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Ga13 Targeting of VE‐cadherin Mediates Disassembly of Adherens Junctions and Endothelial Permeability
Author(s) -
Gong Haixia,
Gao Xiaopei,
Siddiqui M Rizwan,
Garcia Alexander,
Bonini Marcelo,
Vogel Stephen M,
Malik Asrar B.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1131.2
Subject(s) - adherens junction , microbiology and biotechnology , cadherin , heterotrimeric g protein , ve cadherin , chemistry , g protein coupled receptor , biology , signal transduction , g protein , cell , biochemistry
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. H 2 O 2 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 H 2 O 2 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.