The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells

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Author(s)  

Zhongji Liao¹, Chen Cao², Jianjie Wang³, Virginia H. Huxley⁴, Olga Baker⁵, Gary A. Weisman², Laurie Erb^2*

Affiliation(s)

¹Department of Medicine, University of California, San Diego, USA.
²Department of Biochemistry, Life Sciences Center, University of Missouri, Columbia, USA.
³Department of Biomedical Sciences, Missouri State University, Springfield, USA.
⁴Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, USA.
⁵School of Dentistry, University of Utah, Salt Lake City, USA.

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 G_q 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.

KEYWORDS

VE-Cadherin, P2Y Receptors, Rac, Endothelium, Adherens Junctions

Cite this paper

Liao, Z. , Cao, C. , Wang, J. , Huxley, V. , Baker, O. , Weisman, G. and Erb, L. (2014) The P2Y₂ Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells. Journal of Biomedical Science and Engineering, 7, 1105-1121. doi: 10.4236/jbise.2014.714109. 

 

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