Abstract
Thrombin-mediated changes in endothelial cell adherens junctions modulate vascular permeability. We demonstrate that the nonreceptor protein-tyrosine phosphatase SHP2 co-precipitates with VE-cadherin complexes in confluent, quiescent human umbilical vein endothelial cells. Ligand-binding blots using a SHP2-glutathione S-transferase fusion peptide established that SHP2 associates selectively with beta-catenin in VE-cadherin complexes. Thrombin treatment of human umbilical vein endothelial cells promotes SHP2 tyrosine phosphorylation and dissociation from VE-cadherin complexes. The loss of SHP2 from the cadherin complexes correlates with a dramatic increase in the tyrosine phosphorylation of beta-catenin, gamma-catenin, and p120-catenin complexed with VE-cadherin. We propose that thrombin regulates the tyrosine phosphorylation of VE-cadherin-associated beta-catenin, gamma-catenin, and p120-catenin by modulating the quantity of SHP2 associated with VE-cadherin complexes. Such changes in adherens junction complex composition likely underlie thrombin-elicited alterations in endothelial monolayer permeability.
Highlights
Dergo contact inhibition of proliferation and stabilization of cell-cell junctions, tyrosine phosphorylation of the catenins decreases dramatically. This correlates with the density-dependent increase in protein-tyrosine phosphatases (PTP),1 especially at cell-cell junctions where they associate with cadherin complex proteins or platelet endothelial cell adhesion molecule (PECAM-1) (10 –12)
In the following studies we found that the cytosolic protein-tyrosine phosphatase SHP2 (PTP2C, PTP1D, and Syp) was associated with VE-cadherin complexes in confluent, quiescent human umbilical vein endothelial cells (HUVEC) and that SHP2 bound selectively to -catenin in the VE-cadherin complexes
When HUVEC monolayers were exposed to thrombin, SHP2 became tyrosine phosphorylated by a Src family kinase and dissociated from the VE-cadherin complexes
Summary
Dergo contact inhibition of proliferation and stabilization of cell-cell junctions, tyrosine phosphorylation of the catenins decreases dramatically. We hypothesized that thrombin receptor (protease-activated receptor 1) activation of endothelial cells altered VE-cadherin complexes by regulating the tyrosine phosphorylation of the cadherin-associated catenins. In the following studies we found that the cytosolic protein-tyrosine phosphatase SHP2 (PTP2C, PTP1D, and Syp) was associated with VE-cadherin complexes in confluent, quiescent human umbilical vein endothelial cells (HUVEC) and that SHP2 bound selectively to -catenin in the VE-cadherin complexes.
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