VE-PTP controls blood vessel development by balancing Tie-2 activity

Max-Planck-Institute of Molecular Biomedicine, D-48149 Münster, Germany.
The Journal of Cell Biology (Impact Factor: 9.83). 06/2009; 185(4):657-71. DOI: 10.1083/jcb.200811159
Source: PubMed

ABSTRACT Vascular endothelial protein tyrosine phosphatase (VE-PTP) is an endothelial-specific receptor-type tyrosine phosphatase that associates with Tie-2 and VE-cadherin. VE-PTP gene disruption leads to embryonic lethality, vascular remodeling defects, and enlargement of vascular structures in extraembryonic tissues. We show here that antibodies against the extracellular part of VE-PTP mimic the effects of VE-PTP gene disruption exemplified by vessel enlargement in allantois explants. These effects require the presence of the angiopoietin receptor Tie-2. Analyzing the mechanism we found that anti-VE-PTP antibodies trigger endocytosis and selectively affect Tie-2-associated, but not VE-cadherin-associated VE-PTP. Dissociation of VE-PTP triggers the activation of Tie-2, leading to enhanced endothelial cell proliferation and enlargement of vascular structures through activation of Erk1/2. Importantly, the antibody effect on vessel enlargement is also observed in newborn mice. We conclude that VE-PTP is required to balance Tie-2 activity and endothelial cell proliferation, thereby controlling blood vessel development and vessel size.

