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Cytokinesis, the conclusive act of cell division, allows cytoplasmic organelles and chromosomes to be faithfully partitioned between two daughter cells. In animal organisms, its accurate regulation is a fundamental task for normal development and for preventing aneuploidy. Cytokinesis failures produce genetically unstable tetraploid cells and ultimately result in chromosome instability, a hallmark of cancer cells. In animal cells, the assembly and constriction of an actomyosin ring drive cleavage furrow ingression, resulting in the formation of a cytoplasmic intercellular bridge, which is severed during abscission, the final event of cytokinesis. Kinase-mediated phosphorylation is a crucial process to orchestrate the spatio-temporal regulation of the different stages of cytokinesis. Several kinases have been described in the literature, such as cyclin-dependent kinase, polo-like kinase 1, and Aurora B, regulating both furrow ingression and/or abscission. However, others exist, with well-established roles in cell-cycle progression but whose specific role in cytokinesis has been poorly investigated, leading to considering these kinases as "minor" actors in this process. Yet, they deserve additional attention, as they might disclose unexpected routes of cell division regulation. Here, we summarize the role of multifunctional kinases in cytokinesis with a special focus on those with a still scarcely defined function during cell cleavage. Moreover, we discuss their implication in cancer. [ABSTRACT FROM AUTHOR]

Casein kinase 2 (CK2) is a type of conserved serine/ threonine protein kinase that phosphorylates many important proteins in the eukaryotes. There are various research revealing the importance of CK2 in cellular process and cancer. It is abnormally elevated in all most all kinds of cancer hence considered one of the major factors in aggressiveness of cancer cells. This is majorly caused due to the CK2 dependent phosphorylation of various of key proteins that are linked to apoptosis. As a result, CK2 has been emerged as a promising target in the treatment of cancer and many therapeutic inhibitors has been discovered and developed. Indeed, of all these developments these inhibitors lack selectivity, cell permeability, metabolic stability and correct pharmacokinetic characteristics, which results in less therapeutic effect in cancer cells. Hence, versatile biological nano carriers should be developed, with the abilities of targeted delivery of developed therapeutic compounds. In brief the current review focuses on the normal functions and role of CK2 in cancer, further we have also described the various therapeutic inhibitors developed for CK2 inhibition with its future perspectives as a therapeutic target. [ABSTRACT FROM AUTHOR]

Casein kinase 2 (CK2) is highly activated in Alzheimer disease (AD) and is associated with neurofibrillary tangles formation. Phosphorylated SET, a potent PP2A inhibitor, mediates tau hyperphosphorylation in AD. However, whether CK2 phosphorylates SET and regulates tau pathological phosphorylation in AD remains unclear. Here, we show that CK2 phosphorylating SET at Ser9 induced tau hyperphosphorylation in AD. We found that either Aβ treatment or tau overexpression stimulated CK2 activation leading to SET Ser9 hyperphosphorylation in neurons and animal models, while inhibition of CK2 by TBB abolished this event. Overexpression of CK2 in mouse hippocampus via virus injection induced cognitive deficit associated with SET Ser9 hyperphosphorylation. Injection of SET Ser9 phosphorylation mimetic mutant induced tau pathology and behavior impairments. Conversely co-injection of non-phosphorylated SET S9A with CK2 abolished the CK2 overexpression-induced AD pathology and cognitive deficit. Together, our data demonstrate that CK2 phosphorylates SET at Ser9 leading to SET cytoplasmic translocation and inhibition of PP2A resulting in tau pathology and cognitive impairments. [ABSTRACT FROM AUTHOR]

During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to pancreatic β cell failure. CCAAT/enhancer-binding protein (C/EBP) β is highly induced by ER stress and AMP-activated protein kinase (AMPK) suppression in pancreatic β cells, and its accumulation reduces pancreatic β cell mass. We investigated the phosphorylation state of C/EBPβ under these conditions. Casein kinase 2 (CK2) was found to co-localize with C/EBPβ in MIN6 cells. It phosphorylated S222 of C/EBPβ, a previously unidentified phosphorylation site. We found that C/EBPβ is phosphorylated by CK2 under AMPK suppression and ER stress, which are important from the viewpoint of the worsening pathological condition of type 2 diabetes, such as decreased insulin secretion and apoptosis of pancreatic β cells. [ABSTRACT FROM AUTHOR]

Intrinsically disordered proteins (IDPs) represent approximately 30% of the human genome and play key roles in cell proliferation and cellular signaling by modulating the function of target proteins via protein–protein interactions. In addition, IDPs are involved in various human disorders, such as cancer, neurodegenerative diseases, and amyloidosis. To understand the underlying molecular mechanism of IDPs, it is important to study their structural features during their interactions with target proteins. However, conventional biochemical and biophysical methods for analyzing proteins, such as X-ray crystallography, have difficulty in characterizing the features of IDPs because they lack an ordered three-dimensional structure. Here, we present biochemical and biophysical studies on nucleolar phosphoprotein 140 (Nopp140), which mostly consists of disordered regions, during its interaction with casein kinase 2 (CK2), which plays a central role in cell growth. Surface plasmon resonance and electron paramagnetic resonance studies were performed to characterize the interaction between Nopp140 and CK2. A single-molecule fluorescence resonance energy transfer study revealed conformational change in Nopp140 during its interaction with CK2. These studies on Nopp140 can provide a good model system for understanding the molecular function of IDPs. [ABSTRACT FROM AUTHOR]

