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

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

doi:10.1016/j.celrep.2016.06.005

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 journal › Article › peer-review

47 Citations (Scopus)

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 language	English
Pages (from-to)	357-367
Number of pages	11
Journal	Cell Reports
Volume	16
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2016.06.005
Publication status	Published - Jul 12 2016
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank Jenna L. O’Neil for expert technical assistance and Alina Patke, Wanhe Li, and Philip B. Kidd for critical review of the manuscript. This work was supported by a grant from the NIH (GM054339) to Michael W. Young. D.T. would like to thank Michael W. Young for his full support. D.T. would like to dedicate this paper to the memory of his friend and colleague, L.S.

Publisher Copyright:
© 2016 The Authors

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2016.06.005

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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.",

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AU - Saez, Lino

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

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