Role Of Protein Kinase CK2 Research Articles

Emerging role of Protein Kinase CK2 in Tumor immunity.

Protein kinase CK2, a conserved serine/threonine-protein kinase, is ubiquitous in cells and regulates various intracellular processes, especially in tumor cells. As one of the earliest discovered protein kinases in humans, CK2 plays a crucial role in phosphorylating or associating with hundreds of substrates to modulate several signaling pathways. Excellent reviews have reported that the overexpression of CK2 could be observed in many cancers and was closely associated with tumor occurrence and development. The elevation of CK2 is also an indicator of a poor prognosis. Recently, increasing attention has been paid to the relationship between CK2 and tumor immunity. However, there is no comprehensive description of how CK2 regulates the immune cells in the tumor microenvironment (TME). Also, the underlying mechanisms are still not very clear. In this review, we systematically summarized the correlation between CK2 and tumor immunity, primarily the effects on various immune cells, both in innate and adaptive immunity in the TME. With the comprehensive development of immunotherapy and the mounting transformation research of CK2 inhibitors from the bench to the clinic, this review will provide vital information to find new treatment options for enhancing the efficacy of immunotherapy.

The Role of Protein Kinase CK2 in Development and Disease Progression: A Critical Review

Protein kinase CK2 (CK2) is a ubiquitous holoenzyme involved in a wide array of developmental processes. The involvement of CK2 in events such as neurogenesis, cardiogenesis, skeletogenesis, and spermatogenesis is essential for the viability of almost all organisms, and its role has been conserved throughout evolution. Further into adulthood, CK2 continues to function as a key regulator of pathways affecting crucial processes such as osteogenesis, adipogenesis, chondrogenesis, neuron differentiation, and the immune response. Due to its vast role in a multitude of pathways, aberrant functioning of this kinase leads to embryonic lethality and numerous diseases and disorders, including cancer and neurological disorders. As a result, CK2 is a popular target for interventions aiming to treat the aforementioned diseases. Specifically, two CK2 inhibitors, namely CX-4945 and CIBG-300, are in the early stages of clinical testing and exhibit promise for treating cancer and other disorders. Further, other researchers around the world are focusing on CK2 to treat bone disorders. This review summarizes the current understanding of CK2 in development, the structure of CK2, the targets and signaling pathways of CK2, the implication of CK2 in disease progression, and the recent therapeutics developed to inhibit the dysregulation of CK2 function in various diseases.

The Immune Regulatory Role of Protein Kinase CK2 and Its Implications for Treatment of Cancer.

Protein Kinase CK2, a constitutively active serine/threonine kinase, fulfills its functions via phosphorylating hundreds of proteins in nearly all cells. It regulates a variety of cellular signaling pathways and contributes to cell survival, proliferation and inflammation. CK2 has been implicated in the pathogenesis of hematologic and solid cancers. Recent data have documented that CK2 has unique functions in both innate and adaptive immune cells. In this article, we review aspects of CK2 biology, functions of the major innate and adaptive immune cells, and how CK2 regulates the function of immune cells. Finally, we provide perspectives on how CK2 effects in immune cells, particularly T-cells, may impact the treatment of cancers via targeting CK2.

Role of Protein Kinase CK2 in Aberrant Lipid Metabolism in Cancer.

Uncontrolled proliferation is a feature defining cancer and it is linked to the ability of cancer cells to effectively adapt their metabolic needs in response to a harsh tumor environment. Metabolic reprogramming is considered a hallmark of cancer and includes increased glucose uptake and processing, and increased glutamine utilization, but also the deregulation of lipid and cholesterol-associated signal transduction, as highlighted in recent years. In the first part of the review, we will (i) provide an overview of the major types of lipids found in eukaryotic cells and their importance as mediators of intracellular signaling pathways (ii) analyze the main metabolic changes occurring in cancer development and the role of oncogenic signaling in supporting aberrant lipid metabolism and (iii) discuss combination strategies as powerful new approaches to cancer treatment. The second part of the review will address the emerging role of CK2, a conserved serine/threonine protein kinase, in lipid homeostasis with an emphasis regarding its function in lipogenesis and adipogenesis. Evidence will be provided that CK2 regulates these processes at multiple levels. This suggests that its pharmacological inhibition combined with dietary restrictions and/or inhibitors of metabolic targets could represent an effective way to undermine the dependency of cancer cells on lipids to interfere with tumor progression.

