Casein kinase 1

The Casein kinase 1 family 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. 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.

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.

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. They reported that Xenopus casein kinase 1 gamma (CK1gamma) is associated 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.

Casein kinase 1 epsilon is also important in the Wnt signaling pathway and the Hedgehog signaling pathway.

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