GSK-3 and CK2 Kinases Converge on Timeless to Regulate the Master Clock

Deniz Top, Emily Harms, Sheyum Syed, Eliza L. Adams, Lino Saez

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

The molecular clock relies on a delayed negative feedback loop of transcriptional regulation to generate oscillating gene expression. Although the principal components of the clock are present in all circadian neurons, different neuronal clusters have varying effects on rhythmic behavior, suggesting that the clocks they house are differently regulated. Combining biochemical and genetic techniques in Drosophila, we identify a phosphorylation program native to the master pacemaker neurons that regulates the timing of nuclear accumulation of the Period/Timeless repressor complex. GSK-3/SGG binds and phosphorylates Period-bound Timeless, triggering a CK2-mediated phosphorylation cascade. Mutations that block the hierarchical phosphorylation of Timeless in vitro also delay nuclear accumulation in both tissue culture and in vivo and predictably change rhythmic behavior. This two-kinase phosphorylation cascade is anatomically restricted to the eight master pacemaker neurons, distinguishing the regulatory mechanism of the molecular clock within these neurons from the other clocks that cooperate to govern behavioral rhythmicity.

Original languageEnglish (US)
Pages (from-to)357-367
Number of pages11
JournalCell Reports
Volume16
Issue number2
DOIs
StatePublished - Jul 12 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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