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Molecular and Cellular Biology, December 2006, p. 9268-9278, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01168-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cripto Binds Transforming Growth Factor ß (TGF-ß) and Inhibits TGF-ß Signaling

Peter C. Gray,^* Gidi Shani, Kevin Aung, Jonathan Kelber, and Wylie Vale

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037

Received 28 June 2006/ Returned for modification 21 July 2006/ Accepted 22 September 2006

Cripto is a developmental oncoprotein and a member of the epidermal growth factor-Cripto, FRL-1, Cryptic family of extracellular signaling molecules. In addition to having essential functions during embryogenesis, Cripto is highly expressed in tumors and promotes tumorigenesis. During development, Cripto acts as an obligate coreceptor for transforming growth factor ß (TGF-ß) ligands, including nodals, growth and differentiation factor 1 (GDF1), and GDF3. As an oncogene, Cripto is thought to promote tumor growth via mechanisms including activation of mitogenic signaling pathways and antagonism of activin signaling. Here, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-ß. Cripto bound TGF-ß and reduced the association of TGF-ß with its type I receptor, TßRI. Consistent with its ability to block receptor assembly, Cripto suppressed TGF-ß signaling in multiple cell types and diminished the cytostatic effects of TGF-ß in mammary epithelial cells. Furthermore, targeted disruption of Cripto expression by use of small inhibitory RNA enhanced TGF-ß signaling, indicating that endogenous Cripto plays a role in restraining TGF-ß responses.

Published ahead of print on 9 October 2006.

P.C.G. and G.S. contributed equally to this work.

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