Elsevier

Cellular Signalling

Volume 17, Issue 6, June 2005, Pages 675-689
Cellular Signalling

Review
The casein kinase 1 family: participation in multiple cellular processes in eukaryotes

https://doi.org/10.1016/j.cellsig.2004.12.011Get rights and content

Abstract

Phosphorylation of serine, threonine and tyrosine residues by cellular protein kinases plays an important role in the regulation of various cellular processes. The serine/threonine specific casein kinase 1 and 2 protein kinase families — (CK1 and CK2) — were among the first protein kinases that had been described. In recent years our knowledge of the regulation and function of mammalian CK1 kinase family members has rapidly increased. Extracellular stimuli, the subcellular localization of CK1 isoforms, their interaction with various cellular structures and proteins, as well as autophosphorylation and proteolytic cleavage of their C-terminal regulatory domains influence CK1 kinase activity. Mammalian CK1 isoforms phosphorylate many different substrates among them key regulatory proteins involved in the control of cell differentiation, proliferation, chromosome segregation and circadian rhythms. Deregulation and/or the incidence of mutations in the coding sequence of CK1 isoforms have been linked to neurodegenerative diseases and cancer. This review will summarize our current knowledge about the function and regulation of mammalian CK1 isoforms.

Introduction

Posttranslational modifications have a great impact on the activity of various proteins exhibiting key roles in almost all cellular processes ranging from, metabolism to cell growth, proliferation, differentiation and apoptosis. The reversible phosphorylation of proteins mediated by protein kinases and phosphatases plays an important role in intracellular signal transduction pathways connected with these processes. At present, several hundred protein kinases (serine/threonine specific and tyrosine specific kinases) and phosphatases have been identified in humans [1], [2]. Mutation of phosphorylation sites of substrates as well as mutations and deregulation of the activity of any of these kinases and phosphatases can lead to the development of a number of disorders and diseases [3], such as neoplasias, cardiovascular diseases, neurodegenerative diseases, immunodeficiency, rheumatoid arthritis and endocrine disorders. Therefore, more and more protein kinases and phosphatases are becoming targets for drug development and recently, interest in targeting specifically members of the casein kinase 1 family (CK1) has increased. In this review we will focus on the mammalian CK1 family members and outline their function in regulating cellular processes and their involvement in various diseases, especially in proliferative diseases such as cancer.

Section snippets

The CK1 kinase family

CK1 represents a unique group within the superfamily of serine/threonine specific protein kinases that is ubiquitously expressed in eukaryotic organisms [4], [5], [6], [7], [8], [9], [10]. The CK1 protein kinase family is evolutionary conserved and several casein kinase genes have been identified and characterized in yeast [11], [12], [13], [14], [15], [16]. So far, at least seven mammalian CK1 isoforms (α, β, γ1, γ2, γ3, δ and ɛ) [17], [18], [19], [20], [21], [22] and their various splice

Substrate specificity and consensus sequence

The characterization of the substrate specificity of CK1 isoforms initially led to the identification of the canonical consensus sequence S/T(P)-X1–2-S/T, indicating that modification of serine or threonine residues by CK1 requires the preceding phosphorylation of amino acid residues N-terminal of the target site [27], [35], [36]. This requirement of a priming phosphorylation by another kinase restricted CK1 to a function in the hierarchical phosphorylation of substrates. However, further

Regulation of CK1 expression and activity

Members of the CK1 family are constitutively active and can be isolated as active enzymes from many different organisms, tissues, and cell lines [10]. Despite this, a number of effectors are able to modulate CK1 expression and activity. Furthermore, several mechanisms have been identified which modulate CK1 activity in vivo and in vitro. Stimulation of cells by insulin [46] or by viral transformation [47] as well as treatment of cells with topoisomerase inhibitors [48], or γ-irradiation [49]

Functions of CK1 in membrane transport processes

Studies in yeast linked CK1 homologues to the regulation of membrane transport [60], [61], cell morphogenetic processes [62] and DNA repair pathways [45]. In eukaryotic cells the subcellular localization of the isoforms CK1α and δ is well characterized. Both isoforms interact with membrane structures of the ER, Golgi and/or TGN and various transport vesicles [23], [54], [63], [64], [65], [66], but their functions in membrane transport have not been elucidated in detail. Furthermore, CK1

CK1 and the circadian rhythm

Almost every organism exhibits an autonomous timer called circadian clock. The circadian clock consists of three components: (i) a signal transduction pathway integrating external signals to adjust the time, (ii) a central oscillator that generates the circadian signal and (iii) a signal transduction pathway manifesting circadian periodicity of biological processes.

