Smad6 functions as an intracellular antagonist of some TGF-beta family members during Xenopus embryogenesis

Genes Cells. 1998 Jun;3(6):387-94. doi: 10.1046/j.1365-2443.1998.00196.x.

Abstract

Background: Bone morphogenetic proteins (BMPs) transmit signals via the intracellular protein Smad1, which is phosphorylated by ligand bound receptors, translocates to the nucleus, and functions to activate BMP target genes. Recently, a subclass of Smad proteins has been shown to inhibit, rather than transduce, BMP signalling, either by binding to the intracellular domain of BMP receptors, thereby preventing phosphorylation-mediated activation of Smad1, or by binding directly to Smad1, thereby inhibiting its ability to activate gene transcription.

Results: We have identified a Xenopus Smad (Smad6) that is 52% identical to mammalian Smad6, an inhibitory Smad. The spatial pattern of expression of Smad6 changes dynamically during embryogenesis and is similar to that of BMP-4 at the tailbud stage. Overexpression of Smad6 in Xenopus embryos phenocopies the effect of blocking BMP-4 signalling, leading to dorsalization of mesoderm and neuralization of ectoderm. Xenopus Smad6 completely blocks the activity of exogenous BMP-4, and, unlike human Smad6, partially blocks the activity of activin, in a mesoderm induction assay. We also find that Smad6 protein accumulates at the membrane in some cells but is partially or completely restricted to nuclei of most overexpressing cells.

Conclusions: We have identified an inhibitory Xenopus Smad, Smad6, that functions as an intracellular antagonist of activin and BMP-4 signalling. Our finding that Smad6 protein is partially or completely restricted to nuclei of most overexpressing cells suggests that it may employ a novel or additional mechanism of action to antagonize TGF-beta family signalling other than that reported for other inhibitory Smads.

Publication types

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

MeSH terms

  • Activins
  • Amino Acid Sequence
  • Animals
  • Body Patterning / physiology
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins / pharmacology
  • Cloning, Molecular
  • DNA, Complementary / chemistry
  • DNA, Complementary / genetics
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Embryo, Nonmammalian / chemistry
  • Embryonic Induction / drug effects
  • Embryonic Induction / genetics
  • Embryonic Induction / physiology
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Immunohistochemistry
  • In Situ Hybridization
  • Inhibins / pharmacology
  • Mesoderm / drug effects
  • Mesoderm / physiology
  • Molecular Sequence Data
  • Nervous System / embryology
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Smad6 Protein
  • Trans-Activators / analysis
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Xenopus / embryology*
  • Xenopus / genetics*
  • Xenopus Proteins

Substances

  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • DNA, Complementary
  • DNA-Binding Proteins
  • Smad6 Protein
  • Smad6 protein, Xenopus
  • Trans-Activators
  • Transforming Growth Factor beta
  • Xenopus Proteins
  • bmp4 protein, Xenopus
  • Activins
  • Inhibins

Associated data

  • GENBANK/AF041839