Assignment of transforming growth factor β1 and β3 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 TCF-beta type I receptor or the activin type IB receptor, both of which can activate an inducible PAI-1 promoter. we show that TGF-beta 1 and TGF-beta 3, 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-l/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.