Studies in model systems such as Drosophila, Neurospora and mice led to the identification and characterization of several clock

Connections between CK1, the tumor suppressor p53 and the oncoprotein Mdm2

A rising number of reports link CK1 isoforms, especially CK1α, δ, and ɛ, to key regulator proteins, which play an important role in the development of cancer. The tumor suppressor p53 and the cellular oncogene mdm2 have been identified as key signal integrator molecules. Alterations in their phosphorylation status can abolish their function resulting in uncontrolled growth of cells [99].

Several CK1 isoforms have been shown to phosphorylate p53. Whereas CK1α is able to phosphorylate p53 only at

Role of CK1 in cell division

The involvement of CK1 in the progression of the cell cycle and in cell division was shown in yeast as well as in mammals. S. cerevisiae casein kinase Hrr25 has been shown to be important for mitotic and meiotic cell division and DNA separation [109]. The S. cerevisiae gene pair YCK1 and YCK2 exhibits essential functions in cell growth, bud morphology and cytokinesis [13], [21], [62], [110]. In mammalian cells, CK1α is speculated to play a role in cell cycle progression, spindle dynamics and

Role of CK1 in apoptosis

At present, evidence is increasing that CK1 isoforms are involved in impeding apoptosis induced through different pathways. CK1 can phosphorylate the p75 tumor necrosis factor receptor and negatively regulate p75-mediated apoptosis [124]. Recently, it has been shown that CK1 isoforms, especially CK1α, are involved in mediating resistance of tumor cells to tumor necrosis-factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis. It is thought that CK1 mediated phosphorylation at the

CK1: positive and negative regulators of the Wnt pathway?

The wingless (Wnt) signalling pathway is crucial for many aspects of development in vertebrates and invertebrates, including dorsal axis formation, tissue patterning, and establishment of cell polarity [139], [140], [141], [142]. In addition, Wnt-signalling plays an important regulatory role in cell proliferation processes. Mutations of Wnt signalling components are often found in various human cancers, including skin, liver, brain, and colon cancer [143], [144], [145], [146], [147], [148],

The involvement of CK1 in neurodegenerative diseases

Within the last couple of years evidence has increased that CK1α, δ, and ɛ play an important role in neurodegenerative diseases, especially in tauopathies like Alzheimer's disease. Elevated CK1δ mRNA and protein levels and kinase activity have been detected in the brain of Alzheimer patients [188], [189]. Furthermore, CK1δ binds to the microtubule-associated protein tau and phosphorylates tau at serine 202/threonine 205 and serine 396/serine 404, sites that modulate microtubule binding of tau

Detection of CK1 expression and activity changes in tumors

Several mechanisms by which CK1 could be involved in uncontrolled cell proliferation were already discussed in previous chapters. In summary, the CK1-mediated modification of the tumor suppressor p53 and the oncogene mdm2, the dual role of CK1 in influencing β-catenin stability, the inhibitory effects of CK1 in induction of apoptosis and its involvement in regulating microtubule stability and centrosome specific functions show that CK1 could influence the progression of tumors through many

Potential of CK1 inhibitors

So far, several CK1 specific inhibitors have been described, among them CK1-7 [196], D4476 [197], IC261 [198], polyhalogenobenzimidazoles [199]), the marine sponge constituent hymenialdisine [200], (−)-matairesinol [201] and meridianins [202]. CK1-7 (N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide) was the first CK1 competitively acting inhibitor described [196]). CK1-7 is specific to CK1 in a micromolar range, but does not show any specificity for CK1 isoforms. In addition, its ability to

Acknowledgements

This work was supported by grants from the Deutsche Krebshilfe, Dr. Mildred Scheel Stiftung, (10-1683-KN2, and 10-2237-KN3) and the Deutsche Forschungsgemeinschaft (SFB 518, B15) to Uwe Knippschild. We thank David Meek, Wolfgang Deppert, and Peter Würl for helpful discussions and critical reading of the manuscript.

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    Present address: Department of Pathology, Stony Brook University New York, BST L9, R132-136, SUNY at Stony Brook Stony Brook NY 11794-8691, USA.

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