Mathematical Modeling and Analysis of Crosstalk between MAPK Pathway and Smad-Dependent TGF-β Signal Transduction

Abstract

Broad evidence exists for cross talk between the Mitogen-activated protein kinases (MAPK) pathway and Smad-dependent TGF-β signal transduction. A variety of studies, oftentimes involving different cell types, have identified several potential mechanisms for the crosstalk. However, there is no clear consensus on the actual mechanism(s) responsible for the crosstalk. This work develops a model of the pathway, including several hypothesized crosstalk mechanisms, and discusses which of the potential mechanisms can appropriately describe observed behaviors. Simulation results show a good agreement of the findings with results reported in the literature.

Network Analysis Identifies Crosstalk Interactions Governing TGF-β Signaling Dynamics during Endoderm Differentiation of Human Embryonic Stem Cells

“…Possibility of p-ERK mediated interactions under low PI3K signaling is interesting. It is known that p-ERK has additional roles in linker phosphorylation of SMAD molecules which can affect the nucleo-cytoplasmic shuttling and ultimately their dynamics as modeled by Liu et al in this issue of the journal [56]. This could be the reason for seeing increasing p-ERK influence on SMAD molecules under low PI3K condition in some samples.…”

Effective sampling trajectory optimisation for sensitivity analysis of biological systems

“…transcription factor, which determines cell proliferation or apoptosis. The nominal values and biological interpretations of all uncertain parameters as well as the initial conditions of all molecular species can be found in the literature [31][32][33]. A continuous 2 ng/ml TGF-β stimulation is added for the simulation.…”

“…In this section, we demonstrate the ability of the TOM to study various sensitivity measures and the sensitivity dynamics of a cellular signalling network. As a model problem, we use the mathematical model of the crosstalk between Mitogen‐activated Protein Kinases (MAPK) pathway and Smad‐dependent TGF‐ β (Transforming Growth Factor ) signal transduction pathway from [31]. In [31], the detailed mathematical model on the crosstalk integrates two individual signal pathways and explains two conflicting performances in the experiments.…”

“…As a model problem, we use the mathematical model of the crosstalk between Mitogen‐activated Protein Kinases (MAPK) pathway and Smad‐dependent TGF‐ β (Transforming Growth Factor ) signal transduction pathway from [31]. In [31], the detailed mathematical model on the crosstalk integrates two individual signal pathways and explains two conflicting performances in the experiments. However, only the crosstalk parameters are analysed through the ordinary Morris method to demonstrate two competing effects of MAPK cascade activation depending on the specific cell types.…”

“…Although other works have focused on the crosstalk, there are no mathematical model and consensus mechanisms description for the crosstalk. In [31], a detailed mathematical model on the crosstalk was developed through integrating the MAPK pathway with TGF‐ β /Smad pathway.…”