Deciphering the role of protein kinase CK2 in the maturation/stability of F508del-CFTR

F508del-CFTR, the most common mutation in cystic fibrosis (CF) patients, impairs CFTR trafficking to plasma membrane leading to its premature proteasomal degradation. Several post-translational modifications have been identified on CFTR with multiple roles in stability, localization and channel function, and the possibility to control the enzymes responsible of these modifications has been long considered a potential therapeutic strategy. Protein kinase CK2 has been previously suggested as an important player in regulating CFTR functions and it has been proposed as a pharmacological target in a combinatory therapy to treat CF patients. However, the real implication of CK2 in F508del-CFTR proteostasis, and in particular the hypothesis that its inhibition could be important in CF therapies, is still elusive. Here, by using immortalized cell lines, primary human cells, and knockout cell lines deprived of CK2 subunits, we do not disclose any direct correlation between F508del-CFTR proteostasis and CK2 expression/activity. Rather, our data indicate that the CK2α′ catalytic subunit should be preserved rather than inhibited for F508del rescue by the correctors of class-1, such as VX-809, disclosing new important features in CF therapeutic approaches.

Down-regulation of CK2\u03b1 correlates with decreased expression levels of DNA replication minichromosome maintenance protein complex (MCM) genes

Protein kinase CK2 is a serine/threonine kinase composed of two catalytic subunits (CK2α and/or CK2α’) and two regulatory subunits (CK2β). It is implicated in every stage of the cell cycle and in the regulation of various intracellular pathways associated with health and disease states. The catalytic subunits have similar biochemical activity, however, their functions may differ significantly in cells and in vivo. In this regard, homozygous deletion of CK2α leads to embryonic lethality in mid-gestation potentially due to severely impaired cell proliferation. To determine the CK2α-dependent molecular mechanisms that control cell proliferation, we established a myoblast-derived cell line with inducible silencing of CK2α and carried out a comprehensive RNA-Seq analysis of gene expression. We report evidence that CK2α depletion causes delayed cell cycle progression through the S-phase and defective response to replication stress. Differential gene expression analysis revealed that the down-regulated genes were enriched in pathways implicated in cell cycle regulation, DNA replication and DNA damage repair. Interestingly, the genes coding for the minichromosome maintenance proteins (MCMs), which constitute the core of the replication origin recognition complex, were among the most significantly down-regulated genes. These findings were validated in cells and whole mouse embryos. Taken together, our study provides new evidence for a critical role of protein kinase CK2 in controlling DNA replication initiation and the expression levels of replicative DNA helicases, which ensure maintenance of proliferative potential and genome integrity in eukaryotic cells.

Protein kinase CK2 is involved in zinc homeostasis in breast and prostate cancer cells.

The intracellular zinc profiles of breast and prostate cancer cells are diametrically opposed, with hyper-accumulation of zinc in breast cancer, and low level in prostate cancer. This phenomenon is poorly understood. This study employs two breast and two prostate cancer cell lines to investigate the role of protein kinase CK2 in regulating zinc homeostasis. CK2 was targeted by its specific inhibitors 4,5,6,7-tetrabromobenzotriazole (TBB) and CX-4945, and by the specific siRNA against each of the three CK2 genes. The effect of zinc exposure after the above CK2 manipulation was observed by MTT [3-(4,5-dimethyliazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] cell viability assay and confocal microscopy for intracellular zinc level. The results demonstrate that CK2 is involved in regulating zinc homeostasis in breast and prostate cancer cells as both TBB and CX-4945 substantially decreased cell viability upon zinc exposure. siRNA-mediated knockdown of the three CK2 subunits (α, α' and β) revealed their discrete roles in regulating zinc homeostasis in breast and prostate cancer cells. Knockdown of CK2α' decreased the intracellular zinc level of breast cancer cells and in turn increased the cell viability while the opposite findings were obtained for the prostate cancer cells. Knockdown of CK2β expression substantially increased the zinc level in breast cancer cell lines whilst decreased the zinc level in prostate cancer cells. Taken together, this study shows that CK2 is involved in zinc homeostasis of breast and prostate cancer cells and opens a new avenue for research on these cancers.

