Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1.
Germ line mutations in one of two distinct genes, endoglin or ALK-1, cause hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disorder of localized angiodysplasia. Both genes encode endothelial cell receptors for the transforming growth factor beta (TGF-beta) ligand superfamily. Endoglin has homology to the type III receptor, betaglycan, although its exact role in TGF-beta signaling is unclear. Activin receptor-like kinase 1 (ALK-1) has homology to the type I receptor family, but its ligand and corresponding type II receptor are unknown. In order to identify the ligand and type II receptor for ALK-1 and to investigate the role of endoglin in ALK-1 signaling, we devised a chimeric receptor signaling assay by exchanging the kinase domain of ALK-1 with either the TGF-beta type I receptor or the activin type IB receptor, both of which can activate an inducible PAI-1 promoter. We show that TGF-beta1 and TGF-beta3, as well as a third unknown ligand present in serum, can activate chimeric ALK-1. HHT-associated missense mutations in the ALK-1 extracellular domain abrogate signaling. The ALK-1/ligand interaction is mediated by the type II TGF-beta receptor for TGF-beta and most likely through the activin type II or type IIB receptors for the serum ligand. Endoglin is a bifunctional receptor partner since it can bind to ALK-1 as well as to type I TGF-beta receptor. These data suggest that HHT pathogenesis involves disruption of a complex network of positive and negative angiogenic factors, involving TGF-beta, a new unknown ligand, and their corresponding receptors.
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Department of Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
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Marchuk
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D029404:Activin Receptors; D028341:Activins; D000818:Animals; D015703:Antigens, CD; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D000071063:Endoglin; D007265:Inhibins / Q000378:metabolism; D008024:Ligands; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism*
D015703:Antigens, CD; D019485:Bone Morphogenetic Proteins; C064206:ENG protein, human; D000071063:Endoglin; D008024:Ligands; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D028341:Activins; C071736:betaglycan; D007265:Inhibins; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors