Modeling a Cellular Signaling Pathway: Adventures in Parameter Space

David Clarke

Chemical and Biological Engineering, CU Boulder

Transforming Growth Factor-beta signaling is an important regulator of cellular processes. The principal intracellular mediators of TGF-beta signaling are the Smad proteins, which upon TGF-beta stimulation accumulate in the nucleus and regulate transcription of target genes. To investigate the mechanisms of Smad nuclear accumulation, we developed a simple mathematical model of canonical Smad signaling. The model was built using both published data and our experimentally determined cellular Smad concentrations (isoforms 2, 3, and 4). Ranges of plausible parameter values were found by randomly generating parameter sets and retaining the sets that led to qualitatively correct model outputs. Systematic variation of the parameter values coupled with statistical analysis revealed the importance of parameters affecting the R-Smad phosphorylation and dephosphorylation rates in determining Smad nuclear accumulation. We propose the novel hypothesis that Smad nuclear accumulation is principally determined by differences in the rates of Smad phosphorylation and dephosphorylation.