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  1 / 179 MEDLINE  
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[PMID]:28464467
[Au] Autor:Torigata M; Yamakawa D; Takakura N
[Ad] Endereço:Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan.
[Ti] Título:Elevated expression of Tie1 is accompanied by acquisition of cancer stemness properties in colorectal cancer.
[So] Source:Cancer Med;6(6):1378-1388, 2017 Jun.
[Is] ISSN:2045-7634
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Tie receptors 1 and 2 (Tie1/2) play crucial roles in embryonic angiogenesis. Recent studies suggest enhanced expression of Tie1 in several types of cancer and negative correlations between Tie1 levels and clinical outcome. These observations suggest important functions of Tie1 not only for vascular formation but also in tumorigenesis. Ligands for Tie2, that is angiopoietins 1-4, have been identified, but not for Tie1. To determine the molecular functions of Tie1, its detailed characterization in tumors would be helpful. Herein, we report that Tie1 is up-regulated in colorectal cancer. Detailed analysis using tumor-bearing models and immunohistochemistry combined with Flow cytometric analysis and cell sorting (FACS) revealed that Tie1 protein was expressed in a small population of malignant tumor cells. Intriguingly, Tie1 expression was observed and could be maintained only in vivo. Further analysis using sphere-formation culture revealed that Tie1-positive cells are enriched within the population of tumor cells with cancer stemness properties. Indeed, Tie1-positive tumor cells derived from a murine model overexpressed Lgr5, a typical stemness marker for colorectal cancer. Our results provide a novel insight into Tie1 function in tumorigenesis and suggest clinical applications to target cancer stem cells.
[Mh] Termos MeSH primário: Neoplasias Colorretais/metabolismo
Receptor de TIE-1/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Proliferação Celular
Neoplasias Colorretais/genética
Seres Humanos
Camundongos
Camundongos Nus
Células-Tronco Neoplásicas
RNA Mensageiro/metabolismo
Receptor de TIE-1/genética
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Messenger); EC 2.7.10.1 (Receptor, TIE-1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/cam4.1072


  2 / 179 MEDLINE  
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[PMID]:28179430
[Au] Autor:Morooka N; Futaki S; Sato-Nishiuchi R; Nishino M; Totani Y; Shimono C; Nakano I; Nakajima H; Mochizuki N; Sekiguchi K
[Ad] Endereço:From the Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka, Japan (N. Morooka, S.F., R.S.-N., M.N., Y.T., C.S., I.N., K.S.); Laboratory of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka, Japan (S.F.); Department of Cell
[Ti] Título:Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling.
[So] Source:Circ Res;120(8):1276-1288, 2017 Apr 14.
[Is] ISSN:1524-4571
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Lymphatic vasculature constitutes a second vascular system essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown. OBJECTIVE: Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9ß1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development. METHODS AND RESULTS: We generated Polydom-deficient mice. mice showed severe edema and died immediately after birth because of respiratory failure. We found that although a primitive lymphatic plexus was formed, it failed to undergo remodeling in embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout of in zebrafish. Polydom was deposited around lymphatic vessels, but secreted from surrounding mesenchymal cells. Expression of Foxc2 (forkhead box protein c2), a transcription factor involved in lymphatic remodeling, was decreased in mice. Polydom bound to the lymphangiogenic factor Ang-2 (angiopoietin-2), which was found to upregulate Foxc2 expression in cultured lymphatic endothelial cells. Expressions of Tie1/Tie2 receptors for angiopoietins were also decreased in mice. CONCLUSIONS: Polydom affects remodeling of lymphatic vessels in both mouse and zebrafish. Polydom deposited around lymphatic vessels seems to ensure Foxc2 upregulation in lymphatic endothelial cells, possibly via the Ang-2 and Tie1/Tie2 receptor system.