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    • "A recent study has demonstrated in mouse that the dissociation of Ve-ptp from VE-cadherin is a prerequisite for the destabilization of EC contacts and for the opening of endothelial junctions [26]. Furthermore in vitro data have demonstrated a role of Ve-ptp in fine-tuning the activity of two tyrosine kinases which play an important role in vascular morphogenesis and in angiogenic/remodeling processes such as Tie-2 and Vegfr2 [27], [28]. "
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    ABSTRACT: Endothelial cell junctions control blood vessel permeability. Altered permeability can be associated with vascular fragility that leads to vessel weakness and haemorrhage formation. In vivo studies on the function of genes involved in the maintenance of vascular integrity are essential to better understand the molecular basis of diseases linked to permeability defects. Ve-ptp (Vascular Endothelial-Protein Tyrosine Phosphatase) is a transmembrane protein present at endothelial adherens junctions (AJs). We investigated the role of Ve-ptp in AJ maturation/stability and in the modulation of endothelial permeability using zebrafish (Danio rerio). Whole-mount in situ hybridizations revealed zve-ptp expression exclusively in the developing vascular system. Generation of altered zve-ptp transcripts, induced separately by two different splicing morpholinos, resulted in permeability defects closely linked to vascular wall fragility. The ultrastructural analysis revealed a statistically significant reduction of junction complexes and the presence of immature AJs in zve-ptp morphants but not in control embryos. Here we show the first in vivo evidence of a potentially critical role played by Ve-ptp in AJ maturation, an important event for permeability modulation and for the development of a functional vascular system.
    PLoS ONE 12/2012; 7(12):e51245. DOI:10.1371/journal.pone.0051245 · 3.23 Impact Factor
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    • "Negative regulation of these and other PTPRJ targets may be important for tumor suppression, because mouse PTPRJ corresponds to the Suppressor of colon cancer1 (Scc1) gene (Ruivenkamp et al., 2002). Two other Type III RPTPs, PTPRB (VE-PTP) and PTPRO, negatively regulate the angiopoietin receptor Tie-2 and the NT-3 receptor TrkC, respectively (Hower et al., 2009; Winderlich et al., 2009). "
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    ABSTRACT: The respiratory (tracheal) system of the Drosophila melanogaster larva is an intricate branched network of air-filled tubes. Its developmental logic is similar in some ways to that of the vertebrate vascular system. We previously described a unique embryonic tracheal tubulogenesis phenotype caused by loss of both of the Type III receptor tyrosine phosphatases (RPTPs), Ptp4E and Ptp10D. In Ptp4E Ptp10D double mutants, the linear tubes in unicellular and terminal tracheal branches are converted into bubble-like cysts that incorporate apical cell surface markers. This tube geometry phenotype is modulated by changes in the activity or expression of the epidermal growth factor receptor (Egfr) tyrosine kinase (TK). Ptp10D physically interacts with Egfr. Here we demonstrate that the Ptp4E Ptp10D phenotype is the consequence of the loss of negative regulation by the RPTPs of three growth factor receptor TKs: Egfr, Breathless and Pvr. Reducing the activity of any of the three kinases by tracheal expression of dominant-negative mutants suppresses cyst formation. By competing dominant-negative and constitutively active kinase mutants against each other, we show that the three RTKs have partially interchangeable activities, so that increasing the activity of one kinase can compensate for the effects of reducing the activity of another. This implies that SH2-domain downstream effectors that are required for the phenotype are likely to be able to interact with phosphotyrosine sites on all three receptor TKs. We also show that the phenotype involves increases in signaling through the MAP kinase and Rho GTPase pathways.
    Biology Open 06/2012; 1(6):548-58. DOI:10.1242/bio.2012471 · 2.42 Impact Factor
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    • "After exposure of human endothelial cell monolayers to Ang-1, Tie-2 receptors are mobilized from the endothelial cell surface to the cell junctions, where oligo- or multimers of Ang-1 [43] bridge Tie-2 receptors of both adjacent cells [41], [44]. This complex also recruits vascular endothelial protein tyrosine phosphatase (VE-PTP) [45]. At these junctions the multimeric complex of Ang-1 and Tie-2 bridges two cells [41], [44] and induces specific Tie-2-mediated signaling that causes activation of small GTPase Rap1 and subsequently Rac1, which enforce the maintenance of the junctions between both cells [46]–[48]. "
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    ABSTRACT: Angiopoietin-2 (Ang-2) is associated with lung injury in ALI/ARDS. As endothelial activation by thrombin plays a role in the permeability of acute lung injury and Ang-2 may modulate the kinetics of thrombin-induced permeability by impairing the organization of vascular endothelial (VE-)cadherin, and affecting small Rho GTPases in human pulmonary microvascular endothelial cells (HPMVECs), we hypothesized that Ang-2 acts as a sensitizer of thrombin-induced hyperpermeability of HPMVECs, opposed by Ang-1. Permeability was assessed by measuring macromolecule passage and transendothelial electrical resistance (TEER). Angiopoietins did not affect basal permeability. Nevertheless, they had opposing effects on the thrombin-induced permeability, in particular in the initial phase. Ang-2 enhanced the initial permeability increase (passage, P = 0.010; TEER, P = 0.021) in parallel with impairment of VE-cadherin organization without affecting VE-cadherin Tyr685 phosphorylation or increasing RhoA activity. Ang-2 also increased intercellular gap formation. Ang-1 preincubation increased Rac1 activity, enforced the VE-cadherin organization, reduced the initial thrombin-induced permeability (TEER, P = 0.027), while Rac1 activity simultaneously normalized, and reduced RhoA activity at 15 min thrombin exposure (P = 0.039), but not at earlier time points. The simultaneous presence of Ang-2 largely prevented the effect of Ang-1 on TEER and macromolecule passage. Ang-1 attenuated thrombin-induced permeability, which involved initial Rac1 activation-enforced cell-cell junctions, and later RhoA inhibition. In addition to antagonizing Ang-1, Ang-2 had also a direct effect itself. Ang-2 sensitized the initial thrombin-induced permeability accompanied by destabilization of VE-cadherin junctions and increased gap formation, in the absence of increased RhoA activity.
    PLoS ONE 08/2011; 6(8):e23448. DOI:10.1371/journal.pone.0023448 · 3.23 Impact Factor
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