Research ArticleSystems Biology

Network-level effects of kinase inhibitors modulate TNF-α–induced apoptosis in the intestinal epithelium

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Sci. Signal.  15 Dec 2015:
Vol. 8, Issue 407, pp. ra129
DOI: 10.1126/scisignal.aac7235

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Rewired for death

The proinflammatory cytokine tumor necrosis factor–α (TNF-α) stimulates various kinases and can trigger cell death. Gierut et al. analyzed the kinetics of the phosphorylation of signaling proteins and the of induction of cell death in the intestinal epithelium of mice pretreated with various kinase inhibitors and then administered TNF-α. Unexpectedly, inhibitors that targeted the same kinase with equal efficiencies had different effects on TNF-α–induced apoptosis. For example, an inhibitor of a kinase enhanced cell death, whereas other inhibitors targeting this kinase reduced cell death. Mathematical analysis of the data predicted, and in vivo experiments confirmed, that the kinase Akt, which usually promotes cell survival, increased TNF-α–induced apoptosis when the network had been altered by the death-enhancing inhibitor. Together, these data illustrate that network context is just as important as drug target when predicting the response to an inhibitor.

Abstract

Individual signaling pathways operate in the context of the broader signaling network. Thus, the response of a cell to signals from the environment is affected by the state of the signaling network, such as the clinically relevant example of whether some components in the network are inhibited. The cytokine tumor necrosis factor–α (TNF-α) promotes opposing cellular behaviors under different conditions; the outcome is influenced by the state of the network. For example, in the mouse intestinal epithelium, inhibition of the mitogen-activated protein kinase (MAPK) kinase MEK alters the timing of TNF-α–induced apoptosis. We investigated whether MAPK signaling directly influences TNF-α–induced apoptosis or whether network-level effects secondary to inhibition of the MAPK pathway alter the cellular response. We found that inhibitors of the MAPK kinase kinase Raf, MEK, or extracellular signal–regulated kinase (ERK) exerted distinct effects on the timing and magnitude of TNF-α–induced apoptosis in the mouse intestine. Furthermore, even different MEK inhibitors exerted distinct effects; one, CH5126766, potentiated TNF-α–induced apoptosis, and the others reduced cell death. Computational modeling and experimental perturbation identified the kinase Akt as the primary signaling node that enhanced apoptosis in the context of TNF-α signaling in the presence of CH5126766. Our work emphasizes the importance of integrated network signaling in specifying cellular behavior in response to experimental or therapeutic manipulation. More broadly, this study highlighted the importance of considering the network-level effects of pathway inhibitors and showed the distinct effects of inhibitors that share the same target.

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