[Mh] Termos MeSH primário: Células Endoteliais/metabolismo
Linfangiogênese
Vasos Linfáticos/metabolismo
Proteínas/metabolismo
[Mh] Termos MeSH secundário: Angiopoietina-2/metabolismo
Animais
Comunicação Celular
Células Cultivadas
Edema/genética
Edema/metabolismo
Edema/fisiopatologia
Células Endoteliais/patologia
Endotélio Linfático/anormalidades
Endotélio Linfático/metabolismo
Endotélio Linfático/fisiopatologia
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/metabolismo
Regulação da Expressão Gênica no Desenvolvimento
Genótipo
Seres Humanos
Vasos Linfáticos/anormalidades
Vasos Linfáticos/fisiopatologia
Mesoderma/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fenótipo
Ligação Proteica
Proteínas/genética
Receptor de TIE-1/genética
Receptor de TIE-1/metabolismo
Receptor TIE-2/genética
Receptor TIE-2/metabolismo
Transdução de Sinais
Ducto Torácico/anormalidades
Ducto Torácico/metabolismo
Ducto Torácico/fisiopatologia
Peixe-Zebra/genética
Peixe-Zebra/metabolismo
Proteínas de Peixe-Zebra/genética
Proteínas de Peixe-Zebra/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Angiopoietin-2); 0 (Forkhead Transcription Factors); 0 (Polydom protein, mouse); 0 (Proteins); 0 (Zebrafish Proteins); 0 (mesenchyme fork head 1 protein); 0 (polydom protein, zebrafish); EC 2.7.10.1 (Receptor, TIE-1); EC 2.7.10.1 (Receptor, TIE-2); EC 2.7.10.1 (Tek protein, mouse)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170428
[Lr] Data última revisão:
170428
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCRESAHA.116.308825


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[PMID]:27941161
[Au] Autor:Eklund L; Kangas J; Saharinen P
[Ad] Endereço:Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, and Biocenter Oulu, Aapistie 5A, FI-90014 Oulu, Finland.
[Ti] Título:Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems.
[So] Source:Clin Sci (Lond);131(1):87-103, 2017 Jan 01.
[Is] ISSN:1470-8736
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)-Tie system is a second endothelial cell specific ligand-receptor signalling system necessary for embryonic cardiovascular and lymphatic development. The Ang-Tie system also regulates postnatal angiogenesis, vessel remodelling, vascular permeability and inflammation to maintain vascular homoeostasis in adult physiology. This system is implicated in numerous diseases where the vasculature has an important contribution, such as cancer, sepsis, diabetes, atherosclerosis and ocular diseases. Furthermore, mutations in the TIE2 signalling pathway cause defects in vascular morphogenesis, resulting in venous malformations and primary congenital glaucoma. Here, we review recent advances in the understanding of the Ang-Tie signalling system, including cross-talk with the vascular endothelial protein tyrosine phosphatase (VE-PTP) and the integrin cell adhesion receptors, focusing on the Ang-Tie system in vascular development and pathogenesis of vascular diseases.
[Mh] Termos MeSH primário: Angiopoietinas/metabolismo
Sistema Cardiovascular/metabolismo
Sistema Linfático/metabolismo
Receptor de TIE-1/metabolismo
Receptor TIE-2/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Angiopoietinas/genética
Animais
Sistema Cardiovascular/enzimologia
Sistema Cardiovascular/crescimento & desenvolvimento
Seres Humanos
Sistema Linfático/enzimologia
Sistema Linfático/crescimento & desenvolvimento
Receptor de TIE-1/genética
Receptor TIE-2/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Angiopoietins); EC 2.7.10.1 (Receptor, TIE-1); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170707
[Lr] Data última revisão:
170707
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161213
[St] Status:MEDLINE


  4 / 179 MEDLINE  
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[PMID]:27695111
[Au] Autor:Dalton AC; Shlamkovitch T; Papo N; Barton WA
[Ad] Endereço:Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, Richmond, Virginia, 23298, United States of America.
[Ti] Título:Constitutive Association of Tie1 and Tie2 with Endothelial Integrins is Functionally Modulated by Angiopoietin-1 and Fibronectin.
