TITLE:
The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells
AUTHORS:
Zhongji Liao, Chen Cao, Jianjie Wang, Virginia H. Huxley, Olga Baker, Gary A. Weisman, Laurie Erb
KEYWORDS:
VE-Cadherin, P2Y Receptors, Rac, Endothelium, Adherens Junctions
JOURNAL NAME:
Journal of Biomedical Science and Engineering,
Vol.7 No.14,
December
31,
2014
ABSTRACT: Vascular endothelial
cadherin (VE-cadherin) mediates homophylic adhesion between endothelial cells
and is an important regulator of angiogenesis, blood vessel permeability and
leukocyte trafficking. Rac1, a member of the Rho family of GTPases, controls
VE-cadherin adhesion by acting downstream of several growth factors, including
angiopoietin-1 and vascular endothelial growth factor (VEGF). Here we show that
UTP-induced activation of the Gq protein-coupled P2Y2 nucleotide receptor (P2Y2R) in human coronary artery endothelial
cells (HCAECs) activated Rac1 and caused a transient complex to form between
P2Y2R, VE-cadherin and VEGF receptor-2 (VEGFR-2). Knockdown of
VE-cadherin expression with siRNA did not affect UTP-induced activation of extracellular
signal-regulated kinases 1/2 (ERK1/2) but led to a loss of UTP-induced Rac1
activation and tyrosine phosphorylation of p120 catenin, a cytoplasmic protein
known to interact with VE- cadherin. Activation of the P2Y2R by UTP
also caused a prolonged interaction between p120 catenin and vav2 (a guanine
nucleotide exchange factor for Rac) that correlated with the kinetics of
UTP-induced tyrosine phosphorylation of p120 catenin and VE-cadherin. Inhibitors
of VEGFR-2 (SU1498) or Src (PP2) significantly diminished UTP-induced Rac1
activation, tyrosine phosphorylation of p120 catenin and VE-cadherin, and
association of the P2Y2R with VE-cadherin and p120 catenin with
vav2. These findings suggest that the P2Y2R uses Src and VEGFR-2 to
mediate association of the P2Y2R with VE-cadherin complexes in
endothelial adherens junctions to activate Rac1.