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George D Yancopoulos - One of the best experts on this subject based on the ideXlab platform.
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expression of tie1 tie2 and Angiopoietins 1 2 and 4 in kaposi s sarcoma and cutaneous angiosarcoma
American Journal of Pathology, 2000Co-Authors: Lawrence F Brown, Bruce J Dezube, Kathi Tognazzi, Harold F Dvorak, George D YancopoulosAbstract:The Angiopoietins are recently described growth factors for vascular endothelium. The Tie1 and Tie2 receptors are expressed by endothelium. Acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS) and cutaneous angiosarcoma are malignancies of endothelial origin. KS involves primarily the skin and mucosal surfaces and is common in AIDS patients. In an effort to determine whether the Angiopoietins and Tie receptors play a role in the pathobiology of angiosarcoma and KS, we studied the expression of Angiopoietin-1, Angiopoietin-2, Angiopoietin-4, Tie1, and Tie2 mRNAs in biopsies of KS from 12 AIDS patients, in biopsies of cutaneous angiosarcoma from two patients, and in control biopsies of normal skin from three volunteers by in situ hybridization. Strong expression of Angiopoietin-2, Tie1, and Tie2 mRNAs was detected in the tumor cells of KS and cutaneous angiosarcomas, in contrast to the focal low-level expression in normal skin biopsies. Focal low-level expression of Angiopoietin-1 was seen in KS, cutaneous angiosarcomas, and in normal skin. Focal low-level expression of Angiopoietin-4 was identified in a minority of KS lesions. These findings suggest that the Angiopoietins and Tie receptors may play an important role in the pathobiology of KS and cutaneous angiosarcoma and identify additional potential targets for therapeutic intervention in these vascular malignancies.
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in situ expression of Angiopoietins in astrocytomas identifies Angiopoietin 2 as an early marker of tumor angiogenesis
Experimental Neurology, 1999Co-Authors: David Zagzag, Wai Chan, George D Yancopoulos, Andrea Hooper, David R Friedlander, Jocelyn Holash, Stanley J Wiegand, Martin GrumetAbstract:Abstract Angiopoietin-1 (Ang-1) and its naturally occurring antagonist Angiopoietin-2 (Ang-2) are novel ligands that regulate tyrosine phosphorylation of the Tie2/Tek receptor on endothelial cells. Proper regulation of Tie2/Tek is absolutely required for normal vascular development, seemingly by regulating vascular remodeling and endothelial cell interactions with supporting pericytes/smooth muscle cells. We investigated the expression of Ang-1 and Ang-2 in human astrocytomas by in situ hybridization and compared them to the distribution of pericytes/smooth muscle cells by immunohistochemistry for α-smooth muscle actin (SMA). Ang-1 mRNA was localized in tumor cells and Ang-2 mRNA was detected in endothelial cells of hyperplastic and nonhyperplastic tumor vessels. Ang-2 was also expressed in partially sclerotic vessels and in vascular channels surrounded by tumor cells in brain adjacent to the tumor. Neither Ang-1 nor Ang-2 was detected in normal brain. Dynamic changes in SMA expression during glioma tumorigenesis appear to progress from fragmentation in early vascular hyperplasia to subsequent reassociation and enhanced expression in later stages of vascular proliferation in hyperplastic complexes in high-grade gliomas. All these vessels displaying dynamic changes in SMA immunoreactivity also expressed Ang-2 mRNA. Moreover, SMA immunoreactive intratumoral vascular channels lacking morphological evidence of hyperplasia also showed upregulation of Ang-2. These results suggest that Angiopoietins are involved in the early stage of vascular activation and in advanced angiogenesis, and they identify Ang-2 as an early marker of glioma-induced neovascularization. The association between Ang-2 expression and alterations in SMA immunoreactivity suggests a role for Ang-2 in tumor-associated activation of pericytes/smooth muscle cells.
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Increased Vascularization in Mice Overexpressing Angiopoietin-1
Science, 1998Co-Authors: Chitra Suri, Gavin Thurston, Hao Zhou, Joyce Mcclain, Donald M. Mcdonald, Eben H. Oldmixon, Thomas N. Sato, George D YancopoulosAbstract:The Angiopoietins and members of the vascular endothelial growth factor (VEGF) family are the only growth factors thought to be largely specific for vascular endothelial cells. Targeted gene inactivation studies in mice have shown that VEGF is necessary for the early stages of vascular development and that Angiopoietin-1 is required for the later stages of vascular remodeling. Here it is shown that transgenic overexpression of Angiopoietin-1 in the skin of mice produces larger, more numerous, and more highly branched vessels. These results raise the possibility that Angiopoietins can be used, alone or in combination with VEGF, to promote therapeutic angiogenesis.