[So] Source:PLoS One;11(10):e0163732, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Functional cross-talk between Tie2 and Integrin signaling pathways is essential to coordinate endothelial cell adhesion and migration in response to the extracellular matrix, yet the mechanisms behind this phenomenon are unclear. Here, we examine the possibility that receptor cross-talk is driven through uncharacterized Tie-integrin interactions on the endothelial surface. Using a live cell FRET-based proximity assay, we monitor Tie-integrin receptor recognition and demonstrate that both Tie1 and Tie2 readily associate with integrins α5ß1 and αVß3 through their respective ectodomains. Although not required, Tie2-integrin association is significantly enhanced in the presence of the extracellular component and integrin ligand fibronectin. In vitro binding assays with purified components reveal that Tie-integrin recognition is direct, and further demonstrate that the receptor binding domain of the Tie2 ligand Ang-1, but not the receptor binding domain of Ang-2, can independently associate with α5ß1 or αVß3. Finally, we reveal that cooperative Tie/integrin interactions selectively stimulate ERK/MAPK signaling in the presence of both Ang-1 and fibronectin, suggesting a molecular mechanism to sensitize Tie2 to extracellular matrix. We provide a mechanistic model highlighting the role of receptor localization and association in regulating distinct signaling cascades and in turn, the angiogenic switch.
[Mh] Termos MeSH primário: Angiopoietina-1/genética
Fibronectinas/genética
Integrina alfa5beta1/genética
Integrina alfaVbeta3/genética
Receptor de TIE-1/genética
Receptor TIE-2/genética
[Mh] Termos MeSH secundário: Angiopoietina-1/metabolismo
Adesão Celular/genética
Células Endoteliais/metabolismo
Matriz Extracelular/genética
Matriz Extracelular/metabolismo
Fibronectinas/metabolismo
Transferência Ressonante de Energia de Fluorescência
Seres Humanos
Integrina alfa5beta1/metabolismo
Integrina alfaVbeta3/metabolismo
Sistema de Sinalização das MAP Quinases/genética
Fosforilação
Ligação Proteica
Receptor de TIE-1/metabolismo
Receptor TIE-2/metabolismo
Fator A de Crescimento do Endotélio Vascular/genética
Fator A de Crescimento do Endotélio Vascular/metabolismo
Proteínas de Transporte Vesicular/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANGPT1 protein, human); 0 (Angiopoietin-1); 0 (C11orf2 protein, human); 0 (FN1 protein, human); 0 (Fibronectins); 0 (Integrin alpha5beta1); 0 (Integrin alphaVbeta3); 0 (Vascular Endothelial Growth Factor A); 0 (Vesicular Transport Proteins); EC 2.7.10.1 (Receptor, TIE-1); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161004
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0163732


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[PMID]:27548530
[Au] Autor:Korhonen EA; Lampinen A; Giri H; Anisimov A; Kim M; Allen B; Fang S; D'Amico G; Sipilä TJ; Lohela M; Strandin T; Vaheri A; Ylä-Herttuala S; Koh GY; McDonald DM; Alitalo K; Saharinen P
[Ti] Título:Tie1 controls angiopoietin function in vascular remodeling and inflammation.
[So] Source:J Clin Invest;126(9):3495-510, 2016 Sep 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a ß1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1- and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability.
[Mh] Termos MeSH primário: Angiopoietina-1/metabolismo
Angiopoietina-2/metabolismo
Inflamação
Receptor de TIE-1/metabolismo
Receptor TIE-2/metabolismo
Remodelação Vascular
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Estudos de Casos e Controles
Estudos de Coortes
Células Endoteliais/metabolismo
Endotélio Vascular/metabolismo
Endotoxemia/metabolismo
Feminino
Deleção de Genes
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Integrina beta1/metabolismo
Lipopolissacarídeos/química
Masculino
Camundongos
Camundongos Transgênicos
Meia-Idade
Fosforilação
Sepse
Transdução de Sinais
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiopoietin-1); 0 (Angiopoietin-2); 0 (Integrin beta1); 0 (Lipopolysaccharides); EC 2.7.10.1 (Receptor, TIE-1); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160823
[St] Status:MEDLINE


  6 / 179 MEDLINE  
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[PMID]:27548526
[Au] Autor:Mueller SB; Kontos CD
[Ti] Título:Tie1: an orphan receptor provides context for angiopoietin-2/Tie2 signaling.
