Interaction of p190RhoGAP with C-terminal Domain of p120-catenin Modulates Endothelial Cytoskeleton and Permeability

Abstract

Background: p120-catenin protein interactions regulate vascular permeability. Results: We identified p190RhoGAP-binding domain of p120-catenin and evaluated its functional significance. Conclusion: Binding of p190RhoGAP occurs at the amino acid 820 -843 domain of p120-catenin and promotes activation of Rac and down-regulation of Rho signaling, leading to increased endothelial barrier.Significance: These data demonstrate functional significance of uncoupling the p120-catenin-p190RhoGAP interaction in the context of agonist-induced endothelial permeability.

Spatial integration of E-cadherin adhesion, signalling and the epithelial cytoskeleton

“…The latter may or may not involve the ROCK partner Shroom3 [62,63], a known regulator of epithelial apical contraction [64]. In endothelial cells and C.elegans, p120 CTN may also dynamically modulate contractility at the lateral domains via its interaction with RhoA upstream regulators [65,66]. PAK family members, serine threonine kinases effectors of Rac1 and Cdc42 GTPase known to modulate contraction [67], could also participate: either via transiently activation by cell-cell contact formation (PAK1) [68] or localization at epithelial junctions (PAK4 and PAK6) [69][70][71][72].…”

Mechanisms Regulating Endothelial Permeability

“…40,63 β-catenin or plakoglobin then binds with α-catenin and links the whole complex with actin cytoskeleton. 64,65 VE-cadherin is required for forming vasculature, because loss of VE-cadherin embryonically induces lethality at E9.5 d. 2,12,66 Neutralization of VE-cadherin with anti-VE-cadherin antibody or chelation of extracellular calcium using EDTA induce endothelial barrier leak. Truncation of the β-catenin binding site at the cytosolic domain of VE-cadherin or conditional inactivation of β-catenin induces lethality in mice because of the disruption of endothelial junctions.…”

Concise Review: Mechanotransduction via p190RhoGAP Regulates a Switch Between Cardiomyogenic and Endothelial Lineages in Adult Cardiac Progenitors

“…It also has a more general role in organogenesis [51] and mammary gland morphogenesis [52] through regulation of Insulin/ IGF1/CREB signaling axis, a nutrient and hormonal sensing pathway. Conversely, p190RhoGAP-A has been previously implicated in neuronal development [53], angiogenesis [6], and RhoA 1) Arthur and Burridge [60] Direct inhibition of RhoA by p190RhoGAP (role in cell spreading and migration) 2) Ponik et al [30] p190RhoGAP-B inhibition of RhoA activity is dependent on p120-Catenin localization 3) Wildenberg et al [41], Zebda et al [31] Direct binding of p190RhoGAP to p120-Catenin lead to reduction of RhoA activity and increased Rac activity Src Brouns et al [61], Brant et al [62] p190RhoGAP is a substrate for Src, an inhibitor of Rho activity Rac 1) Levay et al [63] First demonstration of Rac GAP activity (reduction in RAC GTP levels) of p190RhoGAP through its PBR 2) Bustos et al [64] Activated Rac1 directly binds to p190RhoGAP-B (leading to its activation) P120RasGap 1) Tomar et al [40] Tyrosine phosphorylation of p190A is lost upon p120RasGap knockdown leading to loss of cell polarity 2) Bradley et al [65] Integrin/adhesion-mediated signaling activates p190RhoGAP-A through its association with p120RasGAP FAK 1)Tomar et al [40] 1) Tyrosine phosphorylation of p190A is lost upon FAK inhibition or mutation at Y397 leading to loss of cell polarity 2) Schober et al [66] 2) FAK is essential for p190RhoGAP-mediated inhibition of RhoA after cell adhesion Rnd proteins (RhoE)…”