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Tie2 Receptor Ligands, Angiopoietin-1 and Angiopoietin-2, Modulate VEGF-Induced Postnatal Neovascularization
Circulation Research, 1998Co-Authors: Takayuki Asahara, George D Yancopoulos, Donghui Chen, Tomono Takahashi, Koshi Fujikawa, Marianne Kearney, Meredith Magner, Jeffrey M. IsnerAbstract:Abstract —Angiopoietin-1 (Ang1) has been recently identified as the major physiological ligand for the tyrosine kinase receptor Tie2 and assigned responsibility for recruiting and sustaining periendothelial support cells. Angiopoietin-2 (Ang2) was found to disrupt blood vessel formation in the developing embryo by antagonizing the effects of Ang1 and Tie2 and was thus considered to represent a natural Ang1/Tie2 inhibitor. In vivo effects of either Angiopoietin on postnatal neovascularization, however, have not been previously described. Accordingly, we used the cornea micropocket assay of neovascularization to investigate the impact of Angiopoietins on neovascularization in vivo. Neither Ang1 nor Ang2 alone promoted neovascularization. Pellets containing vascular endothelial growth factor (VEGF) alone induced corneal neovascularity extending from the limbus across the cornea. Addition of Ang1 to VEGF (Ang1+VEGF) produced an increase in macroscopically evident perfusion of the corneal neovasculature without affecting macroscopic measurements of length (0.58±0.03 mm) or circumferential neovascularity (136±10°). In contrast, pellets containing Ang2+VEGF promoted significantly longer (0.67±0.05 mm) and more circumferential (160±15°) neovascularity than VEGF alone or Ang1+VEGF ( P +9 versus 1.23±0.17 e +9 , P P P =NS). These findings constitute what is to our knowledge the first direct demonstration of postnatal bioactivity associated with either Angiopoietin. In particular, these results indicate that Angiopoietins may potentiate the effects of other angiogenic cytokines. Moreover, these findings provide in vivo evidence that Ang1 promotes vascular network maturation, whereas Ang2 works to initiate neovascularization.
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chemotactic properties of Angiopoietin 1 and 2 ligands for the endothelial specific receptor tyrosine kinase tie2
Journal of Biological Chemistry, 1998Co-Authors: Bernhard Witzenbichler, George D Yancopoulos, Peter C Maisonpierre, Pamela Jones, Jeffrey M. IsnerAbstract:Abstract Angiopoietin-1 and its putative natural antagonist, Angiopoietin-2, were recently isolated, and the critical role of Angiopoietin-1 in embryogenic angiogenesis was demonstrated by targeted gene disruption. Specific biological effects of Angiopoietin-1, however, have yet to be defined. In this study we demonstrate that Angiopoietin-1, but not Angiopoietin-2, is chemotactic for endothelial cells. In contrast, Angiopoietin-1 as well as Angiopoietin-2 exhibit no proliferative effect on endothelial cells. Excess soluble Tie2, but not Tie1 receptor, abolish the chemotactic response of endothelial cells toward Angiopoietin-1. Angiopoietin-2 dose-dependently blocks directed migration toward Angiopoietin-1, consistent with the role of Angiopoietin-2 as a naturally occurring inhibitor of Angiopoietin-1. Fibroblasts stably transfected with Tie2 receptor exhibit chemotactic responses for both Angiopoietin-1 and Angiopoietin-2. Fibroblasts stably expressing a transfected chimeric receptor consisting of the ectodomain of TrkC fused to the cytoplasmic domain of Tie2 also exhibit a chemotactic response to neurotrophin 3 (NT-3), a specific ligand for TrkC. Endothelial cells are shown to express Angiopoietin-2 mRNA and protein, indicating the potential for autocrine activation of Angiopoietin/Tie2. Finally, the demonstration that Tie2 as well as Angiopoietin-1 are expressed in normal human arteries and veins suggests that the role of Angiopoietin/Tie2 may extend beyond embryonic angiogenesis to maintaining integrity of the adult vasculature.
Daniel J. Dumont - One of the best experts on this subject based on the ideXlab platform.
