Casein kinase Is

Kloss B, Price JL, Saez L et al 1998 The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Is. Cell 94 97—107 Kloss B, Rothenfluh A, Young MW, Saez L 2001 Phosphorylation of period is influenced by cycling physical associations of double-time, period, and timeless In the Drosophila clock. Neuron 30 699-706... 

A genetic screen for novel clock mutations in Drosophila sA to the discovery of the first kinase that plays a role in circadian rhythmicity (Price et al 1998). Doubletime dht) is a member of the casein kinase 1 (CKl) family, and is 86% identical to human casein kinase Is (CKls) within the kinase domain (Kloss et al 1998). Originally, two mutations were isolated that produce short (18 h dht ) and long (27 h dbt ) behavioural rhythms. Since then, many period-altering mutations and loss-of-function alleles have been described. The majority of these mutations reside in the kinase domain of dbt, altering its ability to bind and/or phosphorylate its substrate (Fig. 1). All of the DBT point mutations analysed alter the phosphorylation state and accumulation of PER, indicating that DBT affects... 

HSFl phosphorylation must be sensitive to nonheat inducers of HSF-DNA binding activity because HSFl phosphorylation can be achieved at 37 °C by other inducers of the HS response. HSF 1 contains polypeptide sequences that could serve as substrates for well characterized protein kinases, but few of these are known to be heat inducible. One family of protein kinases, the S6 protein kinases, have already been shown to exhibit heat inducible activity however, their peak level of activity during HS occurs well after the maximal induction of HSF phosphorylation (Jurivich et al., 1991). Thus, other protein kinases are likely to be directly linked to the phosphorylation of HSF. Some of the putative protein phosphorylation sites on HSF include motifs for protein kinase C, casein kinase, and enterokinase. There are tyrosine sequences that match substrates for known tyrosine kinases, but whether these residues are accessible to phosphorylation is not established. 

The ability of DARPP-32 and inhibitor-1 to be phosphorylated at their PKA site is affected by phosphorylation at numerous other sites. DARPP-32 is phosphorylated by CDK5 and casein kinases I and II, all of which affect the phosphorylation state at Thr34. Inhibitor-1 also serves as a substrate of CDK5, at a site that is not homologous to the CDK5 site on DARPP-32. Further work is needed to understand the physiological significance of these other phosphorylation reactions. 

The effect of sphingosine on other enzymes may also contribute to its apoptotic effect. These include the inhibition of calcium/calmodulin-requiring enzymes and DNA primase and the stimulation of casein kinase II and several unidentified kinases (Alessenko, 2000). In addition, sphingosine can increase the cellular concentration of cyclic AMP, which is inhibitory for proliferation in many cell types (Pyne and Pyne, 1996). 

Difficulties in detecting nucleolin on the cell surface could be explained by its very low concentration in this compartment (Hovanessian et al, 2000). Moreover, this cell surface expressed nucleolin protein has a different isoelectric point and it is recognized by only one monoclonal antibody (mAb D3) in its native conformation (Hovanessian et al, 2000). This probably reflects specific post-translational modifications undergone by nucleolin on the cell surface. Consistent with this hypothesis, extracellular nucleolin is a substrate of ecto-protein kinases including casein kinase II (Dumler et al, 1999 Jordan et al., 1994). Interestingly, indirect evidence suggests... 

Dumler 1, Stepanova V, Jerke U, Mayboroda OA, Vogel F, Bouvet P, Tkachuk V, Haller H, Gulba DC (1999) Urokinase-induced mitogenesis is mediated by casein kinase 2 and nucleolin. Cutr Biol 9 1468-1476... 

There is growing evidence that clock proteins are regulated dynamically in both temporal (production and degradation) and spatial (nuclear and cytoplasmic) dimensions. The phosphorylation of mPERl and mPER2 by casein kinase le (CKIe) is known as an important step for the accumulation of negatively active clock proteins (Lowrey et al 2000) as in Drosophila (Kloss et al 1998). 

Young In the original paper we saw evidence for a functional requirement for dht in the nucleus. You refer to hypo-phosphorylated PER in the model, but casein kinase 1 delta is still there. I thought in tau mutants the phosphorylation patterns for PER were not really distinguishable from wild-... 

Vielhaber E, Eide E, Rivers A, Gao ZH, Virshup DM 2000 Nuclear entry of the circadian regulator mPERl is controlled by mammalian casein kinase I epsilon. Mol Cell Biol 20 4888-4899... 

Casein kinase II (casein kinase gets its name from the observation that casein, milk protein, is a good substrate)... 

Fig. 7.2. Structure and substrate binding sites of Ser/Thr-spedfic protein kinases, a) Peptide binding site structure of the catalytic subunit of the cAMP-dependent protein kinase A from mouse, with bound inhibitor peptide PKI (5-22), shown in dark in the figure. PKI (5-22) is a fragment (amino adds 5-22) of the naturally occurring heat-stable protein kinase inhibitor PKI. The inhibitor peptide binds in the region of the substrate binding site between the two lobes of protein kinase A (Knighton et al., 1991). The P-loop is involved in binding the phosphate residue of ATP. b) ATP binding site structure of casein kinase I with bound Mg-ATP. The Mg is shown as a sphere. MOLSKRIPT representation according to Kraulis, (1991).

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