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Sci. Signal., 11 November 2008
Vol. 1, Issue 45, p. ra13
[DOI: 10.1126/scisignal.1165027]

RESEARCH ARTICLES

Cripto Localizes Nodal at the Limiting Membrane of Early Endosomes

Marie-Hélène Blanchet1, J. Ann Le Good1, Viola Oorschot2, Stéphane Baflast1, Gabriella Minchiotti3, Judith Klumperman2, and Daniel B. Constam1*

1 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Chemin des Boveresses 155, CH 1066 Epalinges, Switzerland.
2 Cell Microscopy Center and Department of Cell Biology, University Medical Centre Utrecht, Heidelberglaan 100, 3584CX Utrecht, the Netherlands.
3 Institute of Genetics and Biophysics "A. Buzzati-Traverso," Via P. Castellino 111, 80131 Naples, Italy.

Abstract: Cripto is a glycosylphosphatidylinositol (GPI)–anchored co-receptor of Nodal and several other transforming growth factor–β (TGF-β) family ligands. It contains an epidermal growth factor (EGF)–like motif and a Cripto-FRL1-Cryptic (CFC) domain, which are conserved in a family of EGF-CFC proteins. The EGF domain is thought to recruit Nodal, whereas the CFC domain mediates binding to activin receptor–like kinase 4 (ALK4). We found that the EGF-like motif of Cripto was not essential for its binding to Nodal. However, through residues phenylalanine 78 and glycine 71, Cripto enriched Nodal at the limiting membrane of early endosomes. Similarly, residues in the CFC domain that mediate binding of Cripto to ALK4 were required to attenuate sequestration of Nodal in the endosomal lumen. Thus, we propose that Cripto stimulates Nodal activity by localizing it at the interface of endosomes with cytoplasmic effectors. To our knowledge, Cripto is the first GPI-anchored protein shown to control intraendosomal sorting of its associated cargo.

* To whom correspondence should be addressed. E-mail: Daniel.Constam{at}epfl.ch

Citation: M.-H. Blanchet, J. A. Le Good, V. Oorschot, S. Baflast, G. Minchiotti, J. Klumperman, D. B. Constam, Cripto Localizes Nodal at the Limiting Membrane of Early Endosomes. Sci. Signal. 1, ra13 (2008).

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