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Differential response of lymphatic, venous and arterial endothelial cells to Angiopoietin-1 and Angiopoietin-2
BMC Cell Biology, 2007Co-Authors: Vicky P. K. H. Nguyen, Stephen H. Chen, Jason Trinh, Brenda L. Coomber, Daniel J. DumontAbstract:The lymphatic system complements the blood circulatory system in absorption and transport of nutrients, and in the maintenance of homeostasis. Angiopoietins 1 and 2 (Ang1 and Ang2) are regulators of both angiogenesis and lymphangiogenesis through the Tek/Tie-2 receptor tyrosine kinase. The response of endothelial cells to stimulation with either Ang1 or Ang2 is thought to be dependent upon the origin of the endothelial cells. In this study, we examined the effects of the Angiopoietins on lymphatic, venous and arterial primary endothelial cells (bmLEC, bmVEC and bmAEC, respectively), which were isolated and cultured from bovine mesenteric vessels. BmLEC, bmVEC and bmAEC cell populations all express Tie-2 and were shown to express the appropriate cellular markers Prox-1, VEGFR3, and Neuropilin-1 that define the particular origin of each preparation. We showed that while bmLECs responded slightly more readily to Angiopoietin-2 (Ang2) stimulation, bmVECs and bmAECs were more sensitive to Ang1 stimulation. Furthermore, exposure of bmLECs to Ang2 induced marginally higher levels of proliferation and survival than did exposure to Ang1. However, exposure to Ang1 resulted in higher levels of migration in bmLECs than did to Ang2. Our results suggest that although both Ang1 and Ang2 can activate the Tie-2 receptor in bmLECs, Ang1 and Ang2 may have distinct roles in mesenteric lymphatic endothelial cells.
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Activation of Tie2 by Angiopoietin-1 and Angiopoietin-2 results in their release and receptor internalization
Journal of Cell Science, 2006Co-Authors: Elena Bogdanovic, Vicky P. K. H. Nguyen, Daniel J. DumontAbstract:The receptor tyrosine kinase Tie2 is highly expressed in endothelial cells and is crucial for angiogenesis and vascular maintenance. The ligands for Tie2 are the Angiopoietins, of which Angiopoietin-1 and Angiopoietin-2 have been the most studied. Angiopoietin-1 has been characterized as the primary activating ligand for Tie2 whereas the role of Angiopoietin-2 remains controversial; activating Tie2 in some studies and inhibiting Tie2 in others. Our studies were aimed at understanding the regulation of Tie2 in endothelial cells by Angiopoietin-1 and Angiopoietin-2 and revealed that both ligands activated Tie2 in a concentration-dependent manner. Angiopoietin-2 was considerably weaker at activating Tie2 compared with Angiopoietin-1 suggesting that Angiopoietin-2 may be a partial agonist. Activation of Tie2 by these ligands resulted in differential turnover of the receptor where binding of Angiopoietin-1, and to a lesser extent Angiopoietin-2, induced rapid internalization and degradation of Tie2. Furthermore, our binding studies demonstrate that both ligands are differentially released from the endothelial cell surface after receptor activation and accumulate in the surrounding medium. Altogether, these data begin our understanding of the regulation of Tie2 and the activity of the Angiopoietins after engaging the endothelial cell surface.
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transgenic expression of Angiopoietin 1 in the liver leads to changes in lymphatic and blood vessel architecture
Biochemical and Biophysical Research Communications, 2006Co-Authors: Alexandra L Haninec, Daniel Voskas, Andrew Needles, Allison S Brown, F S Foster, Daniel J. DumontAbstract:To investigate the possible role of the Angiopoietins in vessel remodelling, we overexpressed one of the Angiopoietins, Angiopoietin-1 (Ang1), in the hepatocytes of mice by means of the conditional binary transgenic system. Animals were examined by Doppler ultrasound, and dissected livers were analyzed by immunohistochemical staining. Double transgenic mice presented with enlarged spleens and kidneys, enlarged, disorganized blood vessels located near the surface of the liver, sprouting, dilation, and disorganization of liver lymphatics, and turbulent flow in about 1/4 of the blood vessels sampled. Most of these characteristics completely resolved within 12 weeks of turning off the expression of the Ang1 transgene, illustrating a dependence on the continual presence of Ang1 for maintenance of the vascular phenotype. Conditional Angiopoietin-1 overexpression in the liver of mice leads to a phenotype highly reminiscent of portal hypertension illustrating that Ang1 can drive both vascular and lymphatic vessel remodelling and may play a role in portal hypertension.