[So] Source:J Clin Invest;126(9):3188-91, 2016 Sep 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Angiopoietin-1/Tie2 (ANG1/Tie2) signaling is well documented as regulating angiogenesis and vessel maturation. This pathway is complicated by involvement of the orphan receptor Tie1, which has been implicated as both a positive and negative regulator of ANG1/Tie2 signaling, and ANG2, which can serve as both a Tie2 agonist and antagonist, depending on the context. Two papers in this issue of the JCI provide new insight into this complicated pathway. Korhonen et al. reveal that Tie1 acts to modulate the effects of ANG1 and ANG2 on Tie2 in vitro and in vivo. Kim et al. demonstrate that ANG2 acts as a Tie2 agonist in non-pathological conditions, whereas in the setting of inflammation, ANG2 functions as a Tie2 antagonist and promotes vascular dysfunction. Both studies indicate that inflammation promotes cleavage of the ectodomain of Tie1 and that this cleavage event corresponds with the switch of ANG2 from a Tie2 agonist to an antagonist. The results of these studies lay the groundwork for future strategies to therapeutically exploit this pathway in diseases characterized by adverse vascular remodeling and increased permeability.
[Mh] Termos MeSH primário: Angiopoietina-2
Receptor TIE-2/agonistas
[Mh] Termos MeSH secundário: Angiopoietina-1
Seres Humanos
Receptor de TIE-1
Transdução de Sinais
Remodelação Vascular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiopoietin-1); 0 (Angiopoietin-2); EC 2.7.10.1 (Receptor, TIE-1); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160823
[St] Status:MEDLINE


  7 / 179 MEDLINE  
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[PMID]:26838752
[Au] Autor:Zhou W; Liu GH; Yang SH; Mi BB; Ye SN
[Ad] Endereço:Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. wuzhoutjmu1986@163.com.
[Ti] Título:Low-intensity treadmill exercise promotes rat dorsal wound healing.
[So] Source:J Huazhong Univ Sci Technolog Med Sci;36(1):121-6, 2016 Feb.
[Is] ISSN:1672-0733
[Cp] País de publicação:China
[La] Idioma:eng
[Ab] Resumo:In order to investigate the promoting effect of low-intensity treadmill exercise on rat dorsal wound healing and the mechanism, 20 Sprague-Dawley rats were randomly divided into two groups: exercise group (Ex) and non-exercise group (non-ex). The rats in Ex group were given treadmill exercise for one month, and those in non-ex group raised on the same conditions without treadmill exercise. Both groups received dorsal wound operation with free access to food and water. By two-week continuous observation and recording of the wound area, the healing rate was analyzed. The blood sample was collected at day 14 post-operation via cardiac puncture for determination of the number of endothelial progenitor cells (EPCs) by flow cytometry, and the concentrations of relevant cytokines such as basic fibroblast growth factor (bFGF), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were measured by ELISA. The skin tissue around the wound was dissected to observe the vascular density under the microscope after HE staining, to detect the mRNA level of VEGFR2 and angiopoietin-1 (Ang-1) receptor using RT-qPCR, and protein expression of a-smooth muscle actin (αSMA) and type III collagen (ColIII) using Western blotting. It was found that the wound area in Ex group was smaller at the same time point than in non-ex group. The number of circulating EPCs was greater and the concentrations of vasoactive factors such as VEGF, eNOS and bFGF were higher in Ex group than in non-ex group. HE staining displayed a higher vessel density in Ex group than in non-ex group. Moreover, the mRNA expression of VEGFR2 and Ang-1 detected in the wound tissue in Ex group was higher than in non-ex group. Meanwhile, the protein expression of αSMA and ColIII was more abundant in Ex group than in non-ex group. Conclusively, the above results demonstrate Ex rats had a higher wound healing rate, suggesting low-intensity treadmill exercise accelerates wound healing. The present work may provide some hint for future study of treating refractory wound.
