Abstract
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 beta 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type I / genetics
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Activin Receptors, Type I / metabolism*
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Activin Receptors, Type II / genetics
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Activin Receptors, Type II / metabolism
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Animals
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Epidermal Growth Factor*
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Epithelial Cells / metabolism
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GPI-Linked Proteins
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Gene Expression Regulation
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Genes, Reporter
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Humans
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Intercellular Signaling Peptides and Proteins
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Kinetics
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Luciferases / genetics
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Mammary Glands, Animal / cytology
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Mammary Glands, Animal / growth & development
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Mammary Glands, Animal / metabolism*
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Membrane Glycoproteins*
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Mice
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nodal Protein
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Peptide Library
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Protein Binding
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Proteins*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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Smad2 Protein
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
Substances
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DNA-Binding Proteins
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GPI-Linked Proteins
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Intercellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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NODAL protein, human
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Neoplasm Proteins
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Nodal Protein
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Nodal protein, mouse
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Peptide Library
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Proteins
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Recombinant Fusion Proteins
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SMAD2 protein, human
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Smad2 Protein
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Smad2 protein, mouse
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TDGF1 protein, human
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Tdgf1 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta
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Epidermal Growth Factor
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Luciferases
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ACVR1B protein, human
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Activin Receptors, Type I
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Activin Receptors, Type II
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Acvr1b protein, mouse
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activin receptor type II-B