Arizona Health Sciences

Altering the Proteoglycan State of Transforming Growth Factor β Type III Receptor (TβRIII)/Betaglycan Modulates Canonical Wnt/β-Catenin Signaling.

TitleAltering the Proteoglycan State of Transforming Growth Factor β Type III Receptor (TβRIII)/Betaglycan Modulates Canonical Wnt/β-Catenin Signaling.
Publication TypeJournal Article
Year of Publication2016
AuthorsJenkins LM, Singh P, Varadaraj A, Lee NY, Shah S, Flores HV, O'Connell K, Mythreye K
JournalJ Biol Chem
Volume291
Issue49
Pagination25716-25728
Date Published2016 Dec 02
ISSN1083-351X
KeywordsAnimals, Cell Line, Tumor, Cercopithecus aethiops, Chondroitin Sulfates, COS Cells, Heparitin Sulfate, Humans, Proteoglycans, Receptors, Transforming Growth Factor beta, Wnt Signaling Pathway, Wnt3A Protein
Abstract

Hyperactive Wnt/β-catenin signaling is linked to cancer progression and developmental abnormalities, making identification of mechanisms controlling Wnt/β-catenin signaling vital. Transforming growth factor β type III receptor (TβRIII/betaglycan) is a transmembrane proteoglycan co-receptor that exists with or without heparan and/or chondroitin sulfate glycosaminoglycan (GAG) modifications in cells and has established roles in development and cancer. Our studies here demonstrate that TβRIII, independent of its TGFβ co-receptor function, regulates canonical Wnt3a signaling by controlling Wnt3a availability through its sulfated GAG chains. Our findings revealed, for the first time, opposing functions for the different GAG modifications on TβRIII suggesting that Wnt interactions with the TβRIII heparan sulfate chains result in inhibition of Wnt signaling, likely via Wnt sequestration, whereas the chondroitin sulfate GAG chains on TβRIII promote Wnt3a signaling. These studies identify a novel, dual role for TβRIII/betaglycan and define a key requirement for the balance between chondroitin sulfate and heparan sulfate chains in dictating ligand responses with implications for both development and cancer.

DOI10.1074/jbc.M116.748624
Alternate JournalJ. Biol. Chem.
PubMed ID27784788
PubMed Central IDPMC5207267
Grant ListP20 GM109091 / GM / NIGMS NIH HHS / United States
R01 CA178443 / CA / NCI NIH HHS / United States
Faculty Member Reference: 
Nam Lee, Ph.D.