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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras

M Kretzschmar1, J Doody, I Timokhina

  • 1Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 USA.

Genes & Development
|April 10, 1999
PubMed

Insights

Oncogenic Ras mutations disrupt normal epithelial cell growth by inhibiting TGF-beta signaling. This Ras-mediated inhibition of Smad2 and Smad3 proteins prevents anti-proliferative responses, contributing to cancer development.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Transforming Growth Factor-beta (TGFbeta) normally inhibits epithelial cell proliferation.
  • Oncogenic Ras mutations are frequently found in cancers and can lead to loss of TGFbeta's growth-inhibitory effects.

Purpose of the Study:

  • To investigate the mechanism by which oncogenic Ras inhibits TGFbeta signaling in epithelial cells.
  • To identify the specific mediators and pathways involved in this Ras-mediated suppression.

Main Methods:

  • Studied TGFbeta signaling in mammary and lung epithelial cells with and without oncogenic Ras.
  • Utilized techniques to assess Smad2 and Smad3 nuclear accumulation and Smad-dependent transcription.
  • Investigated the role of Erk MAP kinases and specific phosphorylation sites on Smad proteins.
  • Employed site-directed mutagenesis to create Ras-resistant Smad3 variants.

Main Results:

  • Oncogenic Ras inhibits TGFbeta signaling by negatively regulating Smad2 and Smad3.
  • Ras, via Erk MAP kinases, phosphorylates Smad2/Smad3 at unique sites, preventing nuclear translocation and transcriptional activity.
  • Mutating these specific Ras-sensitive sites in Smad3 restored TGFbeta's growth inhibitory function in Ras-transformed cells.
  • Epidermal Growth Factor (EGF) showed a weaker inhibitory effect on Smad2/Smad3 compared to oncogenic Ras.

Conclusions:

  • Ras-MAPK signaling antagonizes TGFbeta-Smad signaling by phosphorylating Smad2/Smad3, leading to cytoplasmic retention.
  • This mechanism explains how hyperactive Ras silences TGFbeta's anti-proliferative functions in cancer cells.
  • Understanding this crosstalk is crucial for developing targeted cancer therapies.

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