Central role of phosphorylation in the circadian control of liver metabolism

Circadian clocks are endogenous oscillators that drive organismal metabolism and physiology. Here, we report the first global in vivo quantification of circadian phosphorylation rhythms in mammals. Of more than 20,000 in vivo phosphosites, 25% significantly oscillate in the mouse liver, including novel sites on core clock proteins. Analyzing kinase substrate motifs, we find that the EGF/RAS/ERK pathway is predominantly activated during the day and the AKT/mTOR/p70S6K at night. The extent and amplitude of phosphorylation cycles dominate the rhythms of transcript and protein abundance. A dominant regulatory role for phosphorylation-dependent circadian tuning of signaling pathways allows the organism to rapidly and economically respond to daily changes in nutrient availability and integrate different signaling triggers.