Bai, R.Y., Koester, C., Ouyang, T., Hahn, S.A., Hammerschmidt, M., Peschel, C., and Duyster, J. (2002) SMIF, a Smad4-interacting protein that functions as a co-activator in TGFbold beta signalling. Nature cell biology. 4(3):181-190.
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.