Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells
| Autor: | Jean-Jacques Feige, Sabine Bailly, Laurent David, Sabine Mazerbourg, Christine Mallet |
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| Přispěvatelé: | Angiogenèse hormono-régulée et angiogenèse tumorale, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Feige, Jean-Jacques, Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA) |
| Rok vydání: | 2006 |
| Předmět: |
MESH: Signal Transduction
Angiogenesis Activin Receptors MESH: Bone Morphogenetic Proteins Activin Receptors Type II Response element Biochemistry Mice 0302 clinical medicine Cell Movement MESH: RNA Small Interfering MESH: Animals MESH: Endothelial Cells RNA Small Interfering Receptor Promoter Regions Genetic MESH: Antigens CD MESH: Cell Movement Cells Cultured 0303 health sciences Cultured MESH: Activin Receptors Type II Hematology Activin receptor Cell biology CD Endothelial stem cell 030220 oncology & carcinogenesis Bone Morphogenetic Proteins MESH: Response Elements Signal transduction MESH: Cells Cultured Signal Transduction MESH: Bone Morphogenetic Protein Receptors Type II Smad5 Protein Cells Immunology GDF2 [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Small Interfering Bone Morphogenetic Protein Receptors Type II Response Elements Type II Smad1 Protein Promoter Regions 03 medical and health sciences MESH: Smad5 Protein Genetic Antigens CD MESH: Cell Proliferation MESH: Promoter Regions Genetic Animals Humans Antigens [SDV.BC] Life Sciences [q-bio]/Cellular Biology MESH: Mice 030304 developmental biology Cell Proliferation MESH: Humans MESH: Smad1 Protein Endothelial Cells Cell Biology Bone Morphogenetic Protein Receptors Endoglin Smad8 Protein RNA MESH: Smad8 Protein |
| Zdroj: | Blood Blood, American Society of Hematology, 2007, 109 (5), pp.1953-61. ⟨10.1182/blood-2006-07-034124⟩ Blood, 2007, 109 (5), pp.1953-61. ⟨10.1182/blood-2006-07-034124⟩ |
| ISSN: | 0006-4971 1528-0020 |
| DOI: | 10.1182/blood-2006-07-034124⟩ |
| Popis: | ALK1 is an endothelial-specific type I receptor of the TGFβ receptor family whose heterozygous mutations cause hereditary hemorrhagic telangiectasia type 2. Although TGFβ1 and TGFβ3 have been shown to bind ALK1 under specific experimental conditions, they may not represent the physiological ligands for this receptor. In the present study, we demonstrate that BMP9 induces the phosphorylation of Smad1/5/8 in microvascular endothelial cells, and this phosphorylation lasts over a period of 24 hours. BMP9 also activates the ID1 promoter–derived BMP response element (BRE) in a dose-dependent manner (EC50 = 45 ± 27 pg/mL), and this activation is abolished by silencing ALK1 expression or addition of ALK1 extracellular domain. Overexpression of endoglin increases the BMP9 response, whereas silencing of both BMPRII and ActRIIA expressions completely abolishes it. BMP10, which is structurally close to BMP9, is also a potent ALK1 ligand. Finally, we demonstrate that BMP9 and BMP10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of ALK1. Taken together, our results suggest that BMP9 and BMP10 are two specific ALK1 ligands that may physiologically trigger the effects of ALK1 on angiogenesis. |
| Databáze: | OpenAIRE |
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