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

Alex S. Choi, Laura M. Jenkins-Lane, Wade Barton, Asha Kumari, Carly Lancaster, Calen Raulerson, Hao Ji, Diego Altomare, Mark D. Starr, Regina Whitaker, Rebecca Phaeton, Rebecca Arend, Michael Shtutman, Andrew B. Nixon, Nadine Hempel, Nam Y. Lee, Karthikeyan Mythreye

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number128
JournalCell Communication and Signaling
Volume22
Issue number1
DOIs
StatePublished - Dec 2024

Keywords

  • Betaglycan
  • Cancer biology
  • Cell signaling
  • Ectodomain shedding
  • Glycosaminoglycan
  • Ovarian cancer
  • Soluble-betaglycan
  • Transforming growth factor β (TGF-β)
  • TβRIII

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Glycosaminoglycan modifications of betaglycan regulate ectodomain shedding to fine-tune TGF-β signaling responses in ovarian cancer'. Together they form a unique fingerprint.

Cite this