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Molecular and Cellular Biology, April 2002, p. 2586-2597, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2586-2597.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cripto-1 Activates Nodal- and ALK4-Dependent and -Independent Signaling Pathways in Mammary Epithelial Cells

Tumor Growth Factor Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,¹ Department of Bioscience and Biotechnology, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan,³ Oncologia Sperimentale D, ITN-Fondazione Pascale, 80131 Naples, Italy,⁴ Department of Biological Science, Hampton University, Hampton, Virginia 23668,⁵ Department of Obstetrics and Gynecology, Free University of Berlin, Berlin, Germany,⁶ Biogen Inc., Cambridge, Massachusetts 02142²

Received 24 August 2001/ Returned for modification 19 October 2001/ Accepted 15 January 2002

Cripto-1 (CR-1), an epidermal growth factor-CFC (EGF-CFC) family member, has a demonstrated role in embryogenesis and mammary gland development and is overexpressed in several human tumors. Recently, EGF-CFC proteins were implicated as essential signaling cofactors for Nodal, a transforming growth factor ß family member whose expression has previously been defined as embryo specific. To identify a receptor for CR-1, a human brain cDNA phage display library was screened using CR-1 protein as bait. Phage inserts with identity to ALK4, a type I serine/threonine kinase receptor for Activin, were identified. CR-1 binds to cell surface ALK4 expressed on mammalian epithelial cells in fluorescence-activated cell sorter analysis, as well as by coimmunoprecipitation. Nodal is coexpressed with mouse Cr-1 in the mammary gland, and CR-1 can phosphorylate the transcription factor Smad-2 in EpH-4 mammary epithelial cells only in the presence of Nodal and ALK4. In contrast, CR-1 stimulation of mitogen-activated protein kinase and AKT in these cells is independent of Nodal and ALK4, suggesting that CR-1 may modulate different signaling pathways to mediate its different functional roles.

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