Cripto-1 activates Nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial cells

Caterina Bianco, Heather B. Adkins, Christian Wechselberger, Masaharu Seno, Nicola Normanno, Antonella De Luca, Youping Sun, Nadia Khan, Nicholas Kenney, Andreas Ebert, Kevin P. Williams, Michele Sanicola, David S. Salomon

Research output: Contribution to journalArticlepeer-review

126 Citations (Scopus)


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 β 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.

Original languageEnglish
Pages (from-to)2586-2597
Number of pages12
JournalMolecular and Cellular Biology
Issue number8
Publication statusPublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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