Abstract
Mitogen-activated protein kinase (MAPK) cascades control cell fate decisions, such as proliferation, differentiation, and apoptosis by integrating and processing intra- and extracellular cues. However, similar MAPK kinetic profiles can be associated with opposing cellular decisions depending on cell type, signal strength, and dynamics. This implies that signaling by each individual MAPK cascade has to be considered in the context of the entire MAPK network. 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. 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. We show that JNK can switch from a transient to sustained activity due to multiple positive feedback loops. Once activated, positive feedback locks JNK in a highly active state and promotes cell death. The switch is modulated by the ERK, p38, and AKT pathways. ERK activation enhances the dual specificity phosphatase (DUSP) mediated dephosphorylation of JNK and shifts the threshold of the apoptotic switch to higher inputs. Activation of p38 restores the threshold by inhibiting ERK activity via the PP1 or PP2A phosphatases. Finally, AKT activation inhibits the JNK positive feedback, thus abrogating the apoptotic switch and allowing only proliferative signaling. Our model facilitates understanding of how cancerous deregulations disturb MAPK signal processing and provides explanations for certain drug resistances. We highlight a critical role of DUSP1 and DUSP2 expression patterns in facilitating the switching of JNK activity and show how oncogene induced ERK hyperactivity prevents the normal apoptotic switch explaining the failure of certain drugs to induce apoptosis.
Highlights
A hallmark of cancer is dysregulation of pivotal cell fate decisions leading to aberrant proliferation and reduced apoptosis (Hanahan and Weinberg, 2011)
We show that Jun N-terminal kinase (JNK) can switch from a transient to sustained activity due to multiple positive feedback loops
We present a dynamic model of multiple Mitogen-activated protein kinase (MAPK) cascade interactions featuring a JNK positive feedback loop that generates a proliferative-apoptotic switch
Summary
A hallmark of cancer is dysregulation of pivotal cell fate decisions leading to aberrant proliferation and reduced apoptosis (Hanahan and Weinberg, 2011). A particular cell fate cannot be attributed to the activity of a single protein in isolation, but rather depends on the context, including the temporal patterns of activation and the regulatory feedback structures within the signaling network (Kholodenko, 2006; Kholodenko et al, 2010; Nakakuki et al, 2010). Because of this complexity, the function of cellular signaling often eludes a naive intuitive understanding, calling for the use of mathematical modeling and analysis (Kitano, 2002, 2010; Ireton et al, 2009). Whereas others approach the problem from a less mechanistic viewpoint using regression (Miller-Jensen et al, 2007) or Boolean and semi-logic models (Saez-Rodriguez et al, 2009, 2011), we focus on dynamic models using ordinary differential equations
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