VE-PTP stabilizes VE-cadherin junctions and the endothelial barrier via a phosphatase-independent mechanism

Vanessa V. Juettner, Kevin Kruse, Arkaprava Dan, Vinh H. Vu, Yousaf Khan, Jonathan Le, Deborah Leckband, Yulia Komarova, Asrar B. Malik

Research output: Contribution to journalArticle

Abstract

Vascular endothelial (VE) protein tyrosine phosphatase (PTP) is an endothelial-specific phosphatase that stabilizes VE-cadherin junctions. Although studies have focused on the role of VE-PTP in dephosphorylating VE-cadherin in the activated endothelium, little is known of VE-PTP’s role in the quiescent endothelial monolayer. Here, we used the photoconvertible fluorescent protein VE-cadherin-Dendra2 to monitor VE-cadherin dynamics at adherens junctions (AJs) in confluent endothelial monolayers. We discovered that VE-PTP stabilizes VE-cadherin junctions by reducing the rate of VE-cadherin internalization independently of its phosphatase activity. VE-PTP serves as an adaptor protein that through binding and inhibiting the RhoGEF GEF-H1 modulates RhoA activity and tension across VE-cadherin junctions. Overexpression of the VEPTP cytosolic domain mutant interacting with GEF-H1 in VE-PTP–depleted endothelial cells reduced GEF-H1 activity and restored VE-cadherin dynamics at AJs. Thus, VE-PTP stabilizes VE-cadherin junctions and restricts endothelial permeability by inhibiting GEF-H1, thereby limiting RhoA signaling at AJs and reducing the VE-cadherin internalization rate.

Original languageEnglish (US)
Pages (from-to)1725-1742
Number of pages18
JournalJournal of Cell Biology
Volume218
Issue number5
DOIs
StatePublished - May 1 2019

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Juettner, V. V., Kruse, K., Dan, A., Vu, V. H., Khan, Y., Le, J., Leckband, D., Komarova, Y., & Malik, A. B. (2019). VE-PTP stabilizes VE-cadherin junctions and the endothelial barrier via a phosphatase-independent mechanism. Journal of Cell Biology, 218(5), 1725-1742. https://doi.org/10.1083/jcb.201807210