Unravelling the role of protein kinase CK2 in metal toxicity using gene deletion mutants

Metal ions, biologically essential or toxic, are present in the surrounding environment of living organisms. Understanding their uptake, homeostasis or detoxification is critical in cell biology and human health. In this study, we investigated the role of protein kinase CK2 in metal toxicity using gene deletion strains of Saccharomyces cerevisiae against a panel of six metal ions. The deletion of CKA2, the yeast orthologue of mammalian CK2α', leads to a pronounced resistant phenotype against Zn2+ and Al3+, whilst the deletion of CKB1 or CKB2 results in tolerance to Cr6+ and As3+. The individual deletion mutants of CK2 subunits (CKA1, CKA2, CKB1 and CKB2) did not have any benefit against Co2+ and Cd2+. The metal ion content in the treated cells was then measured by inductively coupled plasma mass spectrometry. Two contrasting findings were obtained for the CKA2 deletion mutant (cka2Δ) against Al3+ or Zn2+. Upon exposure to Al3+, cka2Δ had markedly lower Al3+ content than the wild type and other CK2 mutants, congruous to the resistant phenotype of cka2Δ against Al3+, indicating that CKA2 is responsible for Al3+ uptake. Upon zinc exposure the same mutant showed similar Zn2+ content to the wild type and cka1Δ. Strikingly, the selective inhibitor of CK2 TBB (4,5,6,7-tetrabromo-1H-benzotriazole) abolished the resistant phenotype of cka2Δ against Zn2+. Hence, the CK2 subunit CKA1 plays a key role in Zn2+ sequestration of the cell. Given that both zinc and CK2 are implicated in cancer development, the findings herein are of significance to cancer research and anticancer drug development.

Emerging roles of protein kinase CK2 in abscisic acid signaling.

The phytohormone abscisic acid (ABA) regulates many aspects of plant growth and development as well as responses to multiple stresses. Post-translational modifications such as phosphorylation or ubiquitination have pivotal roles in the regulation of ABA signaling. In addition to the positive regulator sucrose non-fermenting-1 related protein kinase 2 (SnRK2), the relevance of the role of other protein kinases, such as CK2, has been recently highlighted. We have recently established that CK2 phosphorylates the maize ortholog of open stomata 1 OST1, ZmOST1, suggesting a role of CK2 phosphorylation in the control of ZmOST1 protein degradation (Vilela et al., 2015). CK2 is a pleiotropic enzyme involved in multiple developmental and stress-responsive pathways. This review summarizes recent advances that taken together suggest a prominent role of protein kinase CK2 in ABA signaling and related processes.

Role of protein kinase CK2 in the dynamic interaction of platelets, leukocytes and endothelial cells during thrombus formation

IntroductionThrombus formation is a complex process, which is characterized by the dynamic interaction of platelets, leukocytes and endothelial cells. The activation of these cells is strictly mediated by different phospho-regulated signaling pathways. Recently, it has been reported that inhibition of protein kinase CK2 affects platelet function by suppressing phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K) signaling. Based on this finding, we herein analyzed whether CK2 acts as a crucial regulator of thrombus formation. Materials and methodsWe examined the effect of CK2 inhibition on platelet activation and aggregation, the formation of platelet-leukocyte aggregates (PLA), the endothelial expression of von Willebrand factor (vWF), intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, and the subcellular localization of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and phospho-p65 in human dermal microvascular endothelial cells (HDMEC). Dorsal skinfold chambers were prepared in BALB/c mice to analyze in vivo the effect of CK2 inhibition on photochemically induced thrombus formation using intravital fluorescence microscopy. ResultsCK2 inhibition by CX-4945 suppressed adenosin diphosphate (ADP)- and proteinase-activated receptor-1-peptide (PAR-1-AP)-stimulated platelet aggregation, which was associated with down-regulation of P-selectin, GPIIb/IIIa and a reduced formation of PLA. Expression and secretion of vWF was diminished in CX-4945-treated HDMEC. Moreover, CK2 inhibition attenuated the endothelial expression of VCAM-1, whereas the expression of ICAM-1 was not affected. Finally, CX-4945-treated mice exhibited a significantly delayed photochemically induced thrombus formation when compared to vehicle-treated controls. ConclusionThese results indicate that CK2 is a pleiotropic regulator of thrombus formation, affecting multiple interactions of platelets, leukocytes and endothelial cells.

