QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 20 February 2007
doi: 10.1242/jcs.002949

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.002949v1 120/6/964    most recent Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scharpfenecker, M. Articles by ten Dijke, P. Search for Related Content PubMed PubMed Citation Articles by Scharpfenecker, M. Articles by ten Dijke, P. Social Bookmarking                         What's this?

BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis

¹ Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
² Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
³ Human Genome Sciences, Inc., Rockville, MD 20850, USA
⁴ CoGenesys, Rockville, MD 20850, USA

^* Author for correspondence (e-mail: p.ten_dijke{at}lumc.nl)

Accepted 21 December 2006

Genetic studies in mice and humans have shown that the transforming growth factor- (TGF-) type-I receptor activin receptor-like kinase 1 (ALK1) and its co-receptor endoglin play an important role in vascular development and angiogenesis. Here, we demonstrate that ALK1 is a signalling receptor for bone morphogenetic protein-9 (BMP-9) in endothelial cells (ECs). BMP-9 bound with high affinity to ALK1 and endoglin, and weakly to the type-I receptor ALK2 and to the BMP type-II receptor (BMPR-II) and activin type-II receptor (ActR-II) in transfected COS cells. Binding of BMP-9 to ALK2 was greatly facilitated when BMPR-II or ActR-II were co-expressed. Whereas BMP-9 predominantly bound to ALK1 and BMPR-II in ECs, it bound to ALK2 and BMPR-II in myoblasts. In addition, we observed binding of BMP-9 to ALK1 and endoglin in glioblastoma cells. BMP-9 activated Smad1 and/or Smad5, and induced ID1 protein and endoglin mRNA expression in ECs. Furthermore, BMP-9 was found to inhibit basic fibroblast growth factor (bFGF)-stimulated proliferation and migration of bovine aortic ECs (BAECs) and to block vascular endothelial growth factor (VEGF)-induced angiogenesis. Taken together, these results suggest that BMP-9 is a physiological ALK1 ligand that plays an important role in the regulation of angiogenesis.

Key words: ALK1, Angiogenesis, bFGF, BMP, Endoglin, Signalling, Smad, VEGF

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				P. D. Upton, R. J. Davies, R. C. Trembath, and N. W. Morrell Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells J. Biol. Chem., June 5, 2009; 284(23): 15794 - 15804. [Abstract] [Full Text] [PDF]

				T. A. Souza, X. Chen, Y. Guo, P. Sava, J. Zhang, J. J. Hill, P. J. Yaworsky, and Y. Qiu Proteomic Identification and Functional Validation of Activins and Bone Morphogenetic Protein 11 as Candidate Novel Muscle Mass Regulators Mol. Endocrinol., December 1, 2008; 22(12): 2689 - 2702. [Abstract] [Full Text] [PDF]

				Y. Yao, E. S. Shao, M. Jumabay, A. Shahbazian, S. Ji, and K. I. Bostrom High-Density Lipoproteins Affect Endothelial BMP-Signaling by Modulating Expression of the Activin-Like Kinase Receptor 1 and 2 Arterioscler. Thromb. Vasc. Biol., December 1, 2008; 28(12): 2266 - 2274. [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. Jiang Bone Morphogenetic Protein-9 Induces Apoptosis in Prostate Cancer Cells, the Role of Prostate Apoptosis Response-4 Mol. Cancer Res., October 1, 2008; 6(10): 1594 - 1606. [Abstract] [Full Text] [PDF]

				L. David, C. Mallet, M. Keramidas, N. Lamande, J.-M. Gasc, S. Dupuis-Girod, H. Plauchu, J.-J. Feige, and S. Bailly Bone Morphogenetic Protein-9 Is a Circulating Vascular Quiescence Factor Circ. Res., April 25, 2008; 102(8): 914 - 922. [Abstract] [Full Text] [PDF]

				N. A. Dallas, S. Samuel, L. Xia, F. Fan, M. J. Gray, S. J. Lim, and L. M. Ellis Endoglin (CD105): A Marker of Tumor Vasculature and Potential Target for Therapy Clin. Cancer Res., April 1, 2008; 14(7): 1931 - 1937. [Abstract] [Full Text] [PDF]

				M. T. Holderfield and C. C.W. Hughes Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-{beta} in Vascular Morphogenesis Circ. Res., March 28, 2008; 102(6): 637 - 652. [Abstract] [Full Text] [PDF]

				P. D. Upton, L. Long, R. C. Trembath, and N. W. Morrell Functional Characterization of Bone Morphogenetic Protein Binding Sites and Smad1/5 Activation in Human Vascular Cells Mol. Pharmacol., February 1, 2008; 73(2): 539 - 552. [Abstract] [Full Text] [PDF]

				S. O. Park, Y. J. Lee, T. Seki, K.-H. Hong, N. Fliess, Z. Jiang, A. Park, X. Wu, V. Kaartinen, B. L. Roman, et al. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2 Blood, January 15, 2008; 111(2): 633 - 642. [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]