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Kari Alitalo - One of the best experts on this subject based on the ideXlab platform.
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structural basis of Tie2 activation and Tie2 Tie1 heterodimerization
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Velimatti Leppanen, Pipsa Saharinen, Kari AlitaloAbstract:The endothelial cell (EC)-specific Receptor tyrosine kinases Tie1 and Tie2 are necessary for the remodeling and maturation of blood and lymphatic vessels. Angiopoietin-1 (Ang1) growth factor is a Tie2 agonist, whereas Ang2 functions as a context-dependent agonist/antagonist. The orphan Receptor Tie1 modulates Tie2 activation, which is induced by association of angiopoietins with Tie2 in cis and across EC–EC junctions in trans. Except for the binding of the C-terminal angiopoietin domains to the Tie2 ligand-binding domain, the mechanisms for Tie2 activation are poorly understood. We report here the structural basis of Ang1-induced Tie2 dimerization in cis and provide mechanistic insights on Ang2 antagonism, Tie1/Tie2 heterodimerization, and Tie2 clustering. We find that Ang1-induced Tie2 dimerization and activation occurs via the formation of an intermolecular β-sheet between the membrane-proximal (third) Fibronectin type III domains (Fn3) of Tie2. The structures of Tie2 and Tie1 Fn3 domains are similar and compatible with Tie2/Tie1 heterodimerization by the same mechanism. Mutagenesis of the key interaction residues of Tie2 and Tie1 Fn3 domains decreased Ang1-induced Tie2 phosphorylation and increased the basal phosphorylation of Tie1, respectively. Furthermore, the Tie2 structures revealed additional interactions between the Fn 2 (Fn2) domains that coincide with a mutation of Tie2 in primary congenital glaucoma that leads to defective Tie2 clustering and junctional localization. Mutagenesis of the Fn2–Fn2 interface increased the basal phosphorylation of Tie2, suggesting that the Fn2 interactions are essential in preformed Tie2 oligomerization. The interactions of the membrane-proximal domains could provide new targets for modulation of Tie Receptor activity.
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endothelial destabilization by angiopoietin 2 via integrin β1 activation
Nature Communications, 2015Co-Authors: Laura Hakanpaa, Kari Alitalo, Tuomas Sipila, Velimatti Leppanen, Prson Gautam, Harri Nurmi, Guillaume Jacquemet, Lauri Eklund, Johanna Ivaska, Pipsa SaharinenAbstract:Angiopoietins regulate vascular homeostasis via the endothelial Tie Receptor tyrosine kinases. Angiopoietin-1 (Ang1) supports endothelial stabilization via Tie2 activation. Angiopoietin-2 (Ang2) functions as a context-dependent Tie2 agonist/antagonist promoting pathological angiogenesis, vascular permeability and inflammation. Elucidating Ang2-dependent mechanisms of vascular destablization is critical for rational design of angiopoietin antagonists that have demonstrated therapeutic efficacy in cancer trials. Here, we report that Ang2, but not Ang1, activates β1-integrin, leading to endothelial destablization. Autocrine Ang2 signalling upon Tie2 silencing, or in Ang2 transgenic mice, promotes β1-integrin-positive elongated matrix adhesions and actin stress fibres, regulating vascular endothelial-cadherin-containing cell-cell junctions. The Tie2-silenced monolayer integrity is rescued by β1-integrin, phosphoinositide-3 kinase or Rho kinase inhibition, and by re-expression of a membrane-bound Tie2 ectodomain. Furthermore, Tie2 silencing increases, whereas Ang2 blocking inhibits transendothelial tumour cell migration in vitro. These results establish Ang2-mediated β1-integrin activation as a promoter of endothelial destablization, explaining the controversial vascular functions of Ang1 and Ang2.
