Modeling the Control of TGF-ß/Smad Nuclear Accumulation by the Hippo Pathway Effectors, Taz/Yap.

ABSTRACT

Integration of transforming growth factor ß (TGF-ß) signals with those of other pathways allows for precise temporal and spatial control of gene expression patterns that drive development and homeostasis. The Hippo pathway nuclear effectors, Taz/Yap, interact with the TGF-ß transcriptional mediators, Smads, to control Smad activity. Key to TGF-ß signaling is the nuclear localization of Smads. Thus, to investigate the role of Taz/Yap in Smad nuclear accumulation, we developed mathematical models of Hippo and TGF-ß cross talk. The models were based on experimental measurements of TGF-ß-induced changes in Taz/Yap and Smad subcellular localization obtained using high-throughput immunofluorescence (IF) imaging in the mouse mammary epithelial cell line, EpH4. Bayesian MCMC DREAM parameter estimation was used to quantify the uncertainty in estimates of the kinetic parameters. Variation of the model parameters and statistical analysis show that our modeling predicts that Taz/Yap can alter TGF-ß receptor activity and directly or indirectly act as nuclear retention factors.