Analysis of the Core Architecture Regulating TGFβ Induced EMT

Transforming growth factor β (TGFβ) has been shown as a potent inducer of epithelial to mesenchymal transition (EMT) in both embryonic and pathological conditions. The complexity of TGFβ signaling is overwhelming due to the large numbers of interacting protein complexes, complicated feedback mechanisms, and crosstalk between multiple signaling pathways. As a result, even understanding the fundamental regulation of cell specific markers remains difficult. Systems biology has been suggested as an essential tool for understanding the orchestration of EMT and omission of such a critical contributor may lead to an inaccurate understanding. Thus, we modeled the molecular interactions of TGFβ induced EMT using mass action kinetics within an ordinary differential equation (ODE) based framework. 2695 unknown model parameters (1700 kinetic constants and 995 non-zero initial conditions) were estimated using 41 steady-state experimental data sets taken from literature sources. Using POETs we implemented a population based approach to identify different opera tional paradigms within EMT. Using signal flow, sensitivity, and robustness analysis, our model suggested three important levels of regulation. The differential role of AP1/SP1, selective de-phosphorylation of the MAPK/ERK cascade, and the availability of LEF1. These results provide insight into the core molecular architecture of TGFβ induced EMT and reveal possible transformational aspects between cellular phenotype.

Figure: Schematic overview of the interaction network used in modeling the TGFβ induced EMT phenomenon. The model describes activation of the MAPK cascade through TGFβ2 followed by and autocrine response of TGFβ3 stimulating the Smad cascade. Cross-talk between MAPK and Smads has been shown at both the cytosolic and nuclear levels.