The term 'casein kinase' has been widely used for decades to denote protein kinases sharing the ability to readily phosphorylate casein in vitro. These fall into three main classes: two of them, later renamed as protein kinases CK1 (casein kinase 1, also known as CKI) and CK2 (also known as CKII), are pleiotropic members of the kinome functionally unrelated to casein, whereas G-CK, or genuine casein kinase, responsible for the phosphorylation of casein in the Golgi apparatus of the lactating mammary gland, has only been identified recently with Fam20C [family with sequence similarity 20C; also known as DMP-4 (dentin matrix protein-4)], a member of the four-jointed family of atypical protein kinases, being responsible for the phosphorylation of many secreted proteins. In hindsight, therefore, the term 'casein kinase' is misleading in every instance; in the case of CK1 and CK2, it is because casein is not a physiological substrate, and in the case of G-CK/Fam20C/DMP-4, it is because casein is just one out of a plethora of its targets, and a rather marginal one at that. Strikingly, casein kinases altogether, albeit representing a minimal proportion of the whole kinome, appear to be responsible for the generation of up to 40-50% of non-redundant phosphosites currently retrieved in human phosphopeptides database. In the present review, a short historical explanation will be provided accounting for the usage of the same misnomer to denote three unrelated classes of protein kinases, together with an update of our current knowledge of these pleiotropic enzymes, sharing the same misnomer while playing very distinct biological roles. [ABSTRACT FROM AUTHOR]

Abstract: Eukaryotic protein kinases are typically strictly controlled by second messenger binding, protein/protein interactions, dephosphorylations or similar processes. None of these regulatory mechanisms is known to work for protein kinase CK2 (former name “casein kinase 2”), an acidophilic and constitutively active eukaryotic protein kinase. CK2 predominantly exists as a heterotetrameric holoenzyme composed of two catalytic subunits (CK2α) complexed to a dimer of non-catalytic subunits (CK2β). One model of CK2 regulation was proposed several times independently by theoretical docking of the first CK2 holoenzyme structure. According to this model, the CK2 holoenzyme forms autoinhibitory aggregates correlated with trans-autophosphorylation and driven by the down-regulatory affinity between an acidic loop of CK2β and the positively charged substrate binding region of CK2α from a neighboring CK2 heterotetramer. Circular trimeric aggregates in which one-half of the CK2α chains show the predicted inhibitory proximity between those regions were detected within the crystal packing of the human CK2 holoenzyme. Here, we present further in vitro support of the “regulation-by-aggregation” model by an alternative crystal form in which CK2 tetramers are arranged as approximately linear aggregates coinciding essentially with the early predictions. In this assembly, the substrate binding region of every CK2α chain is blocked by a CK2β acidic loop from a neighboring tetramer. We found these crystals with CK2 Andante that contains a CK2β variant mutated in a CK2α-contact helix and described to be responsible for a prolonged circadian rhythm in Drosophila. The increased propensity of CK2 Andante to form aggregates with completely blocked active sites may contribute to this phenotype. [Copyright &y& Elsevier]

Highlights: [•] HP1β contains two primary sites for CK2 with distinct phosphorylation kinetics. [•] Localized conformational and dynamic changes occur at the sites of phosphorylation. [•] HP1β phosphorylated at S89 and S175 retains its ability to bind chromatin. [ABSTRACT FROM AUTHOR]

Highlights: [•] AMPK mediates leptin-induced PTEN inactivation. [•] AMPK-mediated PTEN inhibition increases KATP channel trafficking. [•] GSK3β mediates AMPK-dependent PTEN inactivation and KATP channel trafficking. [ABSTRACT FROM AUTHOR]

Intracellular accumulation of α-synuclein (α-Syn) as filamentous aggregates is a pathological feature shared by Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, referred to as synucleinopathies. To understand the mechanisms underlying α-Syn aggregation, we established a tetracycline-off inducible transfectant (3D5) of neuronal lineage overexpressing human wild-type α-Syn. α-Syn aggregation was initiated by exposure of 3D5 cells to FeCl2. The exposure led to formation of α-Syn inclusions and oligomers of 34, 54, 68 kDa and higher molecular weights. The oligomers displayed immunoreactivity with antibodies to the amino-, but not to the carboxyl(C)-, terminus of α-Syn, indicating that C-terminally truncated α-Syn is a major component of oligomers. FeCl2 exposure also promoted accumulation of S129 phosphorylated monomeric α-Syn (Pα-Syn) and casein kinase 2 (CK2); however, G-protein-coupled receptor kinase 2 was reduced. Treatment of FeCl2-exposed cells with CK2 inhibitors (DRB or TBB) led to decreased formation of α-Syn inclusions, oligomers and Pα-Syn. FeCl2 exposure also enhanced the activity/level of cathepsin D. Treatment of the FeCl2-exposed cells with pepstatin A or NH4Cl led to reduced formation of oligomers/inclusions as well as of ∼ 10 and 12 kDa truncated α-Syn. Our results indicate that α-Syn phosphorylation caused by FeCl2 is due to CK2 upregulation, and that lysosomal proteases may have a role in producing truncated α-Syn for oligomer assembly. [ABSTRACT FROM AUTHOR]