Ga13 Targeting of VE‐cadherin Mediates Disassembly of Adherens Junctions and Endothelial Permeability

Abstract

The heterotrimeric G protein α unit Gα13 transmits signals from G protein coupled receptors (GPCRs) to effectors to regulate cell spreading, differentiation, migration, and cell polarity. Both conventional and endothelial cell‐specific Gα13 gene knockouts are embryonically lethal because of impaired vasculogenesis. Here we describe a new pro‐inflammatory function of Gα13 through its displacement from the GPCR protease‐activated receptor 1 (PAR1) to the endothelial adherens junction (AJ) protein VE‐cadherin. H2O2 production induced by multiple mediators (thrombin, LPS or TNFα) induced a shift in Gα13 binding to VE‐cadherin and disassembly of AJs. Gα13/VE‐cadherin interaction activated c‐Src resulting in phosphorylation of VE‐cadherin at Tyr 658, the p120‐ catenin binding site responsible for VE‐cadherin endocytosis from the membrane. Preventing Gα13/VE‐cadherin interaction by Cre recombinase‐mediated Gα13 knockout in mice or an interfering myristoylated peptide derived from VE‐cadherin, inhibited AJ disruption and inflammatory response to sepsis. These studies establish a crucial Gα13 switch mechanism activated by H2O2 generation that mediates Gα13 binding to VE‐cadherin and thereby disrupts AJ integrity. Therefore, blocking Gα13 translocation and Gα13/VE‐cadherin interaction represents a potential anti‐inflammatory target.