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the Tie Receptor family
2015Co-Authors: Pipsa Saharinen, Velimatti Leppanen, Markku M Jeltsch, Mayte M Santoyo, Kari AlitaloAbstract:The endothelial Tie1 and Tie2 Receptor tyrosine kinases form a distinct subfamily characterized by their unique extracellular domains. Together with the angiopoietin growth factors (ANGPT1, ANGPT2, ANGPT4, also abbreviated as ANG), the Tie Receptors form an endothelial specific signaling pathway with important functions in the regulation of lymphatic and cardiovascular development and vascular homeostasis. Angiopoietins exist in multimeric forms that activate the Tie Receptors via unique mechanism. In endothelial cell–cell contacts, angiopoietins induce the formation of homomeric in trans Tie Receptor complexes extending across the cell junctions, whereas matrix-bound angiopoietin-1 (ANG1) activates the Tie Receptors in a cis configuration. In comparison to the vascular endothelial growth factor Receptors, the Tie Receptors undergo little ubiquitin-mediated degradation after activation, whereas Tie2 signaling is negatively regulated by the vascular endothelial protein tyrosine phosphatase, VE-PTP. ANG1 activation of Tie2 supports vascular stabilization, whereas angiopoietin-2 (ANG2), a context-dependent weak Tie2 agonist/antagonist, promotes pathological tumor angiogenesis, vascular permeability, and inflammation. Recently, ANG2 has been found to mediate some of its vascular destabilizing and angiogenic functions via integrin signalling. The circulating levels of ANG2 are increased in cancer, and in several human diseases associated with inflammation and vascular leak, for example, in sepsis. Blocking of ANG2 has emerged as a potential novel therapeutic strategy for these diseases. In addition, preclinical results demonstrate that genetic Tie1 deletion in mice inhibits the vascularization and growth of tumor isografts and protects from atherosclerosis, with little effect on normal vascular homeostasis in adult mice. The ability of the ANG-Tie pathway to control vessel stability and angiogenesis makes it an interesting vascular target for the treatment of the various diseases.
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endothelial Tie Receptor antigen in maternal and cord blood of healthy and preeclamptic subjects
Obstetrics & Gynecology, 1998Co-Authors: Piia Vuorela, Kari Alitalo, Marjaterttu Matikainen, Pentti Kuusela, Olavi Ylikorkala, Erja HalmesmakiAbstract:Abstract Objective: To measure the vascular endothelial Receptor tyrosine kinase Tie, essential in the process of angiogenesis, in blood from healthy and preeclamptic pregnant women, in umbilical cord blood from both, and in blood from nonpregnant women. Methods: A total of 143 women participated in four arms of the study. Blood samples were collected from 54 healthy nonlaboring pregnant women (gestational weeks 14–41). Samples were collected immediately prepartum and postpartum from another 40 healthy women (15 delivered vaginally and 25 by cesarean) and 15 preeclamptic women (all delivered by cesarean). Arterial and venous cord samples were collected, when possible, from infants born by cesarean. Single blood samples were drawn from 34 nonpregnant controls. Of these, weekly samples from 11 were drawn during one menstrual cycle. A time-resolved fluoroimmunoassay was developed for the detection of the soluble extracellular domain of Tie. Results: Maternal serum Tie levels decreased with advancing gestational age after 26 weeks (r = .6, P Conclusion: The high levels of the extracellular domain of Tie in healthy term maternal and cord blood may indicate a role for Tie in the vascular development of human fetuses and placentas.
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endothelial Tie growth factor Receptor provides antigenic marker for assessment of breast cancer angiogenesis
British Journal of Cancer, 1996Co-Authors: Petri Salven, Marjaterttu Matikainen, Heikki Joensuu, Paivi Heikkila, Velimatti Wasenius, A Alanko, Kari AlitaloAbstract:Breast cancer prognosis has previously been linked to the degree of tumour vascularisation. In order to establish additional markers for tumour angiogenesis, we have used monoclonal antibodies against the endothelial Tie Receptor tyrosine kinase to study the degree of vascularisation of breast carcinomas and the regulation of Tie expression in the vascular endothelial cells. Antibodies were used for Tie detection and the results were correlated with other prognostic markers. Of four monoclonal antibodies directed against different epitopes of the Tie extracellular domain, two reacted against Tie in unfixed histopathological sections of breast carcinomas. One of these antibodies (clone 7e8) was specific for the endothelial cells whereas the other (clone 10f11) also reacted with basement membranes and occasional carcinoma cells. When Tie expression was studied with the antibody clone 7e8, all 27 carcinomas, two in situ carcinomas, samples of histologically normal breast tissue (n = 16) or normal skin or lymph node tissue (n = 5) showed staining. Microvessel counts were higher in carcinomas (median 14; range 3-27) than in fibrodenomas (median 10; range 5-18) or histologically normal breast tissue (median 7; range 3-15, P = 0.0006). A similar result was obtained using antibodies against the CD31 (PECAM) antigen. Microvessel counts in 7e8 staining were not significantly associated with primary tumour size, axillary nodal status, histological grade or staining for oestrogen Receptor, progesterone Receptor, Ki-67 proliferation marker or p53 oncoprotein.
Pipsa Saharinen - One of the best experts on this subject based on the ideXlab platform.
