Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction

Casein kinase 2 from rat liver cytosol phosphorylated human fibrinogen in a reaction that was not stimulated by Ca2+ or cyclic AMP, but was markedly inhibited by heparin, and proceeded at a similar rate when either ATP or GTP was used as phosphate donor. Analysis of casein kinase 2 by glycerol-density-gradient centrifugation showed that the activities towards fibrinogen, casein, phosvitin, high-mobility-group protein 14 and glycogen synthase coincided. Maximal incorporation into fibrinogen by casein kinase 2 averaged 1 mol of phosphate/mol of protein substrate, most of it in the alpha-chain, although some phosphorylation of the beta-chain was also detected. Analysis of phosphorylated alpha-chain revealed that most of the phosphate was incorporated on serine. Phosphorylation of human fibrinogen was also performed by casein kinase 2 from human polymorphonuclear leucocytes, lymphocytes and platelets.

Download Full-text

The mechanism of agrin-induced acetylcholine receptor aggregation

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1991.0016 ◽

1991 ◽

Vol 331 (1261) ◽

pp. 273-280 ◽

Cited By ~ 14

Keyword(s):

Neuromuscular Junction ◽

Tyrosine Phosphorylation ◽

Acetylcholine Receptor ◽

Acetylcholine Receptors ◽

Neuromuscular Junctions ◽

Electric Organ ◽

Motor Axon ◽

Β Subunit ◽

Axon Terminals ◽

Receptor Aggregation

Agrin, a protein isolated from the synapse-rich electric organ of Torpedo californica , induces the formation of specializations on myotubes in culture which resemble the post-synaptic apparatus at the vertebrate skeletal neuromuscular junction. For example, the specializations contain aggregates of acetylcholine receptors and acetylcholinesterase. This report summarizes the evidence that the formation of the postsynaptic apparatus at developing and regenerating neuromuscular junctions is triggered by the release of agrin from motor axon terminals and describes results of recent experiments which suggest that agrininduced tyrosine phosphorylation of the β subunit of the acetylcholine receptor may play a role in receptor aggregation.

Download Full-text

Obesity-Linked Phosphorylation of SIRT1 by Casein Kinase 2 Inhibits Its Nuclear Localization and Promotes Fatty Liver

Molecular and Cellular Biology ◽

10.1128/mcb.00006-17 ◽

2017 ◽

Vol 37 (15) ◽

Cited By ~ 14

Author(s):

Sung E. Choi ◽

Sanghoon Kwon ◽

Sunmi Seok ◽

Zhen Xiao ◽

Kwan-Woo Lee ◽

...

Keyword(s):

Fatty Liver ◽

Nuclear Localization ◽

Liver Steatosis ◽

Phosphorylation Site ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Serine Phosphorylation ◽

Acid Oxidation ◽

Specific Expression ◽

Nonalcoholic Fatty Liver

ABSTRACT Sirtuin1 (SIRT1) deacetylase delays and improves many obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD) and diabetes, and has received great attention as a drug target. SIRT1 function is aberrantly low in obesity, so understanding the underlying mechanisms is important for drug development. Here, we show that obesity-linked phosphorylation of SIRT1 inhibits its function and promotes pathological symptoms of NAFLD. In proteomic analysis, Ser-164 was identified as a major serine phosphorylation site in SIRT1 in obese, but not lean, mice, and this phosphorylation was catalyzed by casein kinase 2 (CK2), the levels of which were dramatically elevated in obesity. Mechanistically, phosphorylation of SIRT1 at Ser-164 substantially inhibited its nuclear localization and modestly affected its deacetylase activity. Adenovirus-mediated liver-specific expression of SIRT1 or a phosphor-defective S164A-SIRT1 mutant promoted fatty acid oxidation and ameliorated liver steatosis and glucose intolerance in diet-induced obese mice, but these beneficial effects were not observed in mice expressing a phosphor-mimic S164D-SIRT1 mutant. Remarkably, phosphorylated S164-SIRT1 and CK2 levels were also highly elevated in liver samples of NAFLD patients and correlated with disease severity. Thus, inhibition of phosphorylation of SIRT1 by CK2 may serve as a new therapeutic approach for treatment of NAFLD and other obesity-related diseases.

Download Full-text

Identification of Erbin Interlinking MuSK and ErbB2 and Its Impact on Acetylcholine Receptor Aggregation at the Neuromuscular Junction

Journal of Neuroscience ◽

10.1523/jneurosci.5778-09.2010 ◽

2010 ◽

Vol 30 (19) ◽

pp. 6620-6634 ◽

Cited By ~ 15

Author(s):

L. Simeone ◽

M. Straubinger ◽

M. A. Khan ◽

N. Nalleweg ◽

T. Cheusova ◽

...

