A Hierarchical Phosphorylation Cascade That Regulates the Timing of PERIOD Nuclear Entry Reveals Novel Roles for Proline-Directed Kinases and GSK-3β/SGG in Circadian Clocks

Sep 24, 2010The Journal of neuroscience : the official journal of the Society for Neuroscience

A step-by-step protein modification process controls the timing of PERIOD protein entering the cell nucleus, revealing new roles for specific enzymes in the body's internal clock

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Abstract

Phosphorylation of serine 661 (Ser661) on the Drosophila PER protein is critical for the timing of its nuclear accumulation.

Mutations blocking phosphorylation at Ser661 do not alter the stability of dPER but delay its nuclear entry in pacemaker neurons.
This delay in nuclear entry results in longer behavioral rhythms.
Abolishing phosphorylation at Ser661 reduces the overall hyperphosphorylation of dPER, indicating a regulatory role.
Ser657 is identified as another phosphorylation site influenced by the priming effect of Ser661.
Mutations preventing phosphorylation at Ser657 also extend behavioral periods, suggesting a regulatory network of kinases affecting dPER's nuclear entry timing.

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The daily timing of when PERIOD (PER) proteins translocate from the cytoplasm to the nucleus is a critical step in clock mechanisms underpinning circadian rhythms in animals. Numerous lines of evidence indicate that phosphorylation plays a prominent role in regulating various aspects of PER function and metabolism, including changes in its daily stability and subcellular distribution. In this report, we show that phosphorylation of serine 661 (Ser661) by a proline-directed kinase(s) is a key phospho-signal on the Drosophila PER protein (dPER) that regulates the timing of its nuclear accumulation. Mutations that block phosphorylation at Ser661 do not affect dPER stability but delay its nuclear entry in key pacemaker neurons, yielding longer behavioral rhythms. Intriguingly, abolishing phosphorylation at Ser661 also attenuates the extent of dPER hyperphosphorylation in vivo, suggesting the phosphorylated state of Ser661 regulates phosphorylation at other sites on dPER. Indeed, we identify Ser657 as a site that is phosphorylated by the glycogen synthase kinase GSK-3β (SHAGGY; SGG) in a manner dependent on priming at Ser661. Although not as dramatic as mutating Ser661, mutations that abolish phosphorylation at Ser657 also lead to longer behavioral periods, suggesting that a multi-kinase hierarchical phosphorylation module regulates the timing of dPER nuclear entry. Together with evidence in mammalian systems, our findings implicate proline-directed kinases in clock mechanisms and suggest that PER proteins are key downstream targets of lithium therapy, a potent inhibitor of GSK-3β used to treat manic depression, a disorder associated with clock malfunction in humans.

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A Hierarchical Phosphorylation Cascade That Regulates the Timing of PERIOD Nuclear Entry Reveals Novel Roles for Proline-Directed Kinases and GSK-3β/SGG in Circadian Clocks

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