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structural basis of Tie2 activation and Tie2 Tie1 heterodimerization
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Velimatti Leppanen, Pipsa Saharinen, Kari AlitaloAbstract:The endothelial cell (EC)-specific Receptor tyrosine kinases Tie1 and Tie2 are necessary for the remodeling and maturation of blood and lymphatic vessels. Angiopoietin-1 (Ang1) growth factor is a Tie2 agonist, whereas Ang2 functions as a context-dependent agonist/antagonist. The orphan Receptor Tie1 modulates Tie2 activation, which is induced by association of angiopoietins with Tie2 in cis and across EC–EC junctions in trans. Except for the binding of the C-terminal angiopoietin domains to the Tie2 ligand-binding domain, the mechanisms for Tie2 activation are poorly understood. We report here the structural basis of Ang1-induced Tie2 dimerization in cis and provide mechanistic insights on Ang2 antagonism, Tie1/Tie2 heterodimerization, and Tie2 clustering. We find that Ang1-induced Tie2 dimerization and activation occurs via the formation of an intermolecular β-sheet between the membrane-proximal (third) Fibronectin type III domains (Fn3) of Tie2. The structures of Tie2 and Tie1 Fn3 domains are similar and compatible with Tie2/Tie1 heterodimerization by the same mechanism. Mutagenesis of the key interaction residues of Tie2 and Tie1 Fn3 domains decreased Ang1-induced Tie2 phosphorylation and increased the basal phosphorylation of Tie1, respectively. Furthermore, the Tie2 structures revealed additional interactions between the Fn 2 (Fn2) domains that coincide with a mutation of Tie2 in primary congenital glaucoma that leads to defective Tie2 clustering and junctional localization. Mutagenesis of the Fn2–Fn2 interface increased the basal phosphorylation of Tie2, suggesting that the Fn2 interactions are essential in preformed Tie2 oligomerization. The interactions of the membrane-proximal domains could provide new targets for modulation of Tie Receptor activity.
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endothelial destabilization by angiopoietin 2 via integrin β1 activation
Nature Communications, 2015Co-Authors: Laura Hakanpaa, Kari Alitalo, Tuomas Sipila, Velimatti Leppanen, Prson Gautam, Harri Nurmi, Guillaume Jacquemet, Lauri Eklund, Johanna Ivaska, Pipsa SaharinenAbstract:Angiopoietins regulate vascular homeostasis via the endothelial Tie Receptor tyrosine kinases. Angiopoietin-1 (Ang1) supports endothelial stabilization via Tie2 activation. Angiopoietin-2 (Ang2) functions as a context-dependent Tie2 agonist/antagonist promoting pathological angiogenesis, vascular permeability and inflammation. Elucidating Ang2-dependent mechanisms of vascular destablization is critical for rational design of angiopoietin antagonists that have demonstrated therapeutic efficacy in cancer trials. Here, we report that Ang2, but not Ang1, activates β1-integrin, leading to endothelial destablization. Autocrine Ang2 signalling upon Tie2 silencing, or in Ang2 transgenic mice, promotes β1-integrin-positive elongated matrix adhesions and actin stress fibres, regulating vascular endothelial-cadherin-containing cell-cell junctions. The Tie2-silenced monolayer integrity is rescued by β1-integrin, phosphoinositide-3 kinase or Rho kinase inhibition, and by re-expression of a membrane-bound Tie2 ectodomain. Furthermore, Tie2 silencing increases, whereas Ang2 blocking inhibits transendothelial tumour cell migration in vitro. These results establish Ang2-mediated β1-integrin activation as a promoter of endothelial destablization, explaining the controversial vascular functions of Ang1 and Ang2.
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the Tie Receptor family
2015Co-Authors: Pipsa Saharinen, Velimatti Leppanen, Markku M Jeltsch, Mayte M Santoyo, Kari AlitaloAbstract:The endothelial Tie1 and Tie2 Receptor tyrosine kinases form a distinct subfamily characterized by their unique extracellular domains. Together with the angiopoietin growth factors (ANGPT1, ANGPT2, ANGPT4, also abbreviated as ANG), the Tie Receptors form an endothelial specific signaling pathway with important functions in the regulation of lymphatic and cardiovascular development and vascular homeostasis. Angiopoietins exist in multimeric forms that activate the Tie Receptors via unique mechanism. In endothelial cell–cell contacts, angiopoietins induce the formation of homomeric in trans Tie Receptor complexes extending across the cell junctions, whereas matrix-bound angiopoietin-1 (ANG1) activates the Tie Receptors in a cis configuration. In comparison to the vascular endothelial growth factor Receptors, the Tie Receptors undergo little ubiquitin-mediated degradation after activation, whereas Tie2 signaling is negatively regulated by the vascular endothelial protein tyrosine phosphatase, VE-PTP. ANG1 activation of Tie2 supports vascular stabilization, whereas angiopoietin-2 (ANG2), a context-dependent weak Tie2 agonist/antagonist, promotes pathological tumor angiogenesis, vascular permeability, and inflammation. Recently, ANG2 has been found to mediate some of its vascular destabilizing and angiogenic functions via integrin signalling. The circulating levels of ANG2 are increased in cancer, and in several human diseases associated with inflammation and vascular leak, for example, in sepsis. Blocking of ANG2 has emerged as a potential novel therapeutic strategy for these diseases. In addition, preclinical results demonstrate that genetic Tie1 deletion in mice inhibits the vascularization and growth of tumor isografts and protects from atherosclerosis, with little effect on normal vascular homeostasis in adult mice. The ability of the ANG-Tie pathway to control vessel stability and angiogenesis makes it an interesting vascular target for the treatment of the various diseases.
