Silencing of TGF-beta signalling by the pseudoreceptor BAMBI.
Members of the transforming growth factor-beta (TGF-beta) superfamily, including TGF-beta, bone morphogenetic proteins (BMPs), activins and nodals, are vital for regulating growth and differentiation. These growth factors transduce their signals through pairs of transmembrane type I and type II receptor kinases. Here, we have cloned a transmembrane protein, BAMBI, which is related to TGF-beta-family type I receptors but lacks an intracellular kinase domain. We show that BAMBI is co-expressed with the ventralizing morphogen BMP4 (refs 5, 6) during Xenopus embryogenesis and that it requires BMP signalling for its expression. The protein stably associates with TGF-beta-family receptors and inhibits BMP and activin as well as TGF-beta signalling. Finally, we provide evidence that BAMBI's inhibitory effects are mediated by its intracellular domain, which resembles the homodimerization interface of a type I receptor and prevents the formation of receptor complexes. The results indicate that BAMBI negatively regulates TGF-beta-family signalling by a regulatory mechanism involving the interaction of signalling receptors with a pseudoreceptor.
Onichtchouk
D
D
Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Chen
Y G
YG
Dosch
R
R
Gawantka
V
V
Delius
H
H
Massagué
J
J
Niehrs
C
C
D028341:Activins; D000595:Amino Acid Sequence; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019556:COS Cells; D046508:Culture Techniques; D004625:Embryo, Nonmammalian / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007265:Inhibins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry; D017978:Receptors, Growth Factor / Q000737:chemistry; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D017385:Sequence Homology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014981:Xenopus; D029867:Xenopus Proteins
C485671:BAMBI protein, human; C525809:BMP4 protein, human; C485672:Bambi protein, mouse; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D008024:Ligands; D008565:Membrane Proteins; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C121859:bambi-A protein, Xenopus; C525812:bmp4 protein, Xenopus; D028341:Activins; D007265:Inhibins; D017346:Protein Serine-Threonine Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I