[Mh] Termos MeSH primário: Esforço Físico
Cicatrização
[Mh] Termos MeSH secundário: Actinas/metabolismo
Animais
Colágeno Tipo III/metabolismo
Citocinas/sangue
Células Progenitoras Endoteliais/citologia
Masculino
Óxido Nítrico Sintase Tipo III/sangue
RNA Mensageiro/sangue
Ratos
Ratos Sprague-Dawley
Receptor de TIE-1/metabolismo
Corrida
Fator A de Crescimento do Endotélio Vascular/sangue
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Actins); 0 (Collagen Type III); 0 (Cytokines); 0 (RNA, Messenger); 0 (Vascular Endothelial Growth Factor A); 0 (smooth muscle actin, rat); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 2.7.10.1 (Kdr protein, rat); EC 2.7.10.1 (Receptor, TIE-1); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:171104
[Lr] Data última revisão:
171104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160204
[St] Status:MEDLINE
[do] DOI:10.1007/s11596-016-1553-3


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[PMID]:26489611
[Au] Autor:Yang P; Chen N; Jia JH; Gao XJ; Li SH; Cai J; Wang Z
[Ad] Endereço:Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. yangping5127@163.com.
[Ti] Título:Tie-1: A potential target for anti-angiogenesis therapy.
[So] Source:J Huazhong Univ Sci Technolog Med Sci;35(5):615-22, 2015 Oct.
[Is] ISSN:1672-0733
[Cp] País de publicação:China
[La] Idioma:eng
[Ab] Resumo:The tyrosine kinase system angiopoietin (Ang)/Tie interacts with vascular endothelial growth factor pathway and regulates vessel quiescence in adults as well as later steps of the angiogenic cascade related to vessel maturation. Since all Angs are able to bind to Tie-2 but none binds to Tie-1, the function of Tie-2 and its ligands have captured attention. However, emerging evidence indicates unique roles of the orphan receptor Tie-1 in angiogenesis under physiological and pathological conditions. It is required for maintaining vascular endothelial cell integrity and survival during murine embryo development and in adult and may be involved in modulating differentiation of hematopoietic cells in adult. Tie-1 exhibits poor tyrosine kinase activity and signals via forming heterodimers with Tie-2, inhibiting Tie-2 signaling mediated by Angs. This inhibition can be relieved by Tie-1 ectodomain cleavage mediated by tumor- and inflammatory-related factors, which causes destabilization of vessels and initiates vessel remodeling. Up-regulated Tie-1 expression has been found not only in some leukemia cells and tumor related endothelial cells but also in cytoplasm of carcinoma cells of a variety of human solid tumors, which is associated with tumor progression. In addition, it has pro-inflammatory functions in endothelial cells and is involved in some inflammatory diseases associated with angiogenesis. Recent research indicated that Tie-1 gene ablation exhibited significant effects on tumor blood- and lymph-angiogenesis and improved anti-Ang therapy, suggesting Tie-1 may be a potential target for tumor anti-angiogenesis treatment.
