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Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth factor-beta

L Ulloa1, S Tabibzadeh

  • 1Department of Pathology, North Shore-Long Island Jewish Health System and Biomedical Research Center, Manhasset, New York 11030, USA.

The Journal of Biological Chemistry
|March 30, 2001
PubMed

Insights

Lefty, a novel TGF-beta superfamily member, inhibits transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signaling. It blocks R-Smad phosphorylation, preventing downstream gene activation.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGF-beta) is a key cytokine regulating cell growth and differentiation.
  • TGF-beta signaling involves receptor activation, Smad protein phosphorylation, and nuclear translocation for gene regulation.
  • Understanding negative regulators of TGF-beta signaling is crucial for deciphering cellular processes.

Purpose of the Study:

  • To investigate the inhibitory role of lefty, a novel TGF-beta superfamily member, on TGF-beta and BMP signaling pathways.
  • To elucidate the mechanism by which lefty modulates Smad protein activity and downstream gene expression.
  • To determine if lefty's action is dependent on protein synthesis.

Main Methods:

  • Investigated lefty's effect on Smad2 phosphorylation after TGF-beta receptor activation.
  • Assessed lefty's impact on R-Smad/Smad4 heterodimerization and nuclear translocation.
  • Analyzed lefty's repression of TGF-beta- and BMP-induced reporter gene expression.
  • Examined lefty's effect on Smad5 phosphorylation in BMP signaling.
  • Evaluated the necessity of protein synthesis for lefty's inhibitory function.

Main Results:

  • Lefty inhibits TGF-beta signaling by preventing Smad2 phosphorylation downstream of TGF-beta receptor activation.
  • Lefty interferes with R-Smad heterodimerization with Smad4 and subsequent nuclear translocation.
  • Lefty represses TGF-beta-induced transcription from p21, cdc25, connective tissue growth factor, and Smad-binding element reporter genes.
  • Lefty also inhibits BMP-mediated Smad5 phosphorylation and downstream gene transcription.
  • Lefty's inhibitory action does not require de novo protein synthesis.

Conclusions:

  • Lefty acts as a negative modulator of both TGF-beta and BMP signaling pathways.
  • Lefty inhibits these pathways primarily by blocking the phosphorylation of receptor-regulated Smad proteins (R-Smads).
  • Lefty establishes a repressed state for TGF-beta- and BMP-responsive genes, independent of protein synthesis.

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