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Lefty blocks a subset of TGFbeta signals by antagonizing EGF-CFC coreceptors

Simon K Cheng1, Felix Olale, Ali H Brivanlou

  • 1Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, and Department of Cell Biology, New York University School of Medicine, New York, USA.

Plos Biology
|February 18, 2004
PubMed

Insights

Epidermal Growth Factor-Cysteine-Rich (EGF-CFC) proteins are crucial for embryonic development and cancer. Lefty, a TGFbeta antagonist, uses EGF-CFC coreceptors, revealing new insights into TGFbeta signaling pathways.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cell Signaling

Background:

  • Epidermal Growth Factor-Cysteine-Rich (EGF-CFC) proteins are vital for embryonic development and implicated in tumorigenesis.
  • Transforming Growth Factor beta (TGFbeta) signaling pathways, including Nodal and Vg1/GDF1, require EGF-CFC coreceptors for Activin receptor activation.

Purpose of the Study:

  • To investigate the mechanism of action for the TGFbeta signaling antagonist Lefty.
  • To determine if Lefty utilizes the EGF-CFC coreceptor pathway.
  • To elucidate the interaction between Lefty, Nodal, and EGF-CFC proteins.

Main Methods:

  • Investigated Lefty's interaction with EGF-CFC proteins.
  • Assessed Lefty's inhibition of Nodal, Vg1, and Activin signaling.
  • Utilized chimeric proteins of Activin and Nodal/Vg1 to identify key functional regions.

Main Results:

  • Lefty inhibits Nodal and Vg1 signaling in an EGF-CFC-dependent manner.
  • Lefty competes with Nodal for binding to EGF-CFC coreceptors.
  • A 14 amino acid region in Nodal/Vg1 confers resistance to Lefty and independence from EGF-CFC coreceptors.

Conclusions:

  • EGF-CFC coreceptors are targets for both TGFbeta agonists (Nodal, Vg1) and antagonists (Lefty).
  • Subtle sequence variations in TGFbeta ligands contribute to functional diversity.
  • This highlights a novel regulatory mechanism in TGFbeta signaling critical for development and disease.

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