Signaling properties in MAPK cycle are modulated by its
downstream substrates
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The Mitogen Activated Protein Kinase (MAPK) is a three-tiered cascade of phosphorylation-dephosphorylation cycles and plays a pivotal role in many aspects of biological processes. Recently, two experimental studies in yeast and in Drosophila embryo suggested that phosphorylation and spatial localization of MAPK can be influenced by the level of its downstream substrates. However, the mechanism through which these substrates control properties of MAPK signaling has been unclear. Here we propose a mass-action kinetic model of MAPK cycle with a substrate, and demonstrate that the substrate can modulate the dynamics of MAPK cycle by directly interacting with MAPK. In the model, the substrate can bind to both unphosphorylated and phosphorylated MAPK, and dissociation constants between the substrate and MAPK determine the degree of substrate anchoring to MAPK in the equilibrium state. We found that the adding the substrate controls the level of MAPK phosphorylation positively or negatively, depending on the balance of dissociation constants between the substrate and MAPK as well as the properties of MAPK cyclic signaling in the absence of the substrate. In addition, by considering nuclear and cytoplasmic compartments, we show that nuclear specific substrates can lead to nuclear accumulation of MAPK, suggesting that these substrates can act as a nuclear anchor of MAPK. Our model gives a possible mechanism that can account for previously unexplained phenomenon of MAPK substrates mediated modulation of MAPK signaling. |
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