Journal articles on the topic 'Protein kinase CK2 – Pathophysiology'
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1
Piazza, Francesco A., Maria Ruzzene, Carmela Gurrieri, Barbara Montini, Luca Bonanni, Gino Chioetto, Giovanni Di Maira, et al. "Multiple myeloma cell survival relies on high activity of protein kinase CK2." Blood 108, no. 5 (September 1, 2006): 1698–707. http://dx.doi.org/10.1182/blood-2005-11-013672.
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Casein kinase 2 (CK2) is a ubiquitous cellular serine-threonine kinase that regulates relevant biologic processes, many of which are dysregulated in malignant plasma cells. Here we investigated its role in multiple myeloma (MM). Analysis of MM cell lines and highly purified malignant plasma cells in patients with MM revealed higher protein and CK2 activity levels than in controls (normal in vitro-generated polyclonal plasma cells and B lymphocytes). The inhibition of CK2 with specific synthetic compounds or by means of RNA interference caused a cytotoxic effect on MM plasma cells that could not be overcome by IL-6 or IGF-I and that was associated with the activation of extrinsic and intrinsic caspase cascades. CK2 blockage lowered the sensitivity threshold of MM plasma cells to the cytotoxic effect of melphalan. CK2 inhibition also resulted in impaired IL-6-dependent STAT3 activation and in decreased basal and TNF-α-dependent IκBα degradation and NF-κB-driven transcription. Our data show that CK2 was involved in the pathophysiology of MM, suggesting that it might play a crucial role in controlling survival and sensitivity to chemotherapeutics of malignant plasma cells.
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Strum, Scott W., Laszlo Gyenis, and David W. Litchfield. "CSNK2 in cancer: pathophysiology and translational applications." British Journal of Cancer 126, no. 7 (November 12, 2021): 994–1003. http://dx.doi.org/10.1038/s41416-021-01616-2.
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AbstractProtein kinase CSNK2 (CK2) is a pleiotropic serine/threonine kinase frequently dysregulated in solid and hematologic malignancies. To consolidate a wide range of biological and clinically oriented data from this unique kinase in cancer, this systematic review summarises existing knowledge from in vitro, in vivo and pre-clinical studies on CSNK2 across 24 different human cancer types. CSNK2 mRNA transcripts, protein levels and activity were found to be routinely upregulated in cancer, and commonly identified phosphotargets included AKT, STAT3, RELA, PTEN and TP53. Phenotypically, it frequently influenced evasion of apoptosis, enhancement of proliferation, cell invasion/metastasis and cell cycle control. Clinically, it held prognostic significance across 14 different cancers, and its inhibition in xenograft experiments resulted in a positive treatment response in 12. In conjunction with commentary on preliminary studies of CSNK2 inhibitors in humans, this review harmonises an extensive body of CSNK2 data in cancer and reinforces its emergence as an attractive target for cancer therapy. Continuing to investigate CSNK2 will be crucial to advancing our understanding of CSNK2 biology, and offers the promise of important new discoveries scientifically and clinically.
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Valentin-Berrios, Shirley D., Jose R. Romero, and Alicia Rivera. "Protein Disulfide Isomerase Regulates Sickle Erythrocyte Volume Via ET-1 Dependent Casein Kinase II Mechanism." Blood 118, no. 21 (November 18, 2011): 2114. http://dx.doi.org/10.1182/blood.v118.21.2114.2114.