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Functional inhibition of secreted Angiopoietin: a novel role for Angiopoietin 1 in coronary vessel patterning
Biochemical and Biophysical Research Communications, 2004Co-Authors: Nicole L. Ward, Paul Van Slyke, Daniel J. DumontAbstract:Abstract The Angiopoietins are a family of growth factors critical for development and maintenance of the vasculature. The primary amino acid sequence of the Angiopoietins predicts that they are comprised of a coiled–coiled and a fibrinogen-like domain. The coiled–coiled domain mediates ligand multimerization, whereas the fibrinogen domain engages the receptor. This multimerization is required to elicit a ligand-mediated biological effect via activation of their receptor Tie2. In vitro and in vivo knockout studies have suggested that the Angiopoietins are chemotactic for endothelial cells. We were interested in ascertaining whether the Angiopoietins have this activity within the animal proper. To accomplish this we engineered a dominant-interfering form of Angiopoietin (Ang) 1, called Ang1cc. Ang1cc contains the coiled–coiled domain, which can heterodimerize with other Angiopoietins produced in the same cell. We show that Ang1cc can inhibit Tie2 activation and can inhibit Ang1 activity in vitro and in vivo.
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the Angiopoietins and tie2 tek adding to the complexity of cardiovascular development
Seminars in Cell & Developmental Biology, 2002Co-Authors: Nicole L. Ward, Daniel J. DumontAbstract:The expansion or remodelling of pre-existing blood vessels, known as angiogenesis, by either nascent sprouting, intercalated or intussusceptive growth is a highly regulated process. Angiogenesis is critical not only during normal embryonic vascular development, but also in the progression of several diseases, including cancer, psoriasis, and diabetes. Mouse molecular genetic experiments have shown that the Angiopoietins and their receptor Tie2/Tek are indispensable for embryonic vessel development. The importance of the Angiopoietin-signalling pathway has also been shown to extend beyond development, into in vitro and in vivo experimental models of angiogenic growth. Currently the precise role of the Angiopoietins remains unclear. However, what is emerging from genetic, xenograft transplant, histochemical and cell culture experiments are that the response of endothelial cells to Angiopoietins appears to be context and endothelial cell type specific.
Hiroshi Tamura - One of the best experts on this subject based on the ideXlab platform.
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angiogenesis in the human corpus luteum changes in expression of Angiopoietins in the corpus luteum throughout the menstrual cycle and in early pregnancy
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Norihiro Sugino, Takashi Suzuki, Aki Sakata, Ichiro Miwa, Hiromi Asada, Toshiaki Taketani, Yoshiaki Yamagata, Hiroshi TamuraAbstract:Context: Blood vessel stabilization is regulated by Angiopoietins and important for angiogenesis in the corpus luteum. Objective: To study angiogenesis and blood vessel stabilization in the human corpus luteum, changes in expression of Angiopoietin (Ang)-1, Ang-2, and their specific receptor, Tie-2, together with the number of blood vessels and pericytes were examined in the corpus luteum throughout the menstrual cycle and in early pregnancy. Design: The number of blood vessels and pericytes was determined by immunohistochemistry for CD34 and α-smooth muscle actin, respectively. Ang and Tie-2 expression were examined by immunohistochemistry or RT-PCR. Results: The number of blood vessels increased during the early luteal phase, whereas the number of pericytes was small in the early luteal phase and increased in the midluteal phase, suggesting that angiogenesis is undergoing during the early luteal phase and blood vessels are stabilized in the midluteal phase. Blood vessels and pericytes decreased in numbe...
Stylianos Loukides - One of the best experts on this subject based on the ideXlab platform.
