Casein kinase 1

Casein kinase 1

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


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 [G. Burnett and E. Kennedy (1954) "The enzymatic phosphorylation of proteins" in "Journal of Biological Chemistry" Volume 211, pages 969-980. Entrez Pubmed|13221602] . 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 [E. Bingham and H. Farrel (1974) "Casein kinase from the Golgi apparatus of lactating mammary gland" in "Journal of Biological Chemistry" Volume 249, pages 3647-3651. Entrez Pubmed|4364664] .


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 [R. Takada, H. Hijikata, H. Kondoh and S. Takada (2005) "Analysis of combinatorial effects of Wnts and Frizzleds on beta-catenin/armadillo stabilization and Dishevelled phosphorylation" in "Genes Cells" Volume 10, pages 919-928. Entrez Pubmed|16115200.] .

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 LRPG. Davidson, W. Wu, J. Shen, J. Bilic, U. Fenger, P. Stannek, A. Glinka and C. Niehrs (2005) "Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction" in "Nature" Volume 438, pages 867-872. Entrez Pubmed|16341016] . 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 [Wojciech Swiatek, I-Chun Tsai, Laura Klimowski, Andrea Pepler, Janet Barnette, H. Joseph Yost and David M. Virshup (2004) "Regulation of casein kinase I epsilon activity by Wnt signaling" in "Journal of Biological Chemistry" Volume 279, pages 13011-13017. Entrez Pubmed|14722104] and the Hedgehog signaling pathway L. Lum and P. A. Beachy (2004) "The Hedgehog response network: sensors, switches, and routers" in "Science" Volume 304, pages 1755-1759 Entrez Pubmed|15205520] .

Casein kinase 1 epsilon also acts in a molecular pathway that regulates the circadian rhythm [Erik J. Eide, Margaret F. Woolf, Heeseog Kang, Peter Woolf, William Hurst, Fernando Camacho, Erica L. Vielhaber, Andrew Giovanni and David M. Virshup (2005) "Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation" in "Molecular and Cellular Biology" Volume 25, pages 2795-2807. Entrez Pubmed|15767683] .

ee also

*Casein kinase 2 - a distinct protein kinase family


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