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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1953-1961. Prepublished online as a Blood First Edition Paper on October 26, 2006; DOI 10.1182/blood-2006-07-034124. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-07-034124v1 109/5/1953    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by David, L. Articles by Bailly, S. Search for Related Content PubMed PubMed Citation Articles by David, L. Articles by Bailly, S. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells Laurent David1,2,3, Christine Mallet1,2,3, Sabine Mazerbourg4, Jean-Jacques Feige1,2,3, and Sabine Bailly1,2,3 1 Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Mixte INSERM (EMI 01-05), Grenoble, France; 2 Commissariat à l'Energie Atomique (CEA), Département Réponse et Dynamique Cellulaires (DRDC)/ANGIO, Grenoble, France; 3 Université Joseph Fourier, Grenoble, France; 4 Université Henri Poincaré, Nancy 1, Unité Propre de Recherche et d'Enseignement Supérieur (UPRES) Equipe Associée (EA) 3442, Vandoeuvre les Nancy, France ALK1 is an endothelial-specific type I receptor of the TGFß receptor family whose heterozygous mutations cause hereditary hemorrhagic telangiectasia type 2. Although TGFß1 and TGFß3 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Bone morphogenetic proteins go endothelial Danny Huylebroeck Blood 2007 109: 1794-1795. [Full Text] [PDF] This article has been cited by other articles: N. Y. Lee, J. C. Haney, J. Sogani, and G. C. Blobe Casein kinase 2{beta} as a novel enhancer of activin-like receptor-1 signaling FASEB J, November 1, 2009; 23(11): 3712 - 3721. [Abstract] [Full Text] [PDF] D. A. Towler Bone morphogenetic proteins Blood, September 3, 2009; 114(10): 2012 - 2013. [Abstract] [Full Text] [PDF] E. 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[Abstract] [Full Text] [PDF] N. Y. Lee, B. Ray, T. How, and G. C. Blobe Endoglin Promotes Transforming Growth Factor {beta}-mediated Smad 1/5/8 Signaling and Inhibits Endothelial Cell Migration through Its Association with GIPC J. Biol. Chem., November 21, 2008; 283(47): 32527 - 32533. [Abstract] [Full Text] [PDF] A. C. Daly, R. A. Randall, and C. S. Hill Transforming Growth Factor {beta}-Induced Smad1/5 Phosphorylation in Epithelial Cells Is Mediated by Novel Receptor Complexes and Is Essential for Anchorage-Independent Growth Mol. Cell. Biol., November 15, 2008; 28(22): 6889 - 6902. [Abstract] [Full Text] [PDF] T. Kokudo, Y. Suzuki, Y. Yoshimatsu, T. Yamazaki, T. Watabe, and K. Miyazono Snail is required for TGF{beta}-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells J. Cell Sci., October 15, 2008; 121(20): 3317 - 3324. [Abstract] [Full Text] [PDF] L. Ye, H. Kynaston, and W. G. 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Behringer, et al. Conditional Deletion of Smad1 and Smad5 in Somatic Cells of Male and Female Gonads Leads to Metastatic Tumor Development in Mice Mol. Cell. Biol., January 1, 2008; 28(1): 248 - 257. [Abstract] [Full Text] [PDF] G. Lagna, M. M. Ku, P. H. Nguyen, N. A. Neuman, B. N. Davis, and A. Hata Control of Phenotypic Plasticity of Smooth Muscle Cells by Bone Morphogenetic Protein Signaling through the Myocardin-related Transcription Factors J. Biol. Chem., December 21, 2007; 282(51): 37244 - 37255. [Abstract] [Full Text] [PDF] P. Brouillard and M. Vikkula Genetic causes of vascular malformations Hum. Mol. Genet., October 15, 2007; 16(R2): R140 - R149. [Abstract] [Full Text] [PDF] L. Lin, E. V. Valore, E. Nemeth, J. B. Goodnough, V. Gabayan, and T. Ganz Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4 Blood, September 15, 2007; 110(6): 2182 - 2189. [Abstract] [Full Text] [PDF] D. Liu, J. Wang, B. Kinzel, M. Mueller, X. Mao, R. Valdez, Y. Liu, and E. Li Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity Blood, September 1, 2007; 110(5): 1502 - 1510. [Abstract] [Full Text] [PDF] K. Goto, Y. Kamiya, T. Imamura, K. Miyazono, and K. Miyazawa Selective Inhibitory Effects of Smad6 on Bone Morphogenetic Protein Type I Receptors J. Biol. Chem., July 13, 2007; 282(28): 20603 - 20611. [Abstract] [Full Text] [PDF] O. Scherner, S. K. Meurer, L. Tihaa, A. M. Gressner, and R. Weiskirchen Endoglin Differentially Modulates Antagonistic Transforming Growth Factor-beta1 and BMP-7 Signaling J. Biol. Chem., May 11, 2007; 282(19): 13934 - 13943. [Abstract] [Full Text] [PDF] L. Umans, L. Cox, M. Tjwa, V. Bito, L. Vermeire, K. Laperre, K. Sipido, L. Moons, D. Huylebroeck, and A. Zwijsen Inactivation of Smad5 in Endothelial Cells and Smooth Muscle Cells Demonstrates that Smad5 Is Required for Cardiac Homeostasis Am. J. Pathol., May 1, 2007; 170(5): 1460 - 1472. [Abstract] [Full Text] [PDF] M. Scharpfenecker, M. van Dinther, Z. Liu, R.L. van Bezooijen, Q. Zhao, L. Pukac, C. W. G. M. Lowik, and P. ten Dijke BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis J. Cell Sci., March 15, 2007; 120(6): 964 - 972. [Abstract] [Full Text] [PDF]

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