ReviewThe casein kinase 1 family: participation in multiple cellular processes in eukaryotes
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.