Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation

Sato, Thomas N.; Tozawa, Yuzuru; Deutsch, Urban; Wolburg‐Buchholz, Karen; Fujiwara, Yuko; Gendron-Maguire, Maureen; Gridley, Thomas; Wolburg, Hartwig; Risau, Werner; Qin, Ying

doi:10.1038/376070a0

Cited by 1,653 publications

(1,223 citation statements)

References 21 publications

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“…44 Tie2-deficient mice have immature vessels that lack branching networks and periendothelial support cells. 44,45 In our earlier study with sVEGFR-1, -2 and -3, 25 we did not notice such liver toxicity. In the combination group V (sVEGFR-1, -3 and sTie2), a tendency towards a greater amount of ascites was found and 63% of the mice presented edema under the skin.…”

Section: Discussionmentioning

confidence: 62%

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

et al. 2010

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Despite optimal surgery and chemotherapy, the prognosis of ovarian cancer patients remains poor and new treatments are urgently needed. Solid tumors require the formation of new vessels for growth and metastasis. In the present study, we have used soluble vascular endothelial growth factor (sVEGF) receptors sVEGFR-1 and -3, soluble receptors Tie1 and Tie2 and their combinations in an ovarian cancer xenograft model. Human ovarian cancer cells were injected intraperitoneally into nude mice (n ¼ 42) and magnetic resonance imaging (MRI) was used for confirming tumors before gene delivery. Treatment with combined AdsVEGFR-1, AdsVEGFR-3 and AdsTie2 significantly decreased the size of the intraperitoneal tumors compared with the controls (AdLacZ; P ¼ 0.038) with significantly less microvessels and vascular area. Unexpectedly, treatment with combined AdsTie1 and AdsTie2 led to a dramatic shortening of the survival which was not observed in the groups receiving either of the soluble receptors alone (P ¼ 0.031). The only difference to other treatments was liver toxicity observed after the combined Tie receptor treatment.In conclusion, combined inhibition of VEGFR-1, VEGFR-3 and Tie2 pathways was safe and provided efficient therapy for ovarian cancer in mice.

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Section: Discussionmentioning

confidence: 62%

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

et al. 2010

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“…Deletion of the rasGAP gene (Henkemeyer et al, 1995) produces a very pleiotropic phenotype as would be expected for a key enzyme which rests downstream of multiple signaling pathways. Vascular defects observed in rasGAP-null embryos (Henkemeyer et al, 1995) resemble the loss of vascular integrity seen in both Tek-and Angiopoietin-1-null embryos (Dumont et al, 1994;Sato et al, 1995;Suri et al, 1996). Furthermore, an abnormal endothelial cell migration pattern was observed in these embryos.…”

Section: Discussionmentioning

confidence: 92%

“…Targeted null mutations in all of these receptors result in embryonic lethality (Shalaby et al, 1995;Fong et al, 1995;Dumont et al, in prep. ;Dumont et al, 1994;Sato et al, 1995;Puri et al, 1995), and the lethal phenotype is distinct for each receptor. These results suggest that the signaling pathways that are mediated by these receptors play unique roles in development.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, Tek immunoprecipitated from these quiescent and angiogenic tissues was found to be tyrosine phosphorylated, suggesting a dual role for this receptor in adult tissues. Mutational analysis of the tek locus by gene targeting has demonstrated that Tek is required for the maintenance of endothelial cells, since null mice exhibit a dramatic reduction in the number of endothelial cells and they die around embryonic day 9.5 ± 10.5 due to malformations of the vascular network (Dumont et al, 1994;Sato et al, 1995). Furthermore, overexpression of activated Tek in the adult leads to a hyperproliferation of endothelial cells which results in venous malformations (Vikkula et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

1998

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Tek/Tie2 is an endothelial cell-speci®c receptor tyrosine kinase that has been shown to play a role in vascular development of the mouse. Targeted mutagenesis of both Tek and its agonistic ligand, Angiopoietin-1, result in embryonic lethality, demonstrating that the signal transduction pathway(s) mediated by this receptor are crucial for normal embryonic development. In an attempt to identify downstream signaling partners of the Tek receptor, we have used the yeast two-hybrid system to identify phosphotyrosine-dependent interactions. Using this approach, we have identi®ed a novel docking molecule called Dok-R, which has sequence and structural homology to p62 dok and IRS-3. Mapping of the phosphotyrosine-interaction domain within Dok-R shows that Dok-R interacts with Tek through a PTB domain. Dok-R is coexpressed with Tek in a number of endothelial cell lines. We show that coexpression of Dok-R with activated Tek results in tyrosine phosphorylation of Dok-R and that rasGAP and Nck coimmunoprecipitate with phosphorylated Dok-R. Furthermore, Dok-R is constitutively bound to Crk presumably through the proline rich tail of Dok-R. The cloning of Dok-R represents the ®rst downstream substrate of the activated Tek receptor, and suggests that Tek can signal through a multitude of pathways.

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“…Ang2 induces proliferation and migration of endothelial cells and stimulates sprouting of new blood vessels when VEGF is present, whereas it promotes endothelial cell death and vessel regression when the activity of endogenous VEGF is inhibited [46]. Null mutation of the gene for the Tie2 angiopoietin rereceptor gave rise to a phenotype similar to both Ang1 null and Ang2 transgenic mice [47,48]. Since Tie2 is thought to be largely specific to endothelial cells, it has been suggested that Ang1 activates the Tie2 receptor on endothelial cells, resulting in a yet uncharacterized paracrine loop between EC and SMC.…”

Section: Angiopoietins and Tie2mentioning

confidence: 99%

The enigmatic role of angiopoietin-1 in tumor angiogenesis

Metheny-Barlow

2003

Cell Res

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A tumor vasculature is highly unstable and immature, characterized by a high proliferation rate of endothelial cells, hyper-permeability, and chaotic blood flow. The dysfunctional vasculature gives rise to continual plasma leakage and hypoxia in the tumor, resulting in constant on-sets of inflammation and angiogenesis. Tumors are thus likened to wounds that will not heal. The lack of functional mural cells, including pericytes and vascular smooth muscle cells, in tumor vascular structure contributes significantly to the abnormality of tumor vessels. Angiopoietin-1 (Ang1) is a physiological angiogenesis promoter during embryonic development. The function of Ang1 is essential to endothelial cell survival, vascular branching, and pericyte recruitment. However, an increasing amount of experimental data suggest that Ang1-stimulated association of mural cells with endothelial cells lead to stabilization of newly formed blood vessels. This in turn may limit the otherwise continuous angiogenesis in the tumor, and consequently give rise to inhibition of tumor growth. We discuss the enigmatic role of Ang1 in tumor angiogenesis in this review.

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Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation

Cited by 1,653 publications

References 21 publications

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

The enigmatic role of angiopoietin-1 in tumor angiogenesis

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