title: The P2Y2Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells.
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 Gqprotein-coupled P2Y2nucleotide 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.
authors: Department of Medicine, University of California, San Diego, USA.
authors: Zhongji
authors: Z
authors: Liao
authors: Department of Biochemistry, Life Sciences Center, University of Missouri, Columbia, USA.
authors: Chen
authors: C
authors: Cao
authors: Department of Biomedical Sciences, Missouri State University, Springfield, USA.
authors: Jianjie
authors: J
authors: Wang
authors: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, USA.
authors: Virginia H
authors: VH
authors: Huxley
authors: School of Dentistry, University of Utah, Salt Lake City, USA.
authors: Olga
authors: O
authors: Baker
authors: Department of Biochemistry, Life Sciences Center, University of Missouri, Columbia, USA.
authors: Gary A
authors: GA
authors: Weisman
authors: Department of Biochemistry, Life Sciences Center, University of Missouri, Columbia, USA.
authors: Laurie
authors: L
authors: Erb
keywords: Adherens Junctions; Endothelium; P2Y Receptors; Rac; VE-Cadherin
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