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Journal Article

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

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Hammerschmidt,  Matthias
Georges Köhler Laboratory, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Bai, R.-Y., Koester, C., Ouyang, T., Hahn, S. A., Hammerschmidt, M., Peschel, C., et al. (2002). SMIF, a Smad4-interacting protein that functions as a co- activator in TGFβ signalling. Nature Cell Biology, 4(3), 181-190.


Cite as: https://hdl.handle.net/11858/00-001M-0000-002B-965D-5
Abstract
Proteins of the transforming growth factor β (TGFβ) superfamily regulate diverse cellular responses, including cell growth and differentiation. After TGFβ 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 TGFβ/bone morphogenetic protein 4 (BMP4)-inducible complex with Smad4, but not with others Smads, and translocates to the nucleus in a TGFβ/BMP4-inducible and Smad4-dependent manner. SMIF possesses strong intrinsic TGFβ-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 TGFβ/BMP regulated genes, whereas a dominant-negative SMIF mutant suppressed expression. Furthermore, dominant-negative SMIF is able to block TGFβ-induced growth inhibition. In a knockdown approach with morpholinoantisense oligonucleotides targeting zebrafish SMIF, severe but distinct phenotypic defects were observed in zebrafish embryos. Thus, we propose that SMIF is a crucial activator of TGFβ signalling.