[Mh] Termos MeSH primário: Angiopoietinas/genética
Regulação Neoplásica da Expressão Gênica
Neoplasias/genética
Neovascularização Patológica/genética
Receptor de TIE-1/genética
Receptor TIE-2/genética
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/uso terapêutico
Angiopoietinas/metabolismo
Animais
Embrião de Mamíferos
Desenvolvimento Embrionário/genética
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Regulação da Expressão Gênica no Desenvolvimento
Seres Humanos
Camundongos
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Neoplasias/patologia
Neovascularização Patológica/tratamento farmacológico
Neovascularização Patológica/metabolismo
Neovascularização Patológica/patologia
Ligação Proteica
Receptor de TIE-1/antagonistas & inibidores
Receptor de TIE-1/metabolismo
Receptor TIE-2/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Angiopoietins); EC 2.7.10.1 (Receptor, TIE-1); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:171104
[Lr] Data última revisão:
171104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151023
[St] Status:MEDLINE
[do] DOI:10.1007/s11596-015-1479-1


  9 / 179 MEDLINE  
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[PMID]:26436659
[Au] Autor:Reinardy JL; Corey DM; Golzio C; Mueller SB; Katsanis N; Kontos CD
[Ad] Endereço:Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
[Ti] Título:Phosphorylation of Threonine 794 on Tie1 by Rac1/PAK1 Reveals a Novel Angiogenesis Regulatory Pathway.
[So] Source:PLoS One;10(10):e0139614, 2015.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The endothelial receptor tyrosine kinase (RTK) Tie1 was discovered over 20 years ago, yet its precise function and mode of action remain enigmatic. To shed light on Tie1's role in endothelial cell biology, we investigated a potential threonine phosphorylation site within the juxtamembrane domain of Tie1. Expression of a non-phosphorylatable mutant of this site (T794A) in zebrafish (Danio rerio) significantly disrupted vascular development, resulting in fish with stunted and poorly branched intersomitic vessels. Similarly, T794A-expressing human umbilical vein endothelial cells formed significantly shorter tubes with fewer branches in three-dimensional Matrigel cultures. However, mutation of T794 did not alter Tie1 or Tie2 tyrosine phosphorylation or downstream signaling in any detectable way, suggesting that T794 phosphorylation may regulate a Tie1 function independent of its RTK properties. Although T794 is within a consensus Akt phosphorylation site, we were unable to identify a physiological activator of Akt that could induce T794 phosphorylation, suggesting that Akt is not the physiological Tie1-T794 kinase. However, the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), which is required for angiogenesis and capillary morphogenesis, was found to associate with phospho-T794 but not the non-phosphorylatable T794A mutant. Pharmacological activation of Rac1 induced downstream activation of p21-activated kinase (PAK1) and T794 phosphorylation in vitro, and inhibition of PAK1 abrogated T794 phosphorylation. Our results provide the first demonstration of a signaling pathway mediated by Tie1 in endothelial cells, and they suggest that a novel feedback loop involving Rac1/PAK1 mediated phosphorylation of Tie1 on T794 is required for proper angiogenesis.
[Mh] Termos MeSH primário: Neovascularização Fisiológica/fisiologia
Fosfotreonina/metabolismo
Processamento de Proteína Pós-Traducional
Receptor de TIE-1/metabolismo
Proteínas de Peixe-Zebra/metabolismo
Quinases Ativadas por p21/metabolismo
Proteínas rac1 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Angiopoietina-1/fisiologia
Animais
Vasos Sanguíneos/embriologia
Colágeno
Combinação de Medicamentos
Endotélio Vascular/metabolismo
Ativação Enzimática
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Laminina
Morfogênese
Mutagênese Sítio-Dirigida
Neovascularização Fisiológica/genética
Fosforilação
Mapeamento de Interação de Proteínas
Estrutura Terciária de Proteína
Proteoglicanas
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais/fisiologia
Peixe-Zebra/embriologia
Peixe-Zebra/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (ANGPT1 protein, human); 0 (Angiopoietin-1); 0 (Drug Combinations); 0 (Laminin); 0 (Proteoglycans); 0 (RAC1 protein, human); 0 (RAC1 protein, zebrafish); 0 (Zebrafish Proteins); 1114-81-4 (Phosphothreonine); 119978-18-6 (matrigel); 9007-34-5 (Collagen); EC 2.7.10.1 (Receptor, TIE-1); EC 2.7.10.1 (tie1 protein, zebrafish); EC 2.7.11.1 (PAK1 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (p21-Activated Kinases); EC 3.6.5.2 (rac1 GTP-Binding Protein)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:161104
[Lr] Data última revisão:
161104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151006
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0139614


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[PMID]:26386379
[Au] Autor:Huang W; Wang J; Liang Y; Ge W; Wang G; Li Y; Chung HY
[Ad] Endereço:Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, China.
