CK1 and GSK3 in the Drosophila and mammalian circadian clock.

Two kinases, DOUBLETIME and SHAGGY, have been shown to play a role in the circadian clock. DOUBLETIME, the Drosophila orthologue of casein kinase 1, can phosphorylate PERIOD in the cytoplasm and in the nucleus. This phosphorylation destabilizes PERIOD in both locations and sets patterns of both cytoplasmic accumulation and nuclear turnover. Cytoplasmic phosphorylation postpones accumulation of PERIOD and affects timing of nuclear accumulation of PERIOD/ TIMELESS complexes. SHAGGY, the Drosophila orthologue of glycogen synthase kinase 3, phosphorylates TIMELESS and promotes nuclear translocation of PERIOD/ TIMELESS complexes. Thus, the opposing effects of these two kinases in the cytoplasm are crucial for establishing the approximately 24 h period of circadian rhythmicity in Drosophila. Casein Kinase 1 has been shown to be a component of the circadian clock in mammals. Recent studies are also pointing to a role for glycogen synthase kinase 3 in the mammalian clock.