whereas N-cadherin forms heterotypic adhesion between endothelial cells and surrounding vascular smooth muscle cells and pericytes. Here we addressed the question whether both cadherin adhesion complexes communicate through intracellular signaling and contribute to the integrity of the endothelial barrier. We demonstrated that deletion of N-cadherin (Cdh2) in either endothelial cells or pericytes increases junctional endothelial permeability in lung and brain secondary to reduced accumulation of VE-cadherin at AJs. N-cadherin functions by increasing the rate of VE-cadherin recruitment to AJs and induces the assembly of VE-cadherin junctions. We identified the dual Rac1/RhoA Rho guanine nucleotide exchange factor (GEF) Trio as a critical component of the N-cadherin adhesion complex, which activates both Rac1 and RhoA signaling pathways at AJs. Trio GEF1-mediated Rac1 activation induces the recruitment of VE-cadherin to AJs, whereas Trio GEF2-mediated RhoA activation increases intracellular tension and reinforces Rac1 activation to promote assembly of VE-cadherin junctions and thereby establish the characteristic restrictive endothelial barrier.

Original languageEnglish (US)
Pages (from-to)299-316
Number of pages18
JournalJournal of Cell Biology
Volume218
Issue number1
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Cell Biology

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    Kruse, K., Lee, Q. S., Sun, Y., Klomp, J., Yang, X., Huang, F., Sun, M. Y., Zhao, S., Hong, Z., Vogel, S. M., Shin, J. W., Leckband, D. E., Tai, L. M., Malik, A. B., & Komarova, Y. A. (2019). N-cadherin signaling via Trio assembles adherens junctions to restrict endothelial permeability. Journal of Cell Biology, 218(1), 299-316. https://doi.org/10.1083/jcb.201802076