Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, β-catenin, and the phosphatase DEP-1/CD148

Abstract

Confluent endothelial cells respond poorly to the proliferative signals of VEGF. Comparing isogenic endothelial cells differing for vascular endothelial cadherin (VE-cadherin) expression only, we found that the presence of this protein attenuates VEGF-induced VEGF receptor (VEGFR) 2 phosphorylation in tyrosine, p44/p42 MAP kinase phosphorylation, and cell proliferation. VE-cadherin truncated in β-catenin but not p120 binding domain is unable to associate with VEGFR-2 and to induce its inactivation. β-Catenin–null endothelial cells are not contact inhibited by VE-cadherin and are still responsive to VEGF, indicating that this protein is required to restrain growth factor signaling. A dominant-negative mutant of high cell density–enhanced PTP 1 (DEP-1)//CD148 as well as reduction of its expression by RNA interference partially restore VEGFR-2 phosphorylation and MAP kinase activation. Overall the data indicate that VE-cadherin–β-catenin complex participates in contact inhibition of VEGF signaling. Upon stimulation with VEGF, VEGFR-2 associates with the complex and concentrates at cell–cell contacts, where it may be inactivated by junctional phosphatases such as DEP-1. In sparse cells or in VE-cadherin–null cells, this phenomenon cannot occur and the receptor is fully activated by the growth factor.

Vascular endothelial cadherin and �-catenin in human fetoplacental vessels of pregnancies complicated by Type 1 diabetes: associations with angiogenesis and perturbed barrier function

“…However, no difference in paracellular PECAM-1 immunoreactivity was observed. These in vivo observations reflect those of in vitro studies where declustering of VE-cadherin and β-catenin, as shown by loss of junctional immunostaining and immunoblotting, resulted in increased proliferation and decreased barrier function [14,15,22]. Transfection of a recombinant VE-cadherin (cytoplasmic domain only) into intact isolated coronary venules has also been seen to result in markedly higher albumin permeability; competition between the recombinant VE-cadherin and the endogenous VEcadherin blocked the association with β-catenin and the maintenance of junctional integrity and microvascular permeability [30].…”

“…This strengthens the hypothesis that increased VEGF levels are part of the mechanism resulting in the junctional perturbations observed in Type 1 diabetic placentae. Although the signalling properties of VE-cadherin and β-catenin are largely VEGF induced [9,22], the levels of other angiogenic growth factors, such as placental growth factor, basic fibroblast growth factor and angiopoetins 1 and 2, may influence vascular development and maturity in the diabetic placenta and should be monitored [9,38]. Differences in the immunostaining intensity of placental VEGF receptor-1 (but not receptor-2) have been reported in cases of Type 1 diabetes [43].…”

“…Similarly, an increase in VE-cadherin causes the recruitment of 'free' cytoplasmic β-catenin by cell-cell junctions and thereby inhibits signalling and lymphoid enhancer binding factor/transcription factor transactivation [20,21]. Indeed, VE-cadherin expression and clustering at intercellular junctions (contact inhibition) blocks the proliferative response of the endothelial cells to VEGF, with the inhibition of VEGF receptor-2 tyrosine phosphorylation contributing to this effect [22].…”

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell Interactions

“…Numerous studies have reported that cadherins interact with growth factor receptors, including VE-cadherin with vascular endothelial growth factor (VEGF) receptor, N-cadherin with FGF receptor, and E-cadherin with EGFR (Williams et al, 2001;Lampugnani et al, 2003;Qian et al, 2004). Cadherins have been found to influence growth factor receptor signaling, either activating (Pece and Gutkind, 2000) or inhibiting (Takahashi and Suzuki, 1996;Qian et al, 2004) signaling.…”

Angiogenesis: The VE-Cadherin Switch

“…Third, VEGF induces VE-cadherin association with the adaptor molecule Shc, and this Lampugnani et al 2003 association increases Shc dephosphorylation, probably through the action of junctional phosphatases ( ). As Shc is Zanetti et al 2002 known to activate the MAP kinase pathway, its capture at the junction by VE-cadherin and its subsequent dephosphorylation may interfere with the VEGF proliferative signal.…”