Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor.
Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. Here we report the existence of a natural inhibitor of this process, Smad6, a longer version of the previously reported JV15-1. In Xenopus embryos and in mammalian cells, Smad6 specifically blocks signaling by the BMP/Smad1 pathway. Smad6 inhibits BMP/Smad1 signaling without interfering with receptor-mediated phosphorylation of Smad1. Smad6 specifically competes with Smad4 for binding to receptor-activated Smad1, yielding an apparently inactive Smad1-Smad6 complex. Therefore, Smad6 selectively antagonizes BMP-activated Smad1 by acting as a Smad4 decoy.
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Cell Biology Program, Howard Hughes Medical Institute and The Sloan-Kettering Division of the Cornell University Graduate School of Medical Sciences, Memorial Sloan-Kettering Cancer Center, The Rockefeller University, New York, NY 10021, USA.
Lagna
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Massagué
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Hemmati-Brivanlou
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D000595:Amino Acid Sequence; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D019556:COS Cells; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D004475:Ectoderm / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors; D011956:Receptors, Cell Surface / Q000502:physiology; D017978:Receptors, Growth Factor; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D051905:Smad6 Protein; D015534:Trans-Activators / Q000502:physiology; D014162:Transfection; D014981:Xenopus; D029867:Xenopus Proteins
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C497402:MXD1 protein, Xenopus; D009414:Nerve Growth Factors; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; C497399:SMAD1 protein, human; C497796:SMAD4 protein, human; C497802:SMAD6 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D051905:Smad6 Protein; C497805:Smad6 protein, Xenopus; D015534:Trans-Activators; D029867:Xenopus Proteins; C490808:smad4.1 protein, Xenopus; C117263:smad4.2 protein, Xenopus; D052004:Bone Morphogenetic Protein Receptors