title: Altering the Proteoglycan State of Transforming Growth Factor β Type III Receptor (TβRIII)/Betaglycan Modulates Canonical Wnt/β-Catenin Signaling.
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.
authors: From the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208.
authors: Laura M
authors: http://orcid.org/0000-0003-0563-9519
authors: LM
authors: Jenkins
authors: From the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208.
authors: Priyanka
authors: P
authors: Singh
authors: From the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208.
authors: Archana
authors: http://orcid.org/0000-0002-1868-1268
authors: A
authors: Varadaraj
authors: the Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio 43210.
authors: Nam Y
authors: NY
authors: Lee
authors: From the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208.
authors: Shreya
authors: S
authors: Shah
authors: From the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208.
authors: Haley V
authors: HV
authors: Flores
authors: From the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208.
authors: Kathleen
authors: K
authors: O'Connell
authors: From the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, mythreye@sc.edu.|the Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, and.
authors: Karthikeyan
authors: http://orcid.org/0000-0001-5478-0098
authors: K
authors: Mythreye
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002809:Chondroitin Sulfates / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002809:Chondroitin Sulfates; D006497:Heparan Sulfate; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D060509:Wnt3A Protein; C555510:WNT3A protein, human; C071736:betaglycan
keywords: TBRIII; Wnt signaling; betaglycan; cancer biology; cell signaling; glycosaminoglycan; transforming growth factor β (TGF-β)