Evidence of a common mechanism of disassembly of adherens junctions through Gα13 targeting of VE-cadherin

The heterotrimeric G protein G alpha 13 transduces signals from G protein-coupled receptors (GPCRs) to induce cell spreading, differentiation, migration, and cell polarity. Here, we describe a novel GPCR-independent function of G alpha 13 in regulating the stability of endothelial cell adherens junctions (AJs). We observed that the oxidant H2O2, which is released in response to multiple proinflammatory mediators, induced the interaction of G alpha 13 with VE-cadherin. G alpha 13 binding to VE-cadherin in turn induced Src activation and VE-cadherin phosphorylation at Tyr 658, the p120-catenin binding site thought to be responsible for VE- cadherin internalization. Inhibition of G alpha 13-VE-cadherin interaction using an interfering peptide derived from the G alpha 13 binding motif on VE-cadherin abrogated the disruption of AJs in response to inflammatory mediators. These studies identify a unique role of G alpha 13 binding to VE-cadherin in mediating VE-cadherin internalization and endothelial barrier disruption and inflammation.