The lysine-specific demethylase 1 is a novel substrate of protein kinase CK2

Protein kinase CK2 is a pleiotropic serine/threonine kinase responsible for the generation of a substantial proportion of the human phosphoproteome. CK2 is generally found as a tetramer with two catalytic, α and α′ and two non catalytic β subunits. CK2α C-terminal tail phosphorylation is regulated during the mitotic events and the absence of these phosphosites in α′ suggests an isoform specialization. We used a proteomic approach to identify proteins specifically phosphorylated by a CK2α phosphomimetic mutant, CK2αT344ET360ES362ES370E (CK2α4E), in human neuroblastoma SKNBE cellular extract. One of these proteins is lysine-specific demethylase 1 (LSD1 or KDM1A), an important player of the epigenetic machinery. LSD1 is a FAD-dependent amine oxidase and promotes demethylation of lysine 4 and lysine 9 of mono- and di-methylated histone H3. We found that LSD1 is a new substrate and an interacting partner of protein kinase CK2. Three CK2 phosphosites, (Ser131, Ser137 and Ser166) in the N-terminal region of LSD1 have been identified. This domain is found in all chordates but not in more ancient organisms and it is not essential for LSD1 catalytic event while it could modulate the interaction with CK2 and with other partners in gene repressing and activating complexes. Our data support the view that the phosphorylation of the N-terminal domain by CK2 may represent a mechanism for regulating histone methylation, disclosing a new role for protein kinase CK2 in epigenetics.

The Role of Protein Kinase CK2 in Glioblastoma Development

Glioblastoma is the most prevalent and malignant primary brain tumor in adults, and its response to current therapies is limited. Protein kinase CK2 is overexpressed in glioblastoma and regulates glioblastoma cell survival, proliferation, and migration and brain tumorigenesis. Targeting CK2 for glioblastoma treatment may benefit patients with glioblastoma.

The Role of Protein Kinase CK2 in Cyclosporine-Induced Nephropathy in Rats

ObjectivesProtein kinase casein kinase II (PKCK2) has multiple, overlapping roles in induction of apoptosis. Apoptosis can be a common pathway of renal injury caused by a nephrotoxic drug or an injury. We evaluated the role of PKCK2 in cyclosporine (CsA)-induced nephropathy in rats by inhibiting PKCK2 with emodin. MethodsMale Sprague-Dawley rats fed a low-sodium diet were divided into four treatment groups: control (0.9% saline injection), CsA (15 mg/kg/d subcutaneously), CsA + emodin (CsA plus emodin 20 mg/kg/d subcutaneously), and emodin only. The expression levels of apoptosis-associated factors and of PKCK2 were examined by Western blot analysis. ResultsOverexpression of PKCK2 noted with CsA treatment was prevented by emodin, a low-molecular-weight PKCK2 inhibitor, which dampend drug-induced up-regulation phosphorylated p53 and activation of caspases 3, 7, and 8. In addition, emodin prevented increased Bax/Bcl-2 ratio induced by CsA. Emodin prevented up-regulation of PKCK2 by CsA treatment, suggesting that its apoptotic-preventing activity was mediated via PKCK2. ConclusionsOur findings indicated that PKCK2 may play a role in apoptotic injury associated with CsA-induced nephropathy in rats.

