SMIF, a Smad4-interacting protein that functions as a co-activator in TGFbeta signalling.

Proteins of the transforming growth factor beta(TGFbeta) superfamily regulate diverse cellular responses, including cell growth and differentiation. After TGFbeta 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 TGFbeta/bone ...
morphogenetic protein 4 (BMP4)-inducible complex with Smad4, but not with others Smads, and translocates to the nucleus in a TGFbeta/BMP4-inducible and Smad4-dependent manner. SMIF possesses strong intrinsic TGFbeta-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 TGFbeta/BMP regulated genes, whereas a dominant-negative SMIF mutant suppressed expression. Furthermore, dominant-negative SMIF is able to block TGFbeta-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 TGFbeta signalling.
Mesh Terms:
Active Transport, Cell Nucleus, Amino Acid Sequence, Animals, Bone Morphogenetic Protein 4, Bone Morphogenetic Proteins, Cell Line, DNA-Binding Proteins, Drosophila, Endoribonucleases, Gene Targeting, Humans, Mice, Molecular Sequence Data, Oligodeoxyribonucleotides, Antisense, Point Mutation, Sequence Homology, Amino Acid, Signal Transduction, Smad4 Protein, Trans-Activators, Transforming Growth Factor beta, Two-Hybrid System Techniques, Zebrafish, Zebrafish Proteins
Nat. Cell Biol.
Date: Mar. 01, 2002
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