VE-PTP Inhibits GEF-H1 to Stabilize VE-cadherin Junctions in Endothelial Cells

Vascular Endothelial Protein Tyrosine Phosphatase (VE-PTP) is an endothelial-specific phosphatase that stabilizes Vascular Endothelial (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 photo-convertible fluorescent protein, VE-cadherin-Dendra2, to monitor VE-cadherin dynamics at 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 which through binding and inhibiting the RhoGEF, GEF-H1 modulates RhoA activity and tension across VE-cadherin junctions. Overexpression of VE-PTP 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 through inhibiting GEF-H1, and thereby limits RhoA signaling at AJs and reduces the VE-cadherin internalization rate.