[Ti] Título:Potent anti-angiogenic component in Croton crassifolius and its mechanism of action.
[So] Source:J Ethnopharmacol;175:185-91, 2015 Dec 04.
[Is] ISSN:1872-7573
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:ETHNOPHARMACOLOGICAL RELEVANCE: The root of Croton crassifolius Geisel is traditionally used in China for the treatment of snake bites, stomach ache, sternalgia, joint pain, pharyngitis, jaundice and rheumatoid arthritis, while in Thailand, it has been used as an anticancer herbal medicine by the indigenous people. Yet, its pharmacological studies are still limited, especially towards its anticancer property. Anti-angiogenesis is a promising therapeutic strategy in the anti-cancer treatment. Previous studies have shown strong anti-angiogenic activity in the low polar fraction of the herb. Nevertheless, the potent compound which is responsible for the anti-angiogenesis, and its molecular mechanism have never been reported. AIM OF THE STUDY: To determine the potent anti-angiogenic component in C. crassifolius and its molecular mechanism of action. MATERIALS AND METHODS: C. crassifolius was extracted using supercritical fluid extraction and steam distillation. The anti-angiogenic activities of the two extracts were evaluated in the zebrafish model by quantitative endogenous alkaline phosphatase assay. The chemical compounds in the active extract were isolated using chromatographic methods, and their structures were elucidated using different spectroscopic techniques. The content/quantity of the active compounds in this extract was determined with HPLC analysis. The molecular mechanism of the most active compound was further studied using the real-time PCR assay. Besides, its cytotoxicity on various cancer and normal cell lines was evaluated using the cell-counting kit. RESULTS: Supercritical fluid extract (SFE) of C. crassifolius showed better anti-angiogenic activity than that of steam distillation extract (SDE). Three sesquiterpenes, namely, cyperenoic acid, 8-hydroxy-α-guaiene and (+)-guaia-l(10),ll-dien-9-one, were isolated and identified in the SFE. Among them, cyperenoic acid displayed the strongest anti-angiogenic activity by 51.7% of the control at 10µM, while the others showed little effect. HPLC results showed that cyperenoic acid was the major component in the SFE with 9.97% (w/w). Results of the real-time PCR assay suggested that the cyperenoic acid affected multiple molecular targets related to angiogenesis including vascular endothelial growth factor (Vegfa), angpiopoietin (Angpt), and their receptors. Cytotoxicity assay showed cyperenoic acid possessed little toxicity toward cancer and normal cells. CONCLUSIONS: Cyperenoic acid is an important anti-angiogenic component present in C. crassifolius and serve as a potent inhibitor in the angiogenesis in the zebrafish embryo model. The anti-angiogenic property, but not the cytotoxicity, of C. crassifolius provides a scientific basis for its traditional use in cancer treatment.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/farmacologia
Croton
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: Angiopoietina-1/genética
Angiopoietina-2/genética
Animais
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Cercopithecus aethiops
Embrião não Mamífero
Seres Humanos
Raízes de Plantas
Receptor de TIE-1/genética
Receptor TIE-2/genética
Fator A de Crescimento do Endotélio Vascular/genética
Células Vero
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Angiopoietin-1); 0 (Angiopoietin-2); 0 (Plant Extracts); 0 (Vascular Endothelial Growth Factor A); EC 2.7.10.1 (Receptor, TIE-1); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:151215
[Lr] Data última revisão:
151215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150920
[St] Status:MEDLINE



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