Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the Angiopoietin receptor Tie-2

Fachinger, Gregor; Deutsch, Urban; Risau, Werner

doi:10.1038/sj.onc.1202992

Cited by 170 publications

(160 citation statements)

References 38 publications

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“…Antibodies against VE-PTP selectively down-regulate the Tie-2-associated but not the VE-cadherin-associated VE-PTP protein fraction VE-PTP associates with Tie-2 (Fachinger et al, 1999;Saharinen et al, 2008) and with VE-cadherin (Nawroth et al, 2002). We confirmed this by showing that VE-PTP and Tie-2, endogenously expressed in mouse and human endothelial cells, can indeed be coprecipitated (Fig.…”

Section: Ve-ptp Controls Blood Vessel Development By Balancing Tie-2 supporting

confidence: 73%

“…Flag VE-PTP (lacking the first 16 FNIII-like repeats, but containing the extracellular most membrane-proximal 17th domain) and Flag VE-PTP C/S (Fachinger et al, 1999) with a phosphatase-dead mutant (cysteine in the active center replaced by seine) were cloned into pENTR 2B (Invitrogen). Using the LR Recombination Reaction (Gateway Technology; Invitrogen), the pAd-DEST vector was created and used for lipofection of 293A cells.…”

Section: Constructs and Adenoviral Transfectionmentioning

confidence: 99%

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

Winderlich¹,

Keller²,

Cagna³

et al. 2009

J Exp Med

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Section: Ve-ptp Controls Blood Vessel Development By Balancing Tie-2 supporting

confidence: 73%

Section: Constructs and Adenoviral Transfectionmentioning

confidence: 99%

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

Winderlich¹,

Keller²,

Cagna³

et al. 2009

J Exp Med

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“…Thus, whereas DEP-1 in accordance with its suggested role as tumor suppressor (59,60) interacts with members of the catenin family, PTP␤ does not recognize these substrates (61). In a recent study, PTP␤ was shown to dephosphorylate the angiopoietin receptor Tie-2 (62). At present it is unclear whether this indicates that PTP␤ is also a tumor suppressor or if specific inhibitors of this PTP potentially could play a role in the clinic.…”

Section: Discussionmentioning

confidence: 93%

Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

Lund

Andersen

Iversen

et al. 2004

Journal of Biological Chemistry

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Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors. In contrast, little attention has been given to other potential drug targets within the PTP family. Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses with wild type and mutant PTPs, we describe the development of a general, low molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor that displays more than 100-fold selectivity for PTP␤ over PTP1B. Of note, our structure-based design principles, which are based on extensive bioinformatics analyses of the PTP family, are general in nature. Therefore, we anticipate that this strategy, here applied to PTP␤, in principle can be used in the design and development of selective inhibitors of many, if not most PTPs.Protein-tyrosine phosphatases (PTPs) 1 are key regulators of signal transduction. Together with the counteracting proteintyrosine kinases, they control the phosphorylation status of many important proteins and are thereby critically involved in the regulation of fundamental cellular processes such as metabolism, cell growth, and differentiation. Aberrant tyrosine phosphorylation levels have been associated with the development of cancer, autoimmunity, and diabetes, thus indicating that PTPs might play important etiological and pathogenic roles in these diseases (1-5). In particular, two elegant studies with PTP1B knockout mice, in which increased insulin sensitivity and resistance to diet-induced obesity were observed (6, 7), indicated that PTP1B is an important negative regulator of insulin and leptin action, suggesting that inhibition of this enzyme could augment and prolong insulin and leptin signaling (8, 9). As a result, a number of academic and industrial laboratories have devoted considerable efforts toward the development of selective inhibitors of PTP1B for treatment of type 2 diabetes and obesity resulting in very significant progress (reviewed in Refs. 10 -12). The field has advanced significantly by a number of x-ray crystallographic structures (reviewed in Refs. 3, 13, and 14), and several research groups have successfully used structure-based designs to synthesize active site-directed, selective PTP1B inhibitors (15-20). Most important, two groups have demonstrated recently that it is possible to develop compounds that are selective for PTP1B over the highly homologous T cell-PTP (21, 22), thereby lending support to the view that selective inhibitors, which discriminate between even closely related PTP...

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“…We next asked whether VE-PTP is a negative regulator of Tie2 phosphorylation in vivo, based upon the above observations and the previous study of cultured endothelial cells (19). Comparison of the phosphorylation levels of Tie2 in VE-PTP het and null teratomas shows that the baseline (untreated) levels of Tie2 phosphorylation were significantly increased in VE-PTP-null tumors compared to control tumors (Fig.…”

Section: Deletion Of Ve-ptp Results In Increased Tie2 Activation In Tmentioning

confidence: 99%

“…VE-PTP, the only known endothelial-specific receptor tyrosine phosphatase with reported activity on Tie2 (19), has been shown to be necessary for embryonic development (9, 10) but has been difficult to otherwise manipulate in vivo. Unlike VE-PTP KO embryos that die embryonically during early vascular development, we found that VE-PTP KO teratomas grew at normal rates and formed extensive ES-derived endothelium.…”

Section: Exploiting Es Tumor Model To Explore Ve-ptp In Tumor Angiogementioning

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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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

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Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the Angiopoietin receptor Tie-2

Cited by 170 publications

References 38 publications

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

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

Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

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

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