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Angiopoietins 1 and 2 in sputum supernatant of optimally treated asthmatics the effect of smoking
European Journal of Clinical Investigation, 2015Co-Authors: Vasiliki Petta, Eleni Tseliou, Petros Bakakos, Konstantinos Kostikas, Georgios Hillas, Davina Camargo Madeira Simoes, Spyros Papiris, Elissavet Konstantellou, Nikolaos Koulouris, Stylianos LoukidesAbstract:Background Angiopoietin-1 (Ang-1) is an essential mediator of angiogenesis by establishing vascular integrity, whereas Angiopoietin-2 (Ang-2) acts as its natural inhibitor. Objective We aimed to determine the levels of Angiopoietins in sputum supernatants of patients with optimally treated asthma and to investigate whether smoking represents a significant covariate on the above possible processes. Methods Eighty-seven patients with asthma (42 smokers) and 28 healthy subjects (14 smokers) were studied. All subjects underwent lung function tests, bronchial hyper-responsiveness assessment and sputum induction for cell count identification and measurement of Ang-1, Ang-2, vascular endothelial growth factor, TGF-β1, MMP-2, IL-13, Eosinophilic cationic protein and IL-8 in supernatants. Airway vascular permeability (AVP) index was also assessed. Results Ang-1 (ng/mL) levels were significantly higher in patients with asthma compared to normal subjects. Smoking significantly increased Ang-1 levels [median, interquartile ranges 24 (13–37) in smoking asthmatics vs 10 (7–14) in nonsmoking asthmatics vs 5·3 (3·7–6·5) and 4·6 (3·8–5·7) in healthy smokers and nonsmokers, respectively, P < 0·001]. Similar results were observed for Ang-2 (pg/mL) [168 (132–203) vs 124 (82–152) vs 94 (78–113) vs 100 (96–108), respectively, P < 0·001]. Regression analysis in the whole study population showed a significant negative association for Ang-1, with AVP index, and MMP-2. Smoking was a significant covariate for both Ang-1 and Ang-2 in asthmatic patients. Conclusions Ang-1 and Ang-2 levels are upregulated in patients with optimally treated asthma. Our data support a possible role for smoking in the angiogenetic process in asthma.
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increased levels of Angiopoietins 1 and 2 in sputum supernatant in severe refractory asthma
Allergy, 2012Co-Authors: Eleni Tseliou, Petros Bakakos, Konstantinos Kostikas, Georgios Hillas, K Mantzouranis, Philip Emmanouil, Davina Camargo Madeira Simoes, Manos Alchanatis, Spyros Papiris, Stylianos LoukidesAbstract:Background: Airway and vascular remodeling may play a prominent role in the clinical severity of severe refractory asthma (SRA). Angiopoietin-1 (Ang-1) is an essential mediator of angiogenesis by establishing vascular integrity, whereas Angiopoietin-2 (Ang-2) acts as its natural inhibitor. Objective: We aimed to determine the levels of Angiopoietins in sputum supernatants of patients with SRA and to investigate the possible associations with mediators and cells involved in both the inflammatory and the vascular remodeling processes. Methods: Thirty-eight patients with SRA, 35 patients with moderate asthma, and 20 healthy subjects were studied. All participants underwent lung function tests, bronchial hyperresponsiveness assessment and sputum induction for cell count identification and Ang-1, Ang-2, VEGF, TGF-β1, Cys-LTs, MMP-2, IL-13, ECP, and IL-8 measurement in supernatants. Airway vascular permeability (AVP) index was also assessed. Results: Ang-1 (ng/ml) and Ang-2 (pg/ml) levels were significantly elevated in patients with SRA compared with patients with moderate asthma and control subjects [median, interquartile ranges: 30 (17–39) vs 7.5 (5–11) vs 4.7 (3.8–5.9) respectively, P < 0.001; and 506 (400–700) vs 190 (146–236) vs 96 (89–120) respectively, P < 0.001]. Regression analysis showed a significant positive association between Ang-2 and AVP index, MMP-2, Ang-1, and VEGF in SRA. A weak association was also observed between Ang-1 and sputum eosinophils% in SRA. Conclusion: Our results indicate that both Angiopoietins levels are higher in SRA compared with moderate asthma and healthy subjects. In SRA, Ang-2 is associated with mediators involved in both the inflammatory and the vascular remodeling processes.
Nicholas P.j. Brindle - One of the best experts on this subject based on the ideXlab platform.
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Molecular control of Angiopoietin signalling.