Sven Klaschik - One of the best experts on this subject based on the ideXlab platform.
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the angiopoietin Tie Receptor system focusing its role for ischemia reperfusion injury
Cytokine & Growth Factor Reviews, 2015Co-Authors: Tobias Hilbert, Sven KlaschikAbstract:Ischemia and reperfusion (I/R) are of fatal consequence for the affected organs, as they provoke a profound inflammatory reaction. This thoroughly destroys cells and tissues, inducing functional failure or even complete loss of organ function. Since I/R is primarily a vascular problem, the interaction between the endothelium and the surrounding environment is of great significance. The angiopoietins (ANG) and the Tie Receptors are key players for the vascular homeostasis. This review summarizes biochemical and cellular mechanisms leading to I/R injury. After a brief introduction to the ANG/Tie system, a comprehensive overview of its role for the development of I/R syndrome is given. Finally, current therapeutic approaches to mitigate the consequences of I/R by modulating ANG/Tie signaling are reviewed in detail.
Nicholas P J Brindle - One of the best experts on this subject based on the ideXlab platform.
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vascular endothelial growth factor activates the Tie family of Receptor tyrosine kinases
Cellular Signalling, 2009Co-Authors: Harprit Singh, Christopher S Milner, Maria Aguilar M Hernandez, Nisha Patel, Nicholas P J BrindleAbstract:The ability of cells to respond appropriately to changes in their environment requires integration and cross-talk between relevant signalling pathways. The vascular endothelial growth factor (VEGF) and angiopoietin families of ligands are key regulators of blood vessel formation. VEGF binds to Receptor tyrosine kinases of the VEGF-Receptor family to activate signalling pathways leading to endothelial migration, proliferation and survival whereas the angiopoietins interact with the Tie Receptor tyrosine kinases to control vessel stability, survival and maturation. Here we show that VEGF can also activate the angiopoietin Receptor Tie2. Activation of human endothelial cells with VEGF caused a four-fold stimulation of tyrosine phosphorylation of Tie2. This stimulation was not due to VEGF-induction of Tie2 ligands as soluble ligand binding domain of Tie2 failed to inhibit VEGF activation of the Receptor. Immunoprecipitation analysis demonstrated no physical interaction between VEGF Receptors and Tie2. However Tie2 does interact with the related Receptor tyrosine kinase Tie1 and this Receptor was found to be essential for VEGF activation of Tie2. VEGF stimulated proteolytic cleavage of Tie1 generating a truncated Tie1 intracellular domain. Similarly, phorbol ester also both stimulated Tie1 truncation and activated Tie2 phosphorylation. Inhibition of Tie1 cleavage with the metalloprotease inhibitor TAPI-2 suppressed VEGF- and phorbol ester-induced phosphorylation of Tie2. Truncated Tie1 formed in response to VEGF was also found to be tyrosine phosphorylated and this was independent of Tie2, though Tie2 could enhance Tie1 intracellular domain phosphorylation. Together these data demonstrate that VEGF activates Tie2 via a mechanism involving proteolytic cleavage of the associated tyrosine kinase Tie1 leading to trans-phosphorylation of Tie2. This novel mechanism of Receptor tyrosine kinase activation is likely to be important in integrating signalling between two of the key Receptor groups regulating angiogenesis.
Gavin Thurston - One of the best experts on this subject based on the ideXlab platform.
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role of angiopoietins and Tie Receptor tyrosine kinases in angiogenesis and lymphangiogenesis
Cell and Tissue Research, 2003Co-Authors: Gavin ThurstonAbstract:This review focuses on the signaling system involving the Angiopoietin1/Tie2 Receptor, which appears to be involved in the secondary stages of blood vessel formation. Although this system is crucial for blood and lymphatic vessel formation, identifying its precise role in embryonic and adult vascular biology has been a major challenge. The evidence for the key role of the Angiopoietin/Tie system is discussed, and some of the other members of the system (Ang2, Tie1) are mentioned. A comparison is made with the VEGF signaling system, which seems to provide a complementary, and somewhat more tractable, signaling system. Some of the basic unanswered questions concerning Tie/Angiopoietin biology and the secondary stages of blood vessel formation are also highlighted.