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Molecular and Cellular Biology, July 2002, p. 4439-4449, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4439-4449.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Dual Roles of Cripto as a Ligand and Coreceptor in the Nodal Signaling Pathway

Yu-Ting Yan,1,2 Jan-Jan Liu,1,2 Yi Luo,3 Chaosu E,1,2 Robert S. Haltiwanger,3 Cory Abate-Shen,1,4 and Michael M. Shen1,2*

Center for Advanced Biotechnology and Medicine,1 Departments of Pediatrics,2 Neuroscience, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854,4 Department of Biochemistry and Cell Biology, Institute for Cell and Developmental Biology, State University of New York at Stony Brook, Stony Brook, New York 117943

Received 28 November 2001/ Returned for modification 15 January 2002/ Accepted 9 April 2002

The EGF-CFC gene Cripto encodes an extracellular protein that has been implicated in the signaling pathway for the transforming growth factor beta (TGFß) ligand Nodal. Although recent findings in frog and fish embryos have suggested that EGF-CFC proteins function as coreceptors for Nodal, studies in cell culture have implicated Cripto as a growth factor-like signaling molecule. Here we reconcile these apparently disparate models of Cripto function by using a mammalian cell culture assay to investigate the signaling activities of Nodal and EGF-CFC proteins. Using a luciferase reporter assay, we found that Cripto has activities consistent with its being a coreceptor for Nodal. However, Cripto can also function as a secreted signaling factor in cell coculture assays, suggesting that it may also act as a coligand for Nodal. Furthermore, we found that the ability of Cripto to bind to Nodal and mediate Nodal signaling requires the addition of an O-linked fucose monosaccharide to a conserved site within EGF-CFC proteins. We propose a model in which Cripto has dual roles as a coreceptor as well as a coligand for Nodal and that this signaling interaction with Nodal is regulated by an unusual form of glycosylation. Our findings highlight the significance of extracellular modulation of ligand activity as an important means of regulating TGFß signaling pathways during vertebrate development.

* Corresponding author. Mailing address: CABM, 679 Hoes Ln., Piscataway, NJ 08854. Phone: (732) 235-5645. Fax: (732) 235-5373. E-mail: mshen{at}cabm.rutgers.edu.

Molecular and Cellular Biology, July 2002, p. 4439-4449, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4439-4449.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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