A Protein Turnover Signaling Motif Controls the Stimulus-Sensitivity of Stress Response Pathways

作者：Loriaux Paul Michael; Hoffmann Alexander^*

来源：PLoS Computational Biology, 2013, 9(2): e1002932.

DOI：10.1371/journal.pcbi.1002932

Stimulus-induced perturbations from the steady state are a hallmark of signal transduction. In some signaling modules, the steady state is characterized by rapid synthesis and degradation of signaling proteins. Conspicuous among these are the p53 tumor suppressor, its negative regulator Mdm2, and the negative feedback regulator of NF kappa B, I kappa B alpha. We investigated the physiological importance of this turnover, or flux, using a computational method that allows flux to be systematically altered independently of the steady state protein abundances. Applying our method to a prototypical signaling module, we show that flux can precisely control the dynamic response to perturbation. Next, we applied our method to experimentally validated models of p53 and NF kappa B signaling. We find that high p53 flux is required for oscillations in response to a saturating dose of ionizing radiation (IR). In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR. In the NF kappa B system, degradation of NF kappa B-bound I kappa B by the I kappa B kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF. Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFkB stress-response pathways, and may constitute a general design principle in signaling pathways.

• 出版日期2013-2