Keyword(s):

Neuromuscular Junction ◽

Acetylcholine Receptor ◽

Receptor Aggregation

Download Full-text

Faculty Opinions recommendation of Neuregulin inhibits acetylcholine receptor aggregation in myotubes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1019299.218470 ◽

2004 ◽

Author(s):

Stanley Froehner

Keyword(s):

Acetylcholine Receptor ◽

Receptor Aggregation

Download Full-text

Statins as the Controlling Agents for Non-Hodgkin's Lymphomas via Increasing the Casein Kinase 2 Interacting Protein-1: A Hypothesis

Current Drug Discovery Technologies ◽

10.2174/1570163816666190628165200 ◽

2020 ◽

Vol 17 (5) ◽

pp. 616-618

Author(s):

Kimia Kazemi ◽

Negin Mozafari ◽

Hajar Ashrafi ◽

Pedram Rafiei ◽

Amir Azadi

Keyword(s):

Cell Proliferation ◽

Mevalonate Pathway ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Interacting Protein ◽

Akt Phosphorylation ◽

Anticancer Properties ◽

Proliferation And Apoptosis ◽

Cellular Signaling Pathway ◽

Hodgkin's Lymphomas

Background: Non-Hodgkin's lymphomas (NHL), derived from B- or T-cell, consist of a heterogeneous group of malignant lymphoproliferative disorders. Knockdown of Casein kinase 2 interacting protein-1 (CKIP-1) in NHL promoted cell proliferation and inhibited apoptosis via enhancing phosphorylated Protein Kinase B (PKB or AKT) expression. Statins are the class of drugs that inhibit the ratelimiting step of the mevalonate pathway, which is essential for the biosynthesis of various compounds, including cholesterol. Also, statins have anticancer properties being mediated by different mechanisms. Methods: A search on databases like Scopus and PubMed with keywords such as statin and non- Hodgkin's lymphomas was performed and Kyoto Encyclopedia of Genes and Genomes (KEGG) website was used to evaluate and reconfirm the involved cellular signaling pathway. Results: CKIP-1 is involved in the regulation of cell proliferation and apoptosis while plays an important role in many cancers. We can hypothesize that statins may increase the expression levels of CKIP-1 which could contribute to the reductions in phospho-AKT level. Hence, they may ameliorate the NHL patients via suppressing AKT phosphorylation and increasing CKIP- expression. Conclusion: Present review confirms the positive effect of statins on NHL by increasing CKIP-1 and reducing cell proliferation, subsequently.

Download Full-text

Novel Anthraquinone Derivatives as Dual Inhibitors of Topoisomerase 2 and Casein Kinase 2: In Silico Studies, Synthesis and Biological Evaluation on Leukemic Cell Lines

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180423111309 ◽

2019 ◽

Vol 18 (11) ◽

pp. 1551-1562 ◽

Cited By ~ 4

Author(s):

Abbas Kabir ◽

Kalpana Tilekar ◽

Neha Upadhyay ◽

C.S. Ramaa

Keyword(s):

Cell Cycle ◽

Cell Line ◽

Cell Lines ◽

Biological Evaluation ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Cell Cycle Analysis ◽

Protein Targets ◽

Topoisomerase 2 ◽

Dual Inhibitors

Background: Cancer being a complex disease, single targeting agents remain unsuccessful. This calls for “multiple targeting”, wherein a single drug is so designed that it will modulate the activity of multiple protein targets. Topoisomerase 2 (Top2) helps in removing DNA tangles and super-coiling during cellular replication, Casein Kinase 2 (CK2) is involved in the phosphorylation of a multitude of protein targets. Thus, in the present work, we have tried to develop dual inhibitors of Top2 and CK2. Objective: With this view, in the present work, 2 human proteins, Top2 and CK2 have been targeted to achieve the anti-proliferative effects. Methods: Novel 1-acetylamidoanthraquinone (3a-3y) derivatives were designed, synthesized and their structures were elucidated by analytical and spectral characterization techniques (FTIR, 1H NMR, 13C NMR and Mass Spectroscopy). The synthesized compounds were then subjected to evaluation of cytotoxic potential by the Sulforhodamine B (SRB) protein assay, using HL60 and K562 cell lines. Ten compounds were analyzed for Top2, CK2 enzyme inhibitory potential. Further, top three compounds were subjected to cell cycle analysis. Results: The compounds 3a to 3c, 3e, 3f, 3i to 3p, 3t and 3x showed excellent cytotoxic activity to HL-60 cell line indicating their high anti-proliferative potential in AML. The compounds 3a to 3c, 3e, 3f, 3i to 3p and 3y have shown good to moderate activity on K-562 cell line. Compounds 3e, 3f, 3i, 3x and 3y were found more cytotoxic than standard doxorubicin. In cell cycle analysis, the cells (79-85%) were found to arrest in the G0/G1 phase. Conclusion: We have successfully designed, synthesized, purified and structurally characterized 1- acetylamidoanthraquinone derivatives. Even though our compounds need design optimization to further increase enzyme inhibition, their overall anti-proliferative effects were found to be encouraging.

Download Full-text

Phosphorylation of glycogen synthase by cyclic AMP-independent casein kinase-2 from rabbit skeletal muscle.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)81101-8 ◽

1982 ◽

Vol 257 (6) ◽

pp. 3236-3242

Author(s):

K P Huang ◽

E Itarte ◽

T J Singh ◽

A Akatsuka

Keyword(s):

Skeletal Muscle ◽

Cyclic Amp ◽

Glycogen Synthase ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Rabbit Skeletal Muscle

Download Full-text

Casein Kinase 2 dependent phosphorylation of eIF4B regulates BACE1 expression in Alzheimer’s disease

Cell Death and Disease ◽

10.1038/s41419-021-04062-3 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Barbara Bettegazzi ◽

Laura Sebastian Monasor ◽

Serena Bellani ◽

Franca Codazzi ◽

Lisa Michelle Restelli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Activity ◽

Neurodegenerative Disorder ◽

Brain Slices ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Bace1 Expression

AbstractAlzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Increased Aβ production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aβ generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.

Download Full-text