Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms.
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.
Yeo
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C
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Whitman
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M
D030201:Activin Receptors, Type I; D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D004815:Epidermal Growth Factor; D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins; D007267:Injections; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D055457:Nodal Protein; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000008:administration & dosage / Q000235:genetics; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D014981:Xenopus / Q000235:genetics; D029867:Xenopus Proteins
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; C497783:Smad2 protein, mouse; C489450:Tdgf1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C525822:bmp7.1 protein, Xenopus; C096788:tdgf1.3 protein, Xenopus; D004815:Epidermal Growth Factor; D030201:Activin Receptors, Type I