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Molecular and Cellular Biology, January 2008, p. 666-677, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01716-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

GRP78 and Cripto Form a Complex at the Cell Surface and Collaborate To Inhibit Transforming Growth Factor β Signaling and Enhance Cell Growth{triangledown}

Gidi Shani, Wolfgang H. Fischer, Nicholas J. Justice, Jonathan A. Kelber, Wylie Vale, and Peter C. Gray*

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

Received 18 September 2007/ Accepted 26 October 2007

Cripto is a multifunctional cell surface protein with important roles in vertebrate embryogenesis and the progression of human tumors. While Cripto has been shown to modulate multiple signaling pathways, its binding partners do not appear to fully explain its molecular actions. Therefore, we conducted a screen aimed at identifying novel Cripto-interacting proteins. This screen led to our identification of glucose-regulated protein 78 (GRP78), an endoplasmic reticulum (ER) chaperone that is also expressed at the surfaces of tumor cells. Here we demonstrate that Cripto and GRP78 interact at the cell surfaces of multiple cell lines and that their interaction is independent of prior association within the ER. Interestingly, short hairpin RNA knockdown of endogenous GRP78 resulted in enhanced transforming growth factor β (TGF-β) signaling, indicating that like Cripto, GRP78 inhibits this pathway. We further show that when coexpressed, GRP78 and Cripto collaborate to antagonize TGF-β responses, including Smad phosphorylation and growth inhibition of prostate cancer cells grown under anchorage-dependent or -independent conditions. Finally, we provide evidence that cells coexpressing GRP78 and Cripto grow much more rapidly in soft agar than do cells expressing either protein individually. Together, our results indicate that these proteins bind at the cell surface to enhance tumor growth via the inhibition of TGF-β signaling.

* Corresponding author. Mailing address: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA, 92037. Phone: (858) 453-4100, ext. 1689. Fax: (858) 552-1546. E-mail: gray{at}salk.edu

{triangledown} Published ahead of print on 8 November 2007.

Molecular and Cellular Biology, January 2008, p. 666-677, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01716-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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