The Role of Protein Kinase CK2 (PKCK2) in the Cyclosporine Induced Nephropathy in Rats

Background: Protein kinase casein kinase II (PKCK2) has multiple, overlapping roles in induction of apoptosis. Apoptosis might to be a common pathway of renal injury caused by nephrotoxic drug or injury. We evaluated the role of PKCK2 in the Cyclosporin A (CsA) induced nephropathy in rats by inhibition of PKCK2. Methods: Male Sprague Dawley rats fed with low sodium diet were divided into four treatment groups: control (0.9% saline injection), CsA (15mg/kg/day by s.c.), CsA + emodin (CsA plus emodin 20mg/kg/day by s.c.), and emodin only. The expression levels of apoptosis-associated factors were examined by western blot analysis. Expression of PKCK2 was also assayed by western blot. Results: Overexpression of PKCK2 was noted in CsA treatment. Emodin, a low molecular weight PKCK2 specific inhibitor, prevented the up-regulation of phosphorylated p53 and the activation of caspase 3, 7, and 8 induced by CsA treatment. In addition, emodin prevented CsA-induced increased expression of Bax/Bcl-2 ratio. Emodin prevented the up-regulation of PKCK2 induced by CsA treatment, indicating that its apoptotic-preventing activity was mediated via PKCK2. Conclusions: Our findings indicate that PKCK2 may play a major role in apoptotic injury in CsA induced nephropathy in rat models.

Developmental Changes in the Localization of Protein Kinase CK2 in Non-Diapause and Diapause Eggs of the Silkworm,Bombyx mori

To analyze the role of protein kinase CK2 (CK2) during early embryogenesis in non-diapause and diapause of the silkworm, the distribution and localization of Bombyx mori CK2 (BmCK2) were investigated by an immunohistochemical technique using antibodies against the α- and β-subunits of BmCK2. Both were localized in blastoderm cells of non-diapause and diapause eggs until 24 h after oviposition. More than 24 h after oviposition, however, the distribution of BmCK2 was different in non-diapause and diapause eggs. In non-diapause eggs, BmCK2 was mainly localized in yolk cells. In contrast, in diapause eggs, the localization was mainly observed in germ-band cells. Furthermore, we confirmed that the RNA helicase-like protein that was localized together with BmCK2 in non-diapause eggs was phosphorylated by BmCK2 in vitro. These data suggest that the role of BmCK2 is different in non-diapause and diapause eggs.

Abstract B67: Phenotype-specific role for protein kinase CK2 in luminal and basal-like breast cancer cells

Abstract Protein Kinase CK2 is a hetero-tetrameric serine/threonine kinase which has been shown to have increased expression in most types of cancer. Previous studies have identified roles for CK2 in transcriptional regulation, proliferation and survival, as well as in epithelial mesenchymal transition. Our previous studies have shown that CK2 is responsible for the phosphorylation of the estrogen receptor (ERα) at two previously unidentified sites. Here we sought to delineate the specific functions of CK2 in ERα (+) luminal and ERα (−) basal-like breast cancer. Breast tissue microarrays studies show that CK2 is expressed in both ERα (+) and ERα (−) breast tumors. In ER dependent cell lines, inhibition of CK2 causes a substantial inhibition of transcriptional activity in luciferase reporter assays. Furthermore, CK2 was found to interact with the promoters of estrogen responsive genes in an ER-dependent fashion. Despite the selective effects on ER dependent gene expression, inhibition of CK2 attenuated proliferation/ cell viability both ERα (+) and ERα (−) cell lines, suggesting that CK2 may have distinct roles in the function of specific breast cancer cell phenotypes. Indeed, Inhibition of CK2 caused cell-type specific changes in the expression of vimentin and E-cadherin, as determined by flow cytometry, as well as cell morphology. Taken together, these studies suggest that CK2 utilizes multiple molecular mechanisms to promote tumorigenesis. Inhibition of CK2 may be a viable therapeutic targeting strategy for treatment of patients with ERα (+) and ERα (−) breast tumor phenotypes. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B67.

