Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells.
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.
Bianco
Caterina
C
Tumor Growth Factor Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Adkins
Heather B
HB
Wechselberger
Christian
C
Seno
Masaharu
M
Normanno
Nicola
N
De Luca
Antonella
A
Sun
Youping
Y
Khan
Nadia
N
Kenney
Nicholas
N
Ebert
Andreas
A
Williams
Kevin P
KP
Sanicola
Michele
M
Salomon
David S
DS
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor; D004847:Epithelial Cells / Q000378:metabolism; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008562:Membrane Glycoproteins; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D055457:Nodal Protein; D019151:Peptide Library; D011485:Protein Binding; D011506:Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C526007:NODAL protein, human; D009363:Neoplasm Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D019151:Peptide Library; D011506:Proteins; D011993:Recombinant Fusion Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C070636:TDGF1 protein, human; C489450:Tdgf1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D008156:Luciferases; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498933:Acvr1b protein, mouse; C425584:activin receptor type II-B