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PMID: 8106553 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites.

The Journal of cell biology ·Vol. 124 ·No. 4 ·1994-02-00 ·Pages 557-68

López-Casillas F, Payne HM, Andres JL, Massagué J

Abstract

Betaglycan, also known as the TGF-beta type III receptor, is a membrane-anchored proteoglycan that presents TGF-beta to the type II signaling receptor, a transmembrane serine/threonine kinase. The betaglycan extracellular region, which can be shed by cells into the medium, contains a NH2-terminal domain related to endoglin and a COOH-terminal domain related to uromodulin, sperm receptors Zp2 and 3, and pancreatic secretory granule GP-2 protein. We identified residues Ser535 and Ser546 in the uromodulin-related region as the glycosaminoglycan (GAG) attachment sites. Their mutation to alanine prevents GAG attachment but does not interfere with betaglycan stability or ability to bind and present TGF-beta to receptor II. Using a panel of deletion mutants, we found that TGF-beta binds to the NH2-terminal endoglin-related region of betaglycan. The remainder of the extracellular domain and the cytoplasmic domain are not required for presentation of TGF-beta to receptor II; however, membrane anchorage is required. Soluble betaglycan can bind TGF-beta but does not enhance binding to membrane receptors. In fact, recombinant soluble betaglycan acts as potent inhibitor of TGF-beta binding to membrane receptors and blocks TGF-beta action, this effect being particularly pronounced with the TGF-beta 2 isoform. The results suggest that release of betaglycan into the medium converts this enhancer of TGF-beta action into a TGF-beta antagonist.

MeSH Terms
Animals Cell Membrane/metabolism Glycosaminoglycans/metabolism Humans Ligands Membrane Proteins/metabolism Mucoproteins/genetics,metabolism Mutation Proteoglycans/metabolism Rats Receptors, Transforming Growth Factor beta/metabolism Signal Transduction Solubility Transforming Growth Factor beta/antagonists & inhibitors,metabolism Uromodulin
Chemicals
Glycosaminoglycans Ligands Membrane Proteins Mucoproteins Proteoglycans Receptors, Transforming Growth Factor beta Transforming Growth Factor beta UMOD protein, human Uromodulin betaglycan
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
López-Casillas F
Cell Biology and Genetics Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Payne H M
Andres J L
Massagué J
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.124.4.557
Published
1994-02-00
Pages
557-68
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2119924
Subset
IM
Grants
NCI NIH HHS · CA34610 · United States
External Links
PubMed source DOI: 10.1083/jcb.124.4.557 PMC Full Text View journal details
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