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Updated: Oct 1, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Disruption of transforming growth factor beta signaling by a novel ligand-dependent mechanism

Tania Fernandez1, Stephanie Amoroso, Shellyann Sharpe

  • 1Laboratory of Cell Regulation and Carcinogenesis, The National Cancer Institute, The National Institutes of Health, Bethesda, MD 20892, USA.

The Journal of Experimental Medicine
|May 22, 2002
PubMed

Insights

Transforming growth factor-beta (TGF-β) can bind to its receptor intracellularly in plasma cell tumors. This binding impacts receptor trafficking but does not appear to activate downstream signaling pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Biology

Background:

  • Transforming growth factor-beta (TGF-β) is a key regulator of cell development and function, acting through autocrine and paracrine pathways.
  • TGF-β is secreted as an inactive latent complex, and its regulation is crucial for pathway activity.
  • Normal cells express both TGF-β isoforms and their receptors, maintaining controlled signaling.

Purpose of the Study:

  • To investigate intracellular TGF-β ligand-receptor interactions within plasma cell tumors (PCTs).
  • To determine if active TGF-β1 binds to intracellular TGF-beta type II receptor (TbetaRII) in PCTs.
  • To elucidate the impact of intracellular TGF-β-TbetaRII binding on receptor trafficking and signaling.

Main Methods:

  • Studied pristane-induced plasma cell tumors (PCTs) to analyze TGF-β signaling.
  • Utilized antisense TGF-β1 mRNA to disrupt TGF-β1 expression and observe TbetaRII localization.
  • Employed retroviral expression of a dominant-negative TbetaRII (dnTbetaRII) to compete for intracellular ligand binding.
  • Analyzed TGF-β receptor-activated Smad2 phosphorylation to assess signaling activation.

Main Results:

  • Demonstrated that active TGF-β1 binds to intracellular TbetaRII in PCTs.
  • Showed that disrupting TGF-β1 expression restores TbetaRII to the cell surface, indicating ligand-induced trafficking impediment.
  • Confirmed that dnTbetaRII competes for intracellular TGF-β1 binding and restores cell surface TbetaRII.
  • Found that the intracellular TGF-β-TbetaRII complex does not appear to activate Smad2-mediated signaling.

Conclusions:

  • Established the first evidence of an intracellular TGF-β-receptor complex formation.
  • Defined a novel mechanism for modulating TGF-β signaling through intracellular interactions.
  • Highlighted a potential regulatory pathway impacting receptor trafficking in cancer cells.

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