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

Winderlich, Mark; Keller, Luise; Cagna, Giuseppe; Broermann, Andre; Kamenyeva, Olena; Kiefer, Friedemann; Deutsch, Urban; Nottebaum, Astrid F.; Vestweber, Dietmar

doi:10.1084/jem2066oia11

Cited by 46 publications

(65 citation statements)

References 32 publications

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“…However, VE-PTP's actions have not been previously manipulated in tumor vessels. In ES cell tumors, VE-PTP KO blood vessels were enlarged, extending the findings in yolk sacs of VE-PTP-deficient embryos (9,10), and strongly supporting the findings in explant models (31). Such a phenotype also resembles the effect of tissue-specific transgenic overexpression of the Tie2 ligand, Ang1 (21,32) or prolonged treatment with exogenous Ang1 (20,22).…”

Section: Discussionsupporting

confidence: 77%

See 1 more Smart Citation

Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis

Huang

Boland

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Inhibiting angiogenesis has become an effective approach for treating cancer and other diseases. However, our understanding of signaling pathways in tumor angiogenesis has been limited by the embryonic lethality of many gene knockouts. To overcome this limitation, we used the plasticity of embryonic stem (ES) cells to develop a unique approach to study tumor angiogenesis. Murine ES cells can be readily manipulated genetically; in addition, ES cells implanted subcutaneously in mice develop into tumors that contain a variety of cell types (teratomas). We show that ES cells differentiate into bona fide endothelial cells within the teratoma, and that these ES-derived endothelial cells form part of the functional tumor vasculature. Using this powerful and flexible system, the Angiopoietin/Tie2 system is shown to have a key role in the regulation of tumor vessel size. Endothelial differentiation in the ES teratoma model allows gene-targeting methods to be used in the study of tumor angiogenesis.teratoma ͉ endothelial cells ͉ VEGF-R2 ͉ VE-PTP

show abstract

Section: Discussionsupporting

confidence: 77%

“…An elegant recent study used antibodies to pharmacologically perturb VE-PTP activity in both cultured cells as well as in explant and developmental models (31). However, VE-PTP's actions have not been previously manipulated in tumor vessels.…”

Section: Discussionmentioning

confidence: 99%

Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis

Huang

Boland

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Thus, HIF2α-dependent upregulation of VE-PTP expression resulting in dephosphorylation of VE-cadherin at Y658, Y685, and Y731 is consistent with the model (Figure 9) that the dephosphorylation switch is a key endogenous barrier-enhancing anti-inflammatory mechanism. phorylates VE-cadherin, as we showed, but also couples with and dephosphorylates TIE2, a receptor for both angiopoietin 1 (ANG1) and ANG2, which regulate endothelial permeability and angiogenesis by antagonizing each other (25,30,35,36). In tumors, VE-PTP inhibition normalized the structure and function of tumor vessels through TIE2 activation (35).…”

Section: Discussionmentioning

confidence: 53%

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

Gong¹,

Rehman²,

Tang³

et al. 2015

J. Clin. Invest.

112

132

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“…Although transcriptional regulation of VE-cadherin has been described (33), Tie2 may also regulate localization of VE-cadherin through phosphorylationdependent endocytosis. For example, Tie2 may limit VE-cadherin phosphorylation by sequestering the tyrosine phosphatase VE-PTP (34,35). Alternatively, activated Tie2 has been shown to inhibit Src family kinases in the context of VEGF costimulation (36).…”

Section: Discussionmentioning

confidence: 99%

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Ghosh

David

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.Tie2 | endothelium | infection | angiopoietin | permeability

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

Cited by 46 publications

References 32 publications

Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis

Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

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