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

Hyperactive Wnt/-catenin signaling is linked to cancer progression and developmental abnormalities, making identification of mechanisms controlling Wnt/-catenin signaling vital. Transforming growth factor type III receptor (TRIII/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 TRIII, independent of its TGF 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 TRIII suggesting that Wnt interactions with the TRIII heparan sulfate chains result in inhibition of Wnt signaling, likely via Wnt sequestration, whereas the chondroitin sulfate GAG chains on TRIII promote Wnt3a signaling. These studies identify a novel, dual role for TRIII/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.