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Abstract Abstract 2114 Disordered K+ efflux and osmotically induced water loss leads to red blood cell (RBC) dehydration and plays a role in the pathophysiology of Sickle Cell Disease. We previously reported that activation of endothelin-1 (ET-1) receptors in sickle erythrocyte was partially responsible for dense sickle cell formation. However, the mechanism by which ET-1 regulates RBC volume remains unclear. Serine/threonine kinases have been shown to regulate K+ transport in RBC. Casein Kinase II (CK2), a serine/threonine kinase, phosphorylates acidic proteins, regulates calmodulin activity and cytoskeletal proteins and is present in RBC. CK2 activity is blocked by apigenin, emodin, heparin, and ornithine decarboxylase. Previous reports have shown a role for flavonoids such as apigenin as substrates for erythrocyte plasma membrane oxidoreductases. We recently observed a role for Protein Disulfide Isomerase (PDI) in regulating cellular hydration and K+ efflux in human RBC. PDI catalyzes disulfide interchange reactions in the plasma membrane, mediates redox modifications and is up-regulated under hypoxic conditions. However the relationship between CK2 and PDI in the setting of cellular hydration status is un-explored. Our results indicate that erythrocyte membrane CK2 activity increases when sickle cells are incubated with 500 nM ET-1 for 30 min (2.8 ± 0.1 to 4.9 ± 0.01 nmol/min/mL * 106 cell) an event that is blunted by pre-incubation with the ET-1 B receptor blocker, BQ788 (2.5 ± 0.1 nmol/min/mL * 106 cell, n=3, p<0.04) and 20 μM apigenin (2.7 ± 0.4 nmol/min/mL * 106 cell, n=3, p<0.04). We examined the role of CK2 activation on cellular dehydration. We incubated sickle erythrocytes for 3 hours in deoxygenation-oxygenation cycles in the presence or absence of 20μM apigenin or 2μM 4,5,6,7-tetrabromobenzotriazole (TBB), a specific CK2 inhibitor, and measured the changes in erythrocyte density by phthalate oil density analysis. We observed that inhibition of CK2 led to reduced deoxygenation-stimulated cellular dehydration in sickle erythrocytes by apigenin (D50= 1.106 to 1.100 g/mL) or TBB (D50 =1.097 g/mL). We then studied the role of CK2 inhibitors on PDI activity by Insulin Turbidity Assay and observed that apigenin and TBB led to significant reductions in PDI activity in vitro (64% and 42% respectively). We also studied the effects of the flavonoids: naringenin, naringin, apigenin and rutin on PDI activity and observed reductions in PDI activity that were greater with apigenin>rutin>TBB>naringin>naringenin (n=2, P<0.05). Furthermore, we observed that K+ flux via Gardos channel activation is correlated with PDI activity in vitro in sickle erythrocytes. Taken together our results implicate CK2 and PDI as intermediate regulators of ET-1 stimulated cellular volume systems in red blood cells. Supported by NIH R01-HL09632 to AR. Disclosures: No relevant conflicts of interest to declare.
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Strum, Scott, Laszlo Gyenis, and David W. Litchfield. "CSNK2 in cancer: Pathophysiology and translational applications." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15594-e15594. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15594.
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e15594 Background: Protein kinase CSNK2 (CK2) is a pleiotropic serine/threonine kinase whose expression levels are frequently elevated in solid and hematologic malignancies. CSNK2 has been discovered to hold prognostic and therapeutic significance across multiple cancers and is an excellent target for oncology research. This systematic review summarizes the current knowledge from in vitro and in vivo studies on the biology of this kinase in cancer alongside pre-clinical/clinical investigations from 24 different human cancer types. Methods: PRISMA methodology was used to generate a study protocol and building-block search strategy, from which a total of 796 publications in PubMed were retrieved across 24 human cancers. 245 of these publications met both screening and inclusion criteria. Data was then systematically extracted, including information about CSNK2 subunit mRNA/protein/activity levels, phosphorylation targets, phenotypic changes, in vivo studies, and prognostic/therapeutic data. The data was thereafter summarized and analyzed. Results: Five targets phosphorylated by CSNK2 were identified in at least 4 cancers: AKT, STAT3, RELA, PTEN, and TP53. The most heavily cited was AKT, identified in 15 cancers. Phenotypically, behaviors influenced by CSNK2 that were reported in 11 or more cancers included: evasion of apoptosis, enhancement of proliferation, enhancement of invasion/metastasis, and cell cycle control. Interestingly, these pathways correlated heavily with the most commonly cited CSNK2 targets. From a clinical perspective, CSNK2 held prognostic significance in 17 of the cancers. Additionally, xenograft experiments were found to have been performed in 13 cancers where CSNK2 inhibition resulted in a positive response to treatment. Lastly, early studies have shown promising results through the clinical application of CSNK2-specific inhibitors, with several clinical trials now underway for further assessment. Conclusions: Overall, our analysis supports CSNK2 as an attractive target for cancer therapy and points to specific areas where additional investigation is critical to advance our understanding of CSNK2 biology. The design of targeted therapies by exploiting the pathophysiology of CSNK2 has the potential to generate impactful treatment strategies across a wide range of cancers, promising exciting new discoveries scientifically and clinically.
