Abstract
Nodal ligands are essential for the patterning of chordate embryos. Genetic evidence indicates that EGF-CFC factors are required for Nodal signaling, but the molecular basis for this requirement is unknown. We have investigated the role of Cripto, an EGF-CFC factor, in Nodal signaling. We find that Cripto interacts with the type I receptor ALK4 via the conserved CFC motif in Cripto. Cripto interaction with ALK4 is necessary both for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal. We also find that Nodal can inhibit BMP signaling by a Cripto-independent mechanism. Inhibition appears to be mediated by heterodimerization between Nodal and BMPs, indicating that antagonism between Nodal and BMPs can occur at the level of dimeric ligand production.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activin Receptors, Type I
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Animals
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Bone Morphogenetic Protein 7
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Bone Morphogenetic Proteins / metabolism
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Conserved Sequence
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DNA-Binding Proteins / metabolism*
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DNA-Binding Proteins / physiology
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Embryo, Mammalian
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Embryo, Nonmammalian
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Epidermal Growth Factor*
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GPI-Linked Proteins
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Homeodomain Proteins*
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Injections
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Intercellular Signaling Peptides and Proteins
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Ligands
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Membrane Glycoproteins*
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Membrane Proteins
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Mice
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Neoplasm Proteins / metabolism
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Neoplasm Proteins / pharmacology*
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Neoplasm Proteins / physiology
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Nodal Protein
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Phosphorylation / drug effects
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Protein Binding / genetics
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RNA, Messenger / administration & dosage
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RNA, Messenger / genetics
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Receptors, Growth Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Smad2 Protein
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Trans-Activators / metabolism*
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Trans-Activators / physiology
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Transcription Factors*
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta / physiology
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Xenopus / genetics
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Xenopus Proteins*
Substances
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Bone Morphogenetic Protein 7
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Bone Morphogenetic Proteins
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DNA-Binding Proteins
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GPI-Linked Proteins
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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Ligands
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Membrane Glycoproteins
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Membrane Proteins
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Neoplasm Proteins
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Nodal Protein
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Nodal protein, mouse
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RNA, Messenger
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Receptors, Growth Factor
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Smad2 Protein
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Smad2 protein, Xenopus
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Smad2 protein, mouse
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Tdgf1 protein, mouse
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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Xenopus Proteins
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bmp7.1 protein, Xenopus
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tdgf1.3 protein, Xenopus
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Epidermal Growth Factor
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Activin Receptors, Type I