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Cripto localizes Nodal at the limiting membrane of early endosomes

Marie-Hélène Blanchet1, J Ann Le Good, Viola Oorschot

  • 1Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Chemin des Boveresses 155, CH 1066 Epalinges, Switzerland.

Science Signaling
|November 13, 2008
PubMed

Insights

Cripto protein guides Nodal localization within early endosomes, enhancing its signaling. This GPI-anchored co-receptor controls intraendosomal sorting, a novel mechanism for regulating TGF-beta family ligands.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Protein interactions

Background:

  • Cripto is a GPI-anchored co-receptor for Nodal and TGF-beta family ligands.
  • It possesses EGF-like and CFC domains involved in ligand and receptor binding.
  • The precise mechanism of Cripto in modulating Nodal activity remained unclear.

Purpose of the Study:

  • To investigate the role of Cripto in Nodal localization and signaling.
  • To elucidate the specific domains and residues of Cripto involved in Nodal interaction and trafficking.
  • To understand how Cripto influences Nodal activity at the endosomal level.

Main Methods:

  • Site-directed mutagenesis of Cripto protein.
  • Analysis of Nodal binding and co-localization with Cripto in endosomes.
  • Cellular assays to assess Nodal signaling pathway activation.

Main Results:

  • The EGF-like motif of Cripto is not essential for Nodal binding.
  • Specific residues (Phe78, Gly71) in Cripto are crucial for enriching Nodal at the early endosome membrane.
  • Cripto's CFC domain residues mediating ALK4 binding are required to prevent Nodal sequestration within the endosome.
  • Cripto acts as a novel GPI-anchored protein controlling intraendosomal cargo sorting.

Conclusions:

  • Cripto enhances Nodal activity by controlling its localization at the interface of endosomes and cytoplasmic effectors.
  • This study reveals a new function for GPI-anchored proteins in regulating the intraendosomal sorting of signaling molecules.
  • Cripto's mechanism provides insights into the spatial regulation of TGF-beta superfamily signaling.

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