Crosstalk and Signaling Switches in Mitogen-Activated Protein Kinase Cascades

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.

Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients

“…Computational modelling has already provided an understanding of the dynamics of signaling pathways (16,(52)(53)(54). Here, we showed that modelling approaches can not only be used to decipher and understand the behavior of complex networks on the cellular level but that they also can be used to relate biochemical pathway behavior to clinical outcomes on the level of individual patients.…”

Control of the G-protein cascade dynamics by GDP dissociation inhibitors

“…Complex dynamic behaviors emerge in these signaling systems, including all-or-none responses and hysteresis driving specific cell fate decisions, for instance, the synchronization of oscillators in the circadian rhythm and the encoding of information in the frequency of p53 pulses during the DNA damage response. 8,[49][50][51] Although the signal processing functions of many cellular systems, for instance kinase/phosphatase cascades, are well recognized [52][53][54] , a detailed understanding of small GTPase networks is largely missing. It is known that GTPase cascades can exhibit complex spatiotemporal dynamics, but how the cell controls the different dynamic behaviors and how GDIs are involved in this regulation is largely unknown.…”

PME-1 Modulates Protein Phosphatase 2A Activity to Promote the Malignant Phenotype of Endometrial Cancer Cells

“…Specific heterotrimers dephosphorylate and stabilize tumor suppressors, such as p53 (5,6) and p107 (7); thus, PP2A activity is important in cell-cycle regulation and tumor suppression. PP2A has been shown to dephosphorylate positive regulators of cell signaling pathways such as ERK and Akt (8)(9)(10)(11), inhibiting them and promoting senescence or apoptosis. Inhibition of PP2A promotes enhanced cell proliferation, impairment of cell differentiation, malignant cell transformation (reviewed in refs.…”