Phosphorylation Is a Central Mechanism for Circadian Control of Metabolism and Physiology

Cell Metab. 2017 Jan 10;25(1):118-127. doi: 10.1016/j.cmet.2016.10.004. Epub 2016 Nov 3.


Circadian clocks are self-sustainable endogenous oscillators, present in virtually every cell, driving daily cycles of metabolism and physiology. The molecular mechanism of the circadian clock is based on interconnected transcriptional and translational feedback loops. While many studies have addressed circadian rhythms of the transcriptome and, to a lesser extent, the proteome, none have investigated the phosphoproteome. We apply mass spectrometry-based phosphoproteomics to obtain the first global in vivo quantification of circadian phosphorylation in mammals. Of more than 20,000 phosphosites, 25% significantly oscillate in the mouse liver, including novel sites on core clock proteins. The extent and amplitude of phosphorylation cycles far exceeds those observed in RNA and protein abundance. Our data indicate a dominant regulatory role for phosphorylation-dependent circadian tuning of signaling pathways. This allows the organism to integrate different signals and rapidly and economically respond to daily changes in nutrient availability and physiological states.

Keywords: circadian clock; mass spectrometry; metabolism; rhythmic phosphorylation; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CLOCK Proteins / chemistry
  • CLOCK Proteins / metabolism
  • Circadian Clocks / physiology*
  • Circadian Rhythm
  • Enzyme Activation
  • Female
  • Liver / metabolism
  • Male
  • Metabolic Networks and Pathways*
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism
  • Proteome / metabolism
  • Signal Transduction
  • Time Factors


  • Phosphoproteins
  • Proteome
  • CLOCK Proteins
  • Protein Kinases