Research ArticleSystems Biology

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

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

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.

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