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Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms

C Yeo1, M Whitman

  • 1Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

Molecular Cell
|June 8, 2001
PubMed

Insights

Cripto, an EGF-CFC factor, is crucial for Nodal signaling in chordate embryos by binding to the ALK4 receptor. This interaction is vital for Nodal binding and Smad2 activation, while Nodal can also inhibit BMP signaling independently.

Area of Science:

  • Developmental biology
  • Molecular signaling pathways
  • Chordate embryogenesis

Background:

  • Nodal ligands are critical for chordate embryo patterning.
  • Epidermal Growth Factor-Cysteine-Rich secretory protein, Follistatin, Cripto, and Cryptic (EGF-CFC) factors are genetically implicated in Nodal signaling.
  • The precise molecular mechanism by which EGF-CFC factors facilitate Nodal signaling remains unclear.

Purpose of the Study:

  • To elucidate the role of Cripto, an EGF-CFC factor, in mediating Nodal signaling.
  • To investigate the molecular interactions between Cripto, Nodal, and their receptors.
  • To understand how Nodal signaling influences Bone Morphogenetic Protein (BMP) signaling.

Main Methods:

  • Investigated the interaction between Cripto and the type I receptor ALK4 using biochemical assays.
  • Assessed the necessity of Cripto-ALK4 interaction for Nodal binding to the receptor complex (ALK4/ActR-IIB).
  • Examined the effect of Cripto on Smad2 activation by Nodal.
  • Studied the potential inhibition of BMP signaling by Nodal and its dependence on Cripto.

Main Results:

  • Cripto directly interacts with the type I receptor ALK4 through its conserved CFC motif.
  • Cripto binding to ALK4 is essential for Nodal to bind the ALK4/ActR-IIB receptor complex.
  • Cripto interaction with ALK4 is required for Nodal-induced Smad2 activation.
  • Nodal can inhibit BMP signaling through a mechanism independent of Cripto, involving heterodimerization with BMPs.

Conclusions:

  • Cripto acts as a critical co-receptor, facilitating Nodal signaling by bridging Nodal to the ALK4 receptor.
  • The Cripto-ALK4 interaction is a key molecular step for Nodal signal transduction and subsequent Smad2 activation.
  • Nodal and BMP signaling pathways can antagonize each other at the ligand-dimerization level, offering a novel mechanism for cross-talk regulation.

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