Tyrosine Phosphorylation of VE-cadherin Prevents Binding of p120- and β-Catenin and Maintains the Cellular Mesenchymal State

Abstract

In several pathological conditions, epithelial cells demonstrate a breakdown of barrier function and acquire an invasive phenotype. Endothelial cells in particular are maintained in a mesenchymal state during the cell invasion phase of angiogenesis. We show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120-and ␤-catenin, respectively, to the cytoplasmic tail of VE-cadherin. In fact, phosphorylation at either site led to the inhibition of cell barrier function. Cells expressing wild-type VE-cadherin showed decreased cell migration compared with cells lacking VE-cadherin, whereas expression of VE-cadherin with a simple phosphomimetic tyrosine-to-glutamic acid mutation of Y658E or Y731E was sufficient to restore the migratory response. These findings demonstrate that a single phosphorylation event within the VE-cadherin cytoplasmic tail is sufficient to maintain cells in a mesenchymal state.

Intracellular Ascorbate Prevents Endothelial Barrier Permeabilization by Thrombin

“…However, tyrosine phosphorylation is a well characterized cause of VE-cadherin junction opening and increased vascular permeability (24). Phosphorylation has been linked to both endocytosis of VE-cadherin (25) and the dissociation of VE-cadherin from ␤-catenin and subsequent loss of stable association with the cortical actin cytoskeleton (26). Because we observed ostensible internalization of VE-cadherin (Fig.…”

Angiogenesis: The VE-Cadherin Switch

“…The Cheresh lab showed that VE-cadherin phosphorylation on Tyr658 or Tyr731, but not other tyrosines, was sufficient to maintain cells in a mesenchymal state ( ). More work is necessary to Potter et al 2005 understand which tyrosine is targeted in which condition.…”

Dynamics between actin and the VE-cadherin/catenin complex

“…[65][66][67] Many of these functions were also demonstrated for regulation of the VE-cadherin in endothelium. [68][69][70][71][72][73][74][75][76] Importantly, recent data indicates the involvement of p120 ctn in controlling ARP2/3 complex-mediated actin polymerization at endothelial junctions, by binding to the nuclear-promoting factors Wiskott-Aldrich Syndrome Protein (N-WASP) 21 and to cortactin. 77,78 Both the ARP2/3 complex 11,21 and cortactin [79][80][81][82][83][84][85] control endothelial integrity, and particularly, N-WASP control ARP2/3 complex-mediated formation of new VE-cadherin adhesion sites, which drive the VE-cadherin dynamics.…”