The Drosophila Clock Gene double-time Encodes a Protein Closely Related to Human Casein Kinase Iε

Abstract

The cloning of double-time (dbt) is reported. DOUBLETIME protein (DBT) is most closely related to human casein kinase Iepsilon. dbtS and dbtL mutations, which alter period length of Drosophila circadian rhythms, produce single amino acid changes in conserved regions of the predicted kinase. dbtP mutants, which eliminate rhythms of per and tim expression and constitutively overproduce hypophosphorylated PER proteins, abolish most dbt expression. dbt mRNA appears to be expressed in the same cell types as are per and tim and shows no evident oscillation in wild-type heads. DBT is capable of binding to PER in vitro and in Drosophila cells, suggesting that a physical association of PER and DBT regulates PER phosphorylation and accumulation in vivo.

Molecular Analysis of Sleep: Wake Cycles inDrosophila

“…1). PER is phosphorylated by casein kinase 1ε (CK1ε) and by casein kinase 2 and TIM is phosphorylated by glycogen synthase kinase 3β (GSK3β) (Kloss et al 1998;Martinek et al 2001;Lin et al 2002;Akten et al 2003). The different phosphorylation events regulate critical aspects of the feedback loop such as stability and nuclear expression of PER/TIM, indicating the importance of posttranslational control in the clock.…”

The ankyrin repeat protein Diversin recruits Casein kinase Iε to the β-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling

“…Ser/Thr kinases of the CKI family function in a number of cellular processes like cell cycle regulation, DNA repair, and circadian rhythms, and were also implicated in Wnt signaling (Santos et al 1996;Kloss et al 1998;Peters et al 1999;Sakanaka et al 1999;Vielhaber and Virshup 2001). Overexpression of CKI⑀ induced secondary body axis in Xenopus embryos, and CKI⑀ was found to interact with and promote phosphorylation of Dishevelled.…”

Molecular genetics of the fruit-fly circadian clock

“…44 Thus, the CLK-CYC dimer forms the positive limb of the feedback loop and when PER enters the nucleus, it interacts with the dimer (incidentally, not via PER PAS as had been commonly assumed, but via a C-terminal region), and represses transcription. 45 PER eventually degrades via the phosphorylation of DBT 15,46 (although phosphorylation by CK2 47,48 is also important for shifting PER from the cytoplasm to the nucleus), and transcription is reactivated. The delay between per mRNA and protein accumulation is also due to DBT.…”