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J. Biol. Chem., Vol. 283, Issue 8, 4490-4500, February 22, 2008

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Cripto Is a Noncompetitive Activin Antagonist That Forms Analogous Signaling Complexes with Activin and Nodal^*

Jonathan A. Kelber, Gidi Shani, Evan C. Booker^¶, Wylie W. Vale¹, and Peter C. Gray²

From the Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037 and the Department of Chemistry and Biochemistry and ^¶Department of Biology, University of California San Diego, La Jolla, California 92037

Cripto plays critical roles during embryogenesis and has been implicated in promoting the growth and spread of tumors. Cripto is required for signaling by certain transforming growth factor-β superfamily members, such as Nodal, but also antagonizes others, such as activin. The opposing effects of Cripto on Nodal and activin signaling seem contradictory, however, because these closely related ligands utilize the same type I (ALK4) and type II (ActRII/IIB) receptors. Here, we have addressed this apparent paradox by demonstrating that Cripto forms analogous receptor complexes with Nodal and activin and functions as a noncompetitive activin antagonist. Our results show that activin-A and Nodal elicit similar maximal signaling responses in the presence of Cripto that are substantially lower than that of activin-A in the absence of Cripto. In addition, we provide biochemical evidence for complexes containing activin-A, Cripto, and both receptor types and show that the assembly of such complexes is competitively inhibited by Nodal. We further demonstrate that Nodal and activin-A share the same binding site on ActRII and that ALK4 has distinct and separable binding sites for activin-A and Cripto. Finally, we show that ALK4 mutants with disrupted activin-A binding retain Cripto binding and prevent the effects of Cripto on both activin-A and Nodal signaling. Together, our data indicate that Cripto facilitates Nodal signaling and inhibits activin signaling by forming receptor complexes with these ligands that are structurally and functionally similar.

Received for publication, June 15, 2007 , and in revised form, December 7, 2007.

^* This work was supported by NCI, National Institutes of Health, Grant R01CA107420, the Foundation for Medical Research, Inc., and the Robert J. Jr. and Helen C. Kleberg Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Senior investigator of the Foundation for Medical Research, Inc.

² To whom correspondence should be addressed: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA, 92037. Fax: 858-552-1546; E-mail: gray{at}salk.edu.

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