BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis.
Genetic studies in mice and humans have shown that the transforming growth factor-beta (TGF-beta) 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.
Mesh Terms:
Activin Receptors, Type I, Activin Receptors, Type II, Animals, Bone Morphogenetic Proteins, COS Cells, Cattle, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cells, Cultured, Cercopithecus aethiops, Endothelial Cells, Fibroblast Growth Factor 2, Growth Differentiation Factor 2, Growth Differentiation Factors, Humans, Hypoxanthine Phosphoribosyltransferase, Mice, Neovascularization, Physiologic, Protein Binding, Receptors, Cell Surface, Signal Transduction, Vascular Endothelial Growth Factor A
Activin Receptors, Type I, Activin Receptors, Type II, Animals, Bone Morphogenetic Proteins, COS Cells, Cattle, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cells, Cultured, Cercopithecus aethiops, Endothelial Cells, Fibroblast Growth Factor 2, Growth Differentiation Factor 2, Growth Differentiation Factors, Humans, Hypoxanthine Phosphoribosyltransferase, Mice, Neovascularization, Physiologic, Protein Binding, Receptors, Cell Surface, Signal Transduction, Vascular Endothelial Growth Factor A
J. Cell. Sci.
Date: Mar. 15, 2007
PubMed ID: 17311849
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