Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin

Frye, Maike; Dierkes, Martina; Küppers, Verena; Vockel, Matthias; Tomm, Janina M.; Zeuschner, Dagmar; Rossaint, Jan; Zarbock, Alexander; Koh, Gou Young; Peters, Kevin G.; Nottebaum, Astrid F.; Vestweber, Dietmar

doi:10.1083/jcb.2116oia294

Cited by 51 publications

(111 citation statements)

References 34 publications

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“…Consistent with previous studies of septic patients and preclinical sepsis models, Kim and colleagues report a reduc-not responsible for ANG2's antagonistic effects (43), pharmacological inhibition of VE-PTP potently activates Tie2, an effect that persists even in the presence of high ANG2 concentrations, such as in diabetic macular edema and cerebral ischemia (44,45). VE-PTP inhibition has been advanced to clinical trials for eye disease (46,47) and has shown promise in LPS-induced vascular leak (48). It is unknown whether VE-PTP's effects on Tie2 are influenced by the presence of Tie1 or its cleavage.…”

Section: The Effect Of Inflammationsupporting

confidence: 57%

Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling

Mueller¹,

Kontos²

2016

Journal of Clinical Investigation

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Section: The Effect Of Inflammationsupporting

confidence: 57%

Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling

Mueller¹,

Kontos²

2016

Journal of Clinical Investigation

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“…Recombinant ANG1, inhibition of ANG2 or increasing Tie2 activity by therapeutic antibodies or a small-molecule phosphatase inhibitor have vascular protective effects in acute inflammation and in sepsis (32,33,34,62,72,73), consistent with an agonist action of ANG1 and antagonistic action of ANG2. Reduced Tie2 protein and Tie2 and Ang1 mRNA levels have been reported in murine sepsis and systemic inflammation (56,74).…”

Section: Methodsmentioning

confidence: 98%

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Korhonen

Lampinen

Giri³

et al. 2016

Journal of Clinical Investigation

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279

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The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β 1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1-and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability. The Journal of Clinical Investigation R E S E A R C H A R T I C L E3 4 9 6 jci.org Volume 126 Number 9 September 2016We found that angiopoietins promoted a direct interaction of Tie1 and Tie2 and that this interaction was regulated by integrin β 1 . ANG1-and ANG2-induced Tie2 activation and vascular remodeling were reduced or absent in mice where Tie1 was deleted in vascular endothelial cells. Tie1 deletion also attenuated ANG1-induced Akt activation and nuclear exclusion of FOXO1. We found that Tie1 was suppressed via ectodomain cleavage during acute inflammation and that this was associated with reduced agonistic activity of ANG2 and decreased Tie2 signaling. These results indicate that the agonist action of ANG2 is attenuated in inflammation and that Tie1 is an essential component of the angiopoietin signaling system that has potential for therapeutic targeting in disease. ResultsAngiopoietins induce direct interaction of Tie1 and Tie2. To investigate the dynamics of the Tie receptors in angiopoietin signaling, we transfected HUVECs with retroviral vectors expressing full-length (FL) Tie1 and Tie2, tagged on the C terminus with mCherry and GFP, respectively. Stimulation of FL-Tie2-GFP and FL-Tie1-mCherry expressing endothelial cells with COMP-Ang1 (CAng1) (49) or with recombinant human ANG2 induced colocalization of Tie1 and Tie2 in endothelial cell-cell junctions ( Figure 1A and Supplemental Video 1; supplemental material available online with this article; doi:10.1172/JCI84923DS1) (44,45,50). To investigat...

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“…This effect was mediated by Tie-2, since it was strongly reduced upon silencing the expression of Tie-2 in these mice [9]. This effect was mediated by Tie-2, since it was strongly reduced upon silencing the expression of Tie-2 in these mice [9].…”

Section: Introductionmentioning

confidence: 90%

“…It is essential for the formation of these junctions and the entire vascular system during embryonic development [4,5]. However, when different organs were compared it was found that adhesion-blocking antibodies [7] and the conditional inactivation of the VE-cadherin gene [9] were sufficient to enhance vascular permeability in some, but not in all, organs of the mouse. However, when different organs were compared it was found that adhesion-blocking antibodies [7] and the conditional inactivation of the VE-cadherin gene [9] were sufficient to enhance vascular permeability in some, but not in all, organs of the mouse.…”

Section: Introductionmentioning

confidence: 99%

VE ‐ PTP inhibition stabilizes endothelial junctions by activating FGD 5

et al. 2019

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Inhibition of VE-PTP, an endothelial receptor-type tyrosine phosphatase, triggers phosphorylation of the tyrosine kinase receptor Tie-2, which leads to the suppression of inflammation-induced vascular permeability. Analyzing the underlying mechanism, we show here that inhibition of VE-PTP and activation of Tie-2 induce tyrosine phosphorylation of FGD5, a GTPase exchange factor (GEF) for Cdc42, and stimulate its translocation to cell contacts. Interfering with the expression of FGD5 blocks the junction-stabilizing effect of VE-PTP inhibition in vitro and in vivo. Likewise, FGD5 is required for strengthening cortical actin bundles and inhibiting radial stress fiber formation, which are each stimulated by VE-PTP inhibition. We identify Y820 of FGD5 as the direct substrate for VE-PTP. The phosphorylation of FGD5-Y820 is required for the stabilization of endothelial junctions and for the activation of Cdc42 by VE-PTP inhibition but is dispensable for the recruitment of FGD5 to endothelial cell contacts. Thus, activation of FGD5 is a two-step process that comprises membrane recruitment and phosphorylation of Y820. These steps are necessary for the junction-stabilizing effect stimulated by VE-PTP inhibition and Tie-2 activation.

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Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin

Cited by 51 publications

References 34 publications

Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling

Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling

Tie1 controls angiopoietin function in vascular remodeling and inflammation

VE ‐ PTP inhibition stabilizes endothelial junctions by activating FGD 5

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