Biochemical Society Transactions, 2011Co-Authors: Harprit Singh, Tariq A. Tahir, Deborah O. A. Alawo, Eyad Issa, Nicholas P.j. BrindleAbstract:The Angiopoietins act through the endothelial receptor tyrosine kinase Tie2 to regulate vessel maturation in angiogenesis and control quiescence and stability of established vessels. The activating ligand, Ang1 (Angiopoietin-1), is constitutively expressed by perivascular cells, and the ability of endothelial cells to respond to the ligand is controlled at the level of the Ang1 receptor. This receptor interacts with the related protein Tie1 on the cell surface, and Tie1 inhibits Ang1 signalling through Tie2. The responsiveness of endothelium to Ang1 is determined by the relative levels of Tie2 and the inhibitory co-receptor Tie1 in the cells. Tie1 undergoes regulated ectodomain cleavage which is stimulated by a range of factors including VEGF (vascular endothelial growth factor), inflammatory cytokines and changes in shear stress. Ectodomain cleavage of Tie1 relieves inhibition of Tie2 and enhances Ang1 signalling. This mechanism regulates Ang1 signalling without requiring changes in the level of the ligand and allows Ang1 signalling to be co-ordinated with other signals in the cellular environment. Regulation of signalling at the level of receptor responsiveness may be an important adaptation in systems in which an activating ligand is normally present in excess or where the ligand provides a constitutive maintenance signal. Abbreviations: Ang1, (etc.), Angiopoietin-1 (etc.); FReD, fibrinogen-related domain; NF-κB, nuclear factor κB; RTK, receptor tyrosine kinase; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor
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effects of Angiopoietins 1 and 2 on the receptor tyrosine kinase tie2 are differentially regulated at the endothelial cell surface
Cellular Signalling, 2010Co-Authors: Tania M Hansen, Harprit Singh, Tariq A. Tahir, Nicholas P.j. BrindleAbstract:Angiopoietin-1 (Ang1) and Ang2 are ligands for the receptor tyrosine kinase Tie2. Structural data suggest that the two ligands bind Tie2 similarly. However, in endothelial cells Ang1 activates Tie2 whereas Ang2 can act as an apparent antagonist. In addition, each ligand exhibits distinct kinetics of release following binding. These observations suggest that additional factors influence function and binding of Angiopoietins with receptors in the cellular context. Previous work has shown that Ang1 binding and activation of Tie2 are inhibited by Tie1, a related receptor that complexes with Tie2 in cells. In this study we have investigated binding of Ang1 and Ang2 to Tie2 in endothelial cells. In contrast to Ang1, binding of Ang2 to Tie2 was found to be not affected by Tie1. Neither PMA-induced Tie1 ectodomain cleavage nor suppression of Tie1 expression by siRNA affected the ability of Ang2 to bind Tie2. Analysis of the level of Tie1 co-immunoprecipitating with Angiopoietin-bound Tie2 demonstrated that Ang2 can bind Tie2 in Tie2:Tie1 complexes whereas Ang1 preferentially binds non-complexed Tie2. Stimulation of Tie1 ectodomain cleavage did not increase the agonist activity of Ang2 for Tie2. Similarly, the Tie2-agonist activity of Ang2 was not affected by siRNA suppression of Tie1 expression. Consistent with previous reports, loss of Tie1 ectodomain enhanced the agonist activity of Ang1 for Tie2. Importantly, Ang2 was still able to antagonize the elevated Ang1-activation of Tie2 that occurs on Tie1 ectodomain loss. Together these data demonstrate that Ang1 and Ang2 bind differently to Tie2 at the cell surface and this is controlled by Tie1. This differential regulation of Angiopoietin binding allows control of Tie2 activation response to Ang1 without affecting Ang2 agonist activity and maintains the ability of Ang2 to antagonize even the enhanced Ang1 activation of Tie2 that occurs on loss of Tie1 ectodomain. This provides a mechanism by which signalling through Tie2 can be modified by stimuli in the cellular microenvironment.
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multiple Angiopoietin recombinant proteins activate the tie1 receptor tyrosine kinase and promote its interaction with tie2
Journal of Cell Biology, 2005Co-Authors: Pipsa Saharinen, Nicholas P.j. Brindle, Katja Kerkela, Niklas Ekman, Marie B Marron, Hellmut G Augustin, Kari AlitaloAbstract:The Tie1 receptor tyrosine kinase was isolated over a decade ago, but so far no ligand has been found to activate this receptor. Here, we have examined the potential of Angiopoietins, ligands for the related Tie2 receptor, to mediate Tie1 activation. We show that a soluble Ang1 chimeric protein, COMP-Ang1, stimulates Tie1 phosphorylation in endothelial cells with similar kinetics and Angiopoietin dose dependence when compared with Tie2. The phosphorylation of overexpressed Tie1 was weakly induced by COMP-Ang1 also in transfected cells that do not express Tie2. When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner. Tie1 phosphorylation was also induced by native Ang1 and Ang4, although less efficiently than with COMP-Ang1. In conclusion, we show that Tie1 phosphorylation is induced by multiple Angiopoietin proteins and that the activation is amplified via Tie2. These results should be important in dissecting the signal transduction pathways and biological functions of Tie1.
