Cripto is a noncompetitive activin antagonist that forms analogous signaling complexes with activin and nodal.
Cripto plays critical roles during embryogenesis and has been implicated in promoting the growth and spread of tumors. Cripto is required for signaling by certain transforming growth factor-beta superfamily members, such as Nodal, but also antagonizes others, such as activin. The opposing effects of Cripto on Nodal and activin signaling seem contradictory, however, because these closely related ligands utilize the same type I (ALK4) and type II (ActRII/IIB) receptors. Here, we have addressed this apparent paradox by demonstrating that Cripto forms analogous receptor complexes with Nodal and activin and functions as a noncompetitive activin antagonist. Our results show that activin-A and Nodal elicit similar maximal signaling responses in the presence of Cripto that are substantially lower than that of activin-A in the absence of Cripto. In addition, we provide biochemical evidence for complexes containing activin-A, Cripto, and both receptor types and show that the assembly of such complexes is competitively inhibited by Nodal. We further demonstrate that Nodal and activin-A share the same binding site on ActRII and that ALK4 has distinct and separable binding sites for activin-A and Cripto. Finally, we show that ALK4 mutants with disrupted activin-A binding retain Cripto binding and prevent the effects of Cripto on both activin-A and Nodal signaling. Together, our data indicate that Cripto facilitates Nodal signaling and inhibits activin signaling by forming receptor complexes with these ligands that are structurally and functionally similar.
Kelber
Jonathan A
JA
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Shani
Gidi
G
Booker
Evan C
EC
Vale
Wylie W
WW
Gray
Peter C
PC
D029404:Activin Receptors / Q000235:genetics / Q000378:metabolism; D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D028341:Activins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055457:Nodal Protein; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C526007:NODAL protein, human; D009363:Neoplasm Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; C070636:TDGF1 protein, human; C489450:Tdgf1 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C096788:tdgf1.3 protein, Xenopus; D028341:Activins; D004815:Epidermal Growth Factor; C498932:ACVR1B protein, human; D029404:Activin Receptors; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498933:Acvr1b protein, mouse; C425584:activin receptor type II-B; C481805:acvr1b protein, Xenopus