Discovery of MARK2 as a physiological kinase for PER2 in the mammalian clock

Mar 11, 2026Cell chemical biology

MARK2 as a natural regulator of the body clock protein PER2 in mammals

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Abstract

S662 phosphorylation by MARK2 is critical for regulating the circadian clock.

  • Human mutations in serine 662 (S662) are linked to familial advanced sleep phase (FASP) syndrome.
  • Phosphorylation of S662 occurs through several kinases, including casein kinase 1 δ and ε, but genetic deletion of these kinases does not produce phase advancement.
  • MARK2 has been identified as a key enzyme that phosphorylates S662, which is essential for stabilizing the Period 2 (PER2) protein.
  • Circadian period is shortened in cells lacking MARK2, indicating its role in this regulation.
  • Neuronal-specific knockout of MARK2 results in both phase advancement and period shortening in mice.

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