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

Abstract

Edited by Xiao-Fan WangHyperactive 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 (T␤RIII/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 T␤RIII, 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 T␤RIII suggesting that Wnt interactions with the T␤RIII heparan sulfate chains result in inhibition of Wnt signaling, likely via Wnt sequestration, whereas the chondroitin sulfate GAG chains on T␤RIII promote Wnt3a signaling. These studies identify a novel, dual role for T␤RIII/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.Wnt glycoproteins regulate three distinct Wnt signaling pathways to mediate cell fate, proliferation, and apoptosis as well as cancer initiation and progression in multiple cancers, including ovarian (1-9). Activation of the canonical Wnt/␤-catenin pathway begins with the binding of Wnt to its cell surface receptors, Frizzled and LDL receptor-related proteins 5/6 (LRP5/6), 3 followed by phosphorylation of LRP5/6, recruitment of Dishevelled to the plasma membrane to interact with Frizzled, and stabilization of cytosolic ␤-catenin (10). Axin interaction with phosphorylated LRP5/6 and Dishevelled leads to inactivation of the ␤-catenin destruction complex, accumulation of ␤-catenin, and translocation to the nucleus to regulate Wnt target genes by binding to TCF/LEF transcription factors (10, 11). The Wnt signaling cascade is controlled in part by transmembrane proteoglycans, which interact with Wnt signaling components and can either stimulate or inhibit signaling activity. For instance, the HSPG glypican-3 and syndecan-1 stimulate canonical Wnt signaling (12, 13), whereas others, including glypican-1 and glypican-6, suppress Wnt signaling (13,14). Type III TGF-␤ receptor (T␤RIII)/betaglycan is a transmembrane proteoglycan with loss resulting in embryonic lethality in mice (15). Beyond its roles in regulating TGF-␤ signaling, T␤RIII also controls several other pathways to inhibit cell migration, invasion, cell growth, and angiogenesis in both in vitro and in vivo cancer models (16 -22) and regulating differentiation through FGF2 signaling (23). Mechanistically, T␤RIII regulates these pathways either by altering the actin cytoskeleton, via T␤RIII/␤-arrestin2 cytoplasmic interactions (24), or by GAG chain interactions with FGF2 (23). Overall, T␤RIII also acts as a tumor suppressor in prostate (19), lung...

Differential Expression of Coding and Long Noncoding RNAs in Keratoconus-affected Corneas

“…Iqbal et al have shown an increased expression of SFRP1 in the KC-affected corneal epithelium 74 ; however , in tears from KC patients, SFRP1 expression was reduced in KC 75 . TGFBR3 has been found to be a suppressor to WNT signaling through binding to Wnt3a and β-catenin 76 . We observed that Lnc-WNT4-2:1 was upregulated more than two-fold in KC versus controls.…”

Endoglin Trafficking/Exosomal Targeting in Liver Cells Depends on N-Glycosylation

“…In case of Eng, defective N -glycosylation has been shown to interfere with membrane localization similar to TβRII [12,13]. For betaglycan it has been shown that changes in the type of glycosylation affect the signaling outcome [14]. Betaglycan is broadly expressed and has been shown to positively regulate ALK5/Smad2/3-signaling [15,16].…”

Differential Expression of Coding and Long Noncoding RNAs in Keratoconus-Affected Corneas

“…76 TGFBR3 suppresses WNT signaling through binding to Wnt3a and β-catenin. 77 We observed increased expression of Lnc-WNT4-2:1 in KC versus controls. Our BLASTN analysis indicated that Lnc-WNT4-2:1 is a sense transcript for its overlapping with exon 5 of WNT4 gene.…”