Abstract
Simple SummaryThe Casein Kinase 1 (CK1) family of serine-threonine specific protein kinases regulates the activity of key regulatory proteins and signaling pathways being involved in embryonic development but also in the adult organism. Furthermore, it plays an important role in the regulation of proliferation, differentiation, apoptotic processes, circadian rhythm, chromosome segregation, and other microtubule-associated processes. Deregulation of CK1 expression and activity, as well as mutations in the coding region, contribute to the development of many human pathologies, including cancer. Alternations in the site-specific phosphorylation of α/β-tubulin and microtubule-associated proteins affect microtubule stability, finally resulting in mitotic defects and genomic instability. Here we review our knowledge about CK1 functions in general and especially in chromosome segregation. Furthermore, an update in modulating CK1 activity by small molecule inhibitors and peptides specifically inhibiting CK1 protein interactions as new therapy concepts for the treatment of cancer will be discussed.Protein kinases of the Casein Kinase 1 family play a vital role in the regulation of numerous cellular processes. Apart from functions associated with regulation of proliferation, differentiation, or apoptosis, localization of several Casein Kinase 1 isoforms to the centrosome and microtubule asters also implicates regulatory functions in microtubule dynamic processes. Being localized to the spindle apparatus during mitosis Casein Kinase 1 directly modulates microtubule dynamics by phosphorylation of tubulin isoforms. Additionally, site-specific phosphorylation of microtubule-associated proteins can be related to the maintenance of genomic stability but also microtubule stabilization/destabilization, e.g., by hyper-phosphorylation of microtubule-associated protein 1A and RITA. Consequently, approaches interfering with Casein Kinase 1-mediated microtubule-specific functions might be exploited as therapeutic strategies for the treatment of cancer. Currently pursued strategies include the development of Casein Kinase 1 isoform-specific small molecule inhibitors and therapeutically useful peptides specifically inhibiting kinase-substrate interactions.
Highlights
Microtubules are helical fibers with an outer diameter of approximately 25 nm that consist of tubulin subunits [1]
The centrosome consists of two centrioles, surrounded by the pericentriolar material (PCM), which contains components such as γ-tubulin, which is important for anchoring and nucleating cytoplasmic microtubules to build up the mitotic spindle during cell division [5]
RITA binds to the beta trefoil domain (BTD) of RBPJ, and in a recent structure–function analysis, we identified this type of interaction as a “RAM-Type” (Figure 5, upper middle panel) since it shows a striking similarity to the interaction of RBPJ with the RAM domain (RBPJ-associated molecule) of nuclear translocation of its intracellular domain (NICD) [106] and explains the mutually exclusive binding of either RITA or NICD to RBPJ on the structural level [107]
Summary
Microtubules are helical fibers with an outer diameter of approximately 25 nm that consist of tubulin subunits (heterodimer of α- and β-tubulin) [1]. Mitosis needs to be strictly regulated and controlled These regulatory processes are mainly driven by components of the mitotic kinome, including several kinase families such as NIMA-related kinases (Neks), cyclin-dependent kinases (CDKs), Polo-like kinases (Plks), and Aurora kinases, as well as phosphatases and kinase inhibitors [7]. Similar to Aurora kinases, Plks are involved in the regulation of cell division by controlling essential mitotic processes. Besides Aurora kinases and Plks, CDKs and Neks play critical roles in cell cycle regulation by phosphorylating multiple mitosis-related substrates. Cyclin/CDK complexes promote DNA replication, centrosome duplication, spindle formation, and other cell cycle-associated processes by the phosphorylation of mitotic key regulators [19]. A detailed presentation of CK1 isoforms in regulating cell cycle progression, modulating cytoskeleton components, and the role in microtubule transport will be described in detail in the following chapters
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