ZFIN ID: ZDB-PUB-020220-11
SMIF, a Smad4-interacting protein that functions as a co-activator in TGFbold beta signalling
Bai, R.Y., Koester, C., Ouyang, T., Hahn, S.A., Hammerschmidt, M., Peschel, C., and Duyster, J.
Date: 2002
Source: Nature cell biology   4(3): 181-190 (Journal)
Registered Authors: Hammerschmidt, Matthias
Keywords: none
MeSH Terms:
  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Animals
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins/metabolism
  • Cell Line
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/metabolism*
  • Drosophila/genetics
  • Endoribonucleases
  • Gene Targeting
  • Humans
  • Mice
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides, Antisense/genetics
  • Oligodeoxyribonucleotides, Antisense/pharmacology
  • Point Mutation
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Smad4 Protein
  • Trans-Activators/genetics*
  • Trans-Activators/metabolism*
  • Transforming Growth Factor beta/metabolism*
  • Two-Hybrid System Techniques
  • Zebrafish/abnormalities
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism*
PubMed: 11836524 Full text @ Nat. Cell Biol.
Proteins of the transforming growth factor [beta](TGF[beta]) superfamily regulate diverse cellular responses, including cell growth and differentiation. After TGF[beta] stimulation, receptor-associated Smads are phosphorylated and form a complex with the common mediator Smad4. Here, we report the cloning of SMIF, a ubiquitously expressed, Smad4-interacting transcriptional co-activator. SMIF forms a TGF[beta]/bone morphogenetic protein 4 (BMP4)-inducible complex with Smad4, but not with others Smads, and translocates to the nucleus in a TGF[beta]/BMP4-inducible and Smad4-dependent manner. SMIF possesses strong intrinsic TGF[beta]-inducible transcriptional activity, which is dependent on Smad4 in mammalian cells and requires p300/CBP. A point mutation in Smad4 abolished binding to SMIF and impaired its activity in transcriptional assays. Overexpression of wild-type SMIF enhanced expression of TGF[beta]/BMP regulated genes, whereas a dominant-negative SMIF mutant suppressed expression. Furthermore, dominant-negative SMIF is able to block TGF[beta]-induced growth inhibition. In a knockdown approach with morpholino-antisense oligonucleotides targeting zebrafish SMIF, severe but distinct phenotypic defects were observed in zebrafish embryos. Thus, we propose that SMIF is a crucial activator of TGF[beta] signalling.