Our model facilitates understanding of how cancerous deregulations disturb MAPK signal processing and provides explanations for certain drug resistances. Finally, AKT activation inhibits the JNK positive feedback, thus abrogating the apoptotic switch and allowing only proliferative signaling. Activation of p38 restores the threshold by inhibiting ERK activity via the PP1 or PP2A phosphatases. ERK activation enhances the dual specificity phosphatase (DUSP) mediated dephosphorylation of JNK and shifts the threshold of the apoptotic switch to higher inputs. The switch is modulated by the ERK, p38, and AKT pathways. Once activated, positive feedback locks JNK in a highly active state and promotes cell death. We show that JNK can switch from a transient to sustained activity due to multiple positive feedback loops. Focusing on the bistable activation characteristics of the JNK pathway, this model explains how pathway crosstalk harmonizes different MAPK responses resulting in pivotal cell fate decisions. Here, we develop a dynamic model of feedback and crosstalk for the three major MAPK cascades extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase (JNK), and also include input from protein kinase B (AKT) signaling. This implies that signaling by each individual MAPK cascade has to be considered in the context of the entire MAPK network. However, similar MAPK kinetic profiles can be associated with opposing cellular decisions depending on cell type, signal strength, and dynamics. Mitogen-activated protein kinase (MAPK) cascades control cell fate decisions, such as proliferation, differentiation, and apoptosis by integrating and processing intra- and extracellular cues. Systems Biology Ireland, University College Dublin, Dublin, Ireland.
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