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Abu Shehab, Majida, Ian Damerill, Tong Shen, Fredrick J. Rosario, Mark Nijland, Peter W. Nathanielsz, Amrita Kamat, Thomas Jansson, and Madhulika B. Gupta. "Liver mTOR Controls IGF-I Bioavailability by Regulation of Protein Kinase CK2 and IGFBP-1 Phosphorylation in Fetal Growth Restriction." Endocrinology 155, no. 4 (April 1, 2014): 1327–39. http://dx.doi.org/10.1210/en.2013-1759.
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Fetal growth restriction (FGR) increases the risk for perinatal complications and predisposes the infant to diabetes and cardiovascular disease later in life. No treatment for FGR is available, and the underlying pathophysiology remains poorly understood. Increased IGFBP-1 phosphorylation has been implicated as an important mechanism by which fetal growth is reduced. However, to what extent circulating IGFBP-1 is phosphorylated in FGR is unknown, and the molecular mechanisms linking FGR to IGFBP-1 phosphorylation have not been established. We used umbilical cord plasma of appropriate for gestational age (AGA) and growth–restricted human fetuses and determined IGFBP-1 and IGF-I concentrations (ELISA) and site-specific IGFBP-1 phosphorylation (Western blotting using IGFBP-1 phospho-site specific antibodies). In addition, we used a baboon model of FGR produced by 30% maternal nutrient restriction and determined mammalian target of rapamycin (mTOR)C1 activity, CK2 expression/activity, IGFBP-1 expression and phosphorylation, and IGF-I levels in baboon fetal liver by Western blot, enzymatic assay, and ELISA. HepG2 cells and primary fetal baboon hepatocytes were used to explore mechanistic links between mTORC1 signaling and IGFBP-1 phosphorylation. IGFBP-1 was hyperphosphorylated at Ser101, Ser119, and Ser169 in umbilical plasma of human FGR fetuses. IGFBP-1 was also hyperphosphorylated at Ser101, Ser119, and Ser169 in the liver of growth–restricted baboon fetus. mTOR signaling was markedly inhibited, whereas expression and activity of CK2 was increased in growth–restricted baboon fetal liver in vivo. Using HepG2 cells and primary fetal baboon hepatocytes, we established a mechanistic link between mTOR inhibition, CK2 activation, IGFBP-1 hyperphosphorylation, and decreased IGF-I–induced IGF-I receptor autophosphorylation. We provide clear evidence for IGFBP-1 hyperphosphorylation in FGR and identified an mTOR and CK2-mediated mechanism for regulation of IGF-I bioavailability. Our findings are consistent with the model that inhibition of mTOR in the fetal liver, resulting in increased CK2 activity and IGFBP-1 hyperphosphorylation, constitutes a novel mechanistic link between nutrient deprivation and restricted fetal growth.
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Laher, Ismail, and John H. Zhang. "Protein Kinase C and Cerebral Vasospasm." Journal of Cerebral Blood Flow & Metabolism 21, no. 8 (August 2001): 887–906. http://dx.doi.org/10.1097/00004647-200108000-00001.
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Twenty-five years after the discovery of protein kinase C (PKC), the physiologic function of PKC, and especially its role in pathologic