The role of protein kinase CK2 in the regulation of the insulin production of pancreatic islets

An appropriate regulation of the insulin production and secretion in pancreatic β-cells is necessary for the control of blood glucose homeostasis. The pancreatic duodenal homeobox factor-1 (Pdx-1) is among the various factors and signals which are implicated in the regulation of the insulin synthesis and secretion in the pancreatic β-cells. Recently, we identified Pdx-1 as a substrate for protein kinase CK2. Since CK2 is implicated in the regulation of many different cellular signaling pathways we now asked whether it might also be involved in the regulation of the insulin regulation in β-cells. Here, we show that insulin treatment of β-cells resulted in an elevated CK2 kinase activity. On the other hand down-regulation of CK2 activity by quinalizarin led to an elevated level of insulin. These results demonstrate that CK2 is implicated in the insulin regulation on pancreatic β-cells.

Role of CK2 and calcineurin in increased NMDA receptor activity of PVN presympathetic neurons in hypertension

Increased glutamatergic input to presympathetic neurons in the paraventricular nucleus (PVN) plays a critical role in increased sympathetic outflow in hypertension. However, the molecular mechanism underlying increased NMDA receptor activity in the PVN in hypertension is not known. Here we determined the role of protein kinase CK2 and protein phosphatase calcineurin in regulating NMDA receptor activity in spinally projecting PVN neurons in brain slices from spontaneously hypertensive rats (SHR) and Wistar‐Kyoto rats (WKY). The NMDA current (0.68 ± 0.05 vs. 0.32 ± 0.06 pA/pF, P < 0.05) and the ratio (0.72 ± 0.07 vs. 0.35 ± 0.02, P < 0.05) of NMDA/AMPA currents of retrogradely labeled PVN neurons were significantly larger in SHR than in WKY. Inhibition of CK2 with DRB or TBB normalized the increase in NMDA currents and had no effect on AMPA currents in SHR. Inhibition of calcineurin with FK506 significantly increased NMDA currents in WKY but not in SHR. Furthermore, in the presence of FK506, DRB had little effect on NMDA currents in SHR and WKY. Our study provides important new information that the phosphorylation and dephosphorylation process tonically regulates NMDA receptor function. The imbalance between CK2 and calcineurin activity in the PVN likely contributes to augmented NMDA receptor activity in presympathetic neurons and increased sympathetic outflow in hypertension.

Protein kinase CK2 in health and disease: From birth to death: the role of protein kinase CK2 in the regulation of cell proliferation and survival.

Protein kinase CK2 is a serine/threonine kinase with a multitude of protein substrates. The enzyme is ubiquitously expressed in mammalian cells, where it functions in a variety of cellular processes, including cell cycle progression, apoptosis, transcription, and viral infection. While the importance of CK2 in the mammalian life cycle is undisputed, the regulatory mechanisms coordinating its numerous functions remain elusive. In this review, we focus on the various roles of CK2 in the mammalian cell, with particular attention on its functions through the stages of the cell cycle and during the decision to undergo cell death. We highlight how these roles are controlled in part through direct transcriptional regulation by CK2, and how the constitutive activity of CK2 can be hijacked in the case of viral infection. Finally, we discuss possible ways in which these functions are integrated to allow the cell to respond appropriately in the presence of multiple signals.

Is there a link between protein kinase CK2 and auxin signaling?

Protein kinase CK2 is a pleitropic Ser/Thr kinase present in all eukaryotes. In order to study the effects of CK2 depletion on plant development, we have recently generated Arabidopsis transgenic plants expressing a CK2α-inactive mutant under the control of an inducible promoter. Our results showed that continuous expression of the transgene had a dominant negative effect and was lethal for Arabidopsis plants. Overexpression of the CK2α-inactive subunit provoked cell cycle arrest, by perturbation of both G1/S and G2 cell-cycle phases. The effects on cell division were particularly strong in root meristems, causing inhibition of lateral root formation even when the mutant protein was transiently induced. Processes that rely on cell expansion, such as hypocotyl elongation in dark-grown seedlings, were also strongly affected. We propose that CK2 regulates auxin-signaling pathways.Addendum to: Moreno-Romero J, Carme Espunya M, Platara M, Ariño J, Carmen Martínez M. A role for protein kinase CK2 in plant development: evidence obtained using a dominant-negative mutant. Plant J. 2008; In press.