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Glycosaminoglycan modifications of betaglycan regulate ectodomain shedding to fine-tune TGF-β signaling responses in ovarian cancer.

Publication ,  Journal Article
Choi, AS; Jenkins-Lane, LM; Barton, W; Kumari, A; Lancaster, C; Raulerson, C; Ji, H; Altomare, D; Starr, MD; Whitaker, R; Phaeton, R; Arend, R ...
Published in: Cell Commun Signal
February 15, 2024

In pathologies including cancer, aberrant Transforming Growth Factor-β (TGF-β) signaling exerts profound tumor intrinsic and extrinsic consequences. Intense clinical endeavors are underway to target this pathway. Central to the success of these interventions is pinpointing factors that decisively modulate the TGF-β responses. Betaglycan/type III TGF-β receptor (TβRIII), is an established co-receptor for the TGF-β superfamily known to bind directly to TGF-βs 1-3 and inhibin A/B. Betaglycan can be membrane-bound and also undergo ectodomain cleavage to produce soluble-betaglycan that can sequester its ligands. Its extracellular domain undergoes heparan sulfate and chondroitin sulfate glycosaminoglycan modifications, transforming betaglycan into a proteoglycan. We report the unexpected discovery that the heparan sulfate glycosaminoglycan chains on betaglycan are critical for the ectodomain shedding. In the absence of such glycosaminoglycan chains betaglycan is not shed, a feature indispensable for the ability of betaglycan to suppress TGF-β signaling and the cells' responses to exogenous TGF-β ligands. Using unbiased transcriptomics, we identified TIMP3 as a key inhibitor of betaglycan shedding thereby influencing TGF-β signaling. Our results bear significant clinical relevance as modified betaglycan is present in the ascites of patients with ovarian cancer and can serve as a marker for predicting patient outcomes and TGF-β signaling responses. These studies are the first to demonstrate a unique reliance on the glycosaminoglycan chains of betaglycan for shedding and influence on TGF-β signaling responses. Dysregulated shedding of TGF-β receptors plays a vital role in determining the response and availability of TGF-βs', which is crucial for prognostic predictions and understanding of TGF-β signaling dynamics.

Duke Scholars

Published In

Cell Commun Signal

DOI

EISSN

1478-811X

Publication Date

February 15, 2024

Volume

22

Issue

1

Start / End Page

128

Location

England

Related Subject Headings

  • Transforming Growth Factor beta
  • Receptors, Transforming Growth Factor beta
  • Proteoglycans
  • Ovarian Neoplasms
  • Humans
  • Heparitin Sulfate
  • Glycosaminoglycans
  • Female
  • Biochemistry & Molecular Biology
  • 3101 Biochemistry and cell biology
 

Citation

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Choi, A. S., Jenkins-Lane, L. M., Barton, W., Kumari, A., Lancaster, C., Raulerson, C., … Mythreye, K. (2024). Glycosaminoglycan modifications of betaglycan regulate ectodomain shedding to fine-tune TGF-β signaling responses in ovarian cancer. Cell Commun Signal, 22(1), 128. https://doi.org/10.1186/s12964-024-01496-y
Journal cover image

Published In

Cell Commun Signal

DOI

EISSN

1478-811X

Publication Date

February 15, 2024

Volume

22

Issue

1

Start / End Page

128

Location

England

Related Subject Headings

  • Transforming Growth Factor beta
  • Receptors, Transforming Growth Factor beta
  • Proteoglycans
  • Ovarian Neoplasms
  • Humans
  • Heparitin Sulfate
  • Glycosaminoglycans
  • Female
  • Biochemistry & Molecular Biology
  • 3101 Biochemistry and cell biology