A mathematical model of the stoichiometric control of Smad complex formation in TGF-beta signal transduction pathway.

Cell fate in multicellular organism is regulated by the diffusible factor from surrounding cells in concentration-dependent manner. TGF-beta is a large protein family of the diffusible proteins secreted from a localized source. The signal of TGF-beta is transduced by Smad family transcription factor. Though it is well known that the stoichiometry of Smads in the transcriptional complex regulates the specificity of target genes of TGF-beta signal, little is known what the stoichiometry of Smads in the transcriptional complex is determined in TGF-beta signal transduction in concentration-dependent manner. To investigate the dynamics of Smad complex formation, we construct a two-compartment model for Smad complex formation in TGF-beta signal transduction. A simplified one-way oligomerization model, which ignores dissociation and well appropriate the full model under high expression levels of R- and Co-Smad, is constructed to analytically investigate the effect of the oligomerization of Smad. Our one-way model reveals that not only shuttling of the Smad from the cytoplasm to the nucleus but also the preferential accumulation of the heteromeric complex in oligomerization can contribute to the predominant production of the heteromeric complex of Smad including both R- and Co-Smad. It is also shown that oligomerization of Smad can contribute to the specificity of signal transduction. In endothelial cells, both Smad-1/5/8 and -2/3 pathways are activated by TGF-beta. The difference of the activity between the two pathways is amplified by trimerization but not by dimerization, suggesting possible importance of trimerization in maintaining the specificity of signal transduction.