(Molecular and Cellular Biology, 30(7), 1757-1768, 2010)Circadian molecular oscillation is generated by a transcription/translation-based feedback loop in which CRY proteins play critical roles as potent inhibitors for E-box-dependent clock gene expression. Although CRY2 undergoes rhythmic phosphorylation in its C-terminal tail structurally distinct from CRY1 tail, little is understood about how protein kinase(s) controls the CRY2-specific phosphorylation and contributes to the molecular clockwork. Kurabayashi et al. found that Ser557 in the C-terminal tail of CRY2 is phosphorylated by DYRK1A as a priming kinase for subsequent GSK-3β-mediated phosphorylation of Ser553, which leads to proteasomal degradation of CRY2. In the mouse liver, DYRK1A kinase activity toward Ser557 of CRY2 showed circadian variation with its peak in the accumulating phase of CRY2 protein. Knockdown of Dyrk1a caused abnormal accumulation of cytosolic CRY2 protein levels, advancing the timing of nuclear increase of CRY2 (Fig. 1), and shortened the period length of the cellular circadian rhythm. Expression of S557A/S553A mutant of CRY2 phenocopied the effect of Dyrk1a-knock down in terms of the circadian period length of the cellular clock. Together, DYRK1A is a novel clock-related protein kinase which governs cytosolic CRY2 level and the timing of nuclear CRY2 accumulation, enabling the circadian clock to oscillate normally (Fig. 2).
