摘要：SummaryIntegration of transforming growth factor β (TGF-β) 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-β transcriptional mediators, Smads, to control Smad activity. Key to TGF-β 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-β cross talk. The models were based on experimental measurements of TGF-β-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-β receptor activity and directly or indirectly act as nuclear retention factors.Graphical AbstractDisplay OmittedHighlights•Taz/Yap modulate TGF-β-induced nuclear accumulation of Smad2/3 and Smad4•TGF-β does not affect Taz/Yap localization when Hippo activity is constant•Taz/Yap loss may alter activity of both Receptor and Smad nuclear retention factors•The mediator complex regulates Smad nuclear accumulationBiological Sciences; Cell Biology; Computational Bioinformatics; Integrative Aspects of Cell Biology; Molecular Network
