Casein kinase 1

The Casein kinase 1 family (EC 2.7.11.1) of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types.

Discovery

By the early 1950s it was known from metabolic labeling studies using radioactive phosphate that the phosphate of phosphoproteins inside cells can sometimes undergo rapid exchange of new phosphate for old. In order to perform experiments that would allow isolation and characterization of the enzymes involved in attaching and removing phosphate from proteins, there was a need for convenient substrates for protein kinases and protein phosphatases. Casein has been used as a substrate since the earliest days of research on protein phosphorylation ^[1]. By the late 1960s, cyclic AMP-dependent protein kinase had been purified and most attention was centered on kinases and phosphatases that could regulate the activity of important enzymes. Casein kinase activity associated with the endoplasmic reticulum of mammary glands was first characterized in 1974 and its activity was shown to not depend on cyclic AMP ^[2].

The CKI family of monomeric serine–threonine pro- tein kinases is found in eukaryotic organisms from yeast to human. Mammals have seven family members (some- times referred to as isoforms, but encoded by distinct genes): alpha, beta 1, gamma 1, gamma 2, gamma 3, delta, and epsilon. The family members have the highest homology in their kinase domains (53%–98% identical) and differ from most other protein kinases by the presence of the sequence S-I-N instead of A-P-E in kinase domain VIII (Hanks and Hunter 1995). The family members appear to have similar substrate specificity in vitro (Pulgar et al. 1999), and substrate se- lection is thought to be regulated in vivo via subcellular localization and docking sites in specific substrates. One consensus phosphorylation site is S/Tp-X-X-S/T, where S/Tp refers to a phospho-serine or phospho-threonine, X refers to any amino acid, and the underlined residues refer to the target site (Flotow and Roach 1989; Flotow et al. 1990). Thus, this CKI consensus site requires priming by another kinase. CKI also phosphorylates a related un- primed site, which optimally contains a cluster of acidic amino acids N-terminal to the target S/T including an acidic residue at n − 3 and a hydrophobic region C-ter- minal to the target S/T (Flotow and Roach 1991; Pulgar et al. 1999). A single acidic residue in the n − 3 position is not sufficient for CKI phosphorylation. In contrast, in several important targets, NF-AT (Zhu et al. 1998) and beta-catenin (Amit et al. 2002; Liu et al. 2002), CKI does not require n − 3 priming but, instead, phosphorylates the first serine in the sequence S-L-S, which is followed by a cluster of acidic residues, albeit less efficiently than the optimal sites (Marin et al. 2003).

Roles

Casein kinase activity was found to be present in most cell types and to be associated with multiple enzymes. The type 1 casein kinase family of related gene products are now given designations such as "casein kinase 1 alpha" and "casein kinase 1 epsilon". Casein kinase 1 alpha has been suggested to play a role in phosphorylation of Disheveled in the Wnt signaling pathway ^[3].

In humans there are three casein kinase 1 gamma enzymes. Working with the Xenopus system, Davidson et al. screened for proteins that can regulate the Wnt signaling pathway by interacting with the Wnt receptor LRP^[4]. They reported that Xenopus casein kinase 1 gamma (CK1gamma) is associated with with the cell membrane and binds to LRP. CK1gamma was found to be needed for Wnt signaling through LRP. is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells. Wnt binding to LRP causes a rapid increase in phosphorylation of the cytoplasmic domain of LRP by CK1gamma. Davidson et al. proposed that phosphorylation of LRP6 by CK1gamma promotes binding of Axin to LRP and activation of the Wnt signaling pathway^[4].

Casein kinase 1 epsilon is also important in the Wnt signaling pathway ^[5] and the Hedgehog signaling pathway ^[6].

Casein kinase 1 epsilon also acts in a molecular pathway that regulates the circadian rhythm ^[7].

See also

• Casein kinase 2 - a distinct protein kinase family

References