Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor

Genes Dev. 1998 Jan 15;12(2):186-97. doi: 10.1101/gad.12.2.186.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bone Morphogenetic Protein Receptors
  • Bone Morphogenetic Proteins / antagonists & inhibitors
  • COS Cells
  • Cells, Cultured
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Ectoderm / physiology
  • Genes, Tumor Suppressor / physiology
  • Humans
  • Immunoblotting
  • Molecular Sequence Data
  • Nerve Growth Factors
  • Receptors, Cell Surface / physiology
  • Receptors, Growth Factor*
  • Signal Transduction / genetics
  • Smad Proteins
  • Smad1 Protein
  • Smad4 Protein
  • Smad6 Protein
  • Trans-Activators / physiology
  • Transfection
  • Xenopus
  • Xenopus Proteins*


  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • MXD1 protein, Xenopus
  • Nerve Growth Factors
  • Receptors, Cell Surface
  • Receptors, Growth Factor
  • SMAD1 protein, human
  • SMAD4 protein, human
  • SMAD6 protein, human
  • Smad Proteins
  • Smad1 Protein
  • Smad4 Protein
  • Smad6 Protein
  • Smad6 protein, Xenopus
  • Trans-Activators
  • Xenopus Proteins
  • smad4.1 protein, Xenopus
  • smad4.2 protein, Xenopus
  • Bone Morphogenetic Protein Receptors