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J Biol Chem, Vol. 274, Issue 15, 9984-9992, April 9, 1999
1 and 3 and a
Third New Ligand to the Type I Receptor ALK-1
,
From the 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 Department of Genetics, Duke University
Medical Center, Durham, North Carolina 27710 and the
¶ Department of Anatomy and Cell Biology, University of Toronto,
Toronto, Ontario M5S 1A8, Canada
(TGF-) ligand superfamily. Endoglin
has homology to the type III receptor, betaglycan, although its exact
role in TGF- 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-
type I receptor or the activin type IB receptor, both of which can
activate an inducible PAI-1 promoter. We show that TGF-1
and TGF-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-1/ligand interaction
is mediated by the type II TGF- receptor for TGF- 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- receptor. These data suggest that HHT
pathogenesis involves disruption of a complex network of positive and
negative angiogenic factors, involving TGF-, a new unknown ligand,
and their corresponding receptors.
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