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Epidermal growth factor signaling via Ras controls the Smad transcriptional co-repressor TGIF

R S Lo1, D Wotton, J Massagué

  • 1Cell Biology Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

The EMBO Journal
|February 28, 2001
PubMed

Insights

Transforming growth factor-beta (TGF-beta) signaling is modulated by the TGIF protein, which is stabilized by epidermal growth factor (EGF) signaling. This stabilization favors TGF-beta co-repression, impacting cellular responses.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Developmental Biology

Background:

  • Smad transcription factors are key mediators of transforming growth factor-beta (TGF-beta) signaling.
  • Smad2 activity is regulated by interactions with co-activators like p300 and co-repressors like TGIF.
  • TGIF levels critically influence TGF-beta response outcomes and are implicated in developmental defects.

Purpose of the Study:

  • To investigate the regulation of TGIF protein levels.
  • To elucidate the mechanism by which epidermal growth factor (EGF) signaling affects TGIF.
  • To understand the interplay between Smad and Ras pathways in transcriptional regulation.

Main Methods:

  • Investigated TGIF protein stability and degradation.
  • Utilized cell-based assays to examine the effects of EGF and TGF-beta signaling.
  • Employed Western blotting and phospho-specific antibodies to detect TGIF phosphorylation.
  • Analyzed Smad2-TGIF complex formation.

Main Results:

  • TGIF protein levels were found to modulate sensitivity to TGF-beta-mediated growth inhibition.
  • TGIF was identified as a short-lived protein.
  • Epidermal growth factor (EGF) signaling, via the Ras-Mek pathway, phosphorylates TGIF at Erk MAP kinase sites.
  • This phosphorylation stabilizes TGIF, promoting Smad2-TGIF co-repressor complex formation in response to TGF-beta.

Conclusions:

  • Identified the first mechanism for regulating TGIF protein levels through EGF-induced stabilization.
  • Demonstrated a direct link between Ras pathway activation and TGIF stability.
  • Revealed a potential convergence point between Smad and Ras signaling pathways at the transcriptional level.

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