Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells

Mol Cell Biol. 2002 Apr;22(8):2586-97. doi: 10.1128/MCB.22.8.2586-2597.2002.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism*
  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / metabolism
  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epidermal Growth Factor*
  • Epithelial Cells / metabolism
  • GPI-Linked Proteins
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Kinetics
  • Luciferases / genetics
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / metabolism*
  • Membrane Glycoproteins*
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nodal Protein
  • Peptide Library
  • Protein Binding
  • Proteins*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Smad2 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • DNA-Binding Proteins
  • GPI-Linked Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NODAL protein, human
  • Neoplasm Proteins
  • Nodal Protein
  • Nodal protein, mouse
  • Peptide Library
  • Proteins
  • Recombinant Fusion Proteins
  • SMAD2 protein, human
  • Smad2 Protein
  • Smad2 protein, mouse
  • TDGF1 protein, human
  • Tdgf1 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Epidermal Growth Factor
  • Luciferases
  • ACVR1B protein, human
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvr1b protein, mouse
  • activin receptor type II-B