Assignment of Transforming Growth Factor β1 and β3 and a Third New Ligand to the Type I Receptor ALK-1*
- From the ‡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
Abstract
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 β (TGF-β) ligand superfamily. Endoglin has homology to the type III receptor, betaglycan, although its exact role in TGF-β 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-β type I receptor or the activin type IB receptor, both of which can activate an inducible PAI-1 promoter. We show that TGF-β1 and TGF-β3, 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-β receptor for TGF-β 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-β receptor. These data suggest that HHT pathogenesis involves disruption of a complex network of positive and negative angiogenic factors, involving TGF-β, a new unknown ligand, and their corresponding receptors.
Footnotes
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↵* This work was supported in part by National Institutes of Health Grant HL 49171 (to D. A. M.) and by a Medical Research Council grant (to L. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ Supported by the Deutsche Forschungsgemeinschaft.
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↵‖ Medical Research Council (Canada) scholar.
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↵** Established Investigator Award of the American Heart Association. To whom correspondence should be addressed. Tel.: 919-684-3290; Fax: 919-681-9193; E-mail: march004{at}mc.duke.edu.
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↵2 En Li, personal communication.
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↵3 D. W. Johnson and D. A. Marchuk, unpublished data.
- Abbreviations:
- HHT
-
hereditary hemorrhagic telangiectasia
- ALK-1
-
activin receptor-like kinase 1
- TGF-β
-
transforming growth factor β
- PAI
-
plasminogen activator inhibitor
- TβR-I or TβR-II
-
type I or type II TGF-β receptor
- ActR-I or ActR-II
-
type I or type II activin receptor
- BMP
-
bone morphogenetic protein
- BMPR-I or II
-
type I or type II bone morphogenetic protein receptor
- GS
-
glycine-serine domain
- TM
-
transmembrane domain
- PAGE
-
polyacrylamide gel electrophoresis
- HA
-
hemagglutinin
- ins
-
insertion
- PCR
-
polymerase chain reaction
- FBS
-
fetal bovine serum
- MEM
-
minimal essential medium
- NEAA
-
nonessential amino acids
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- Received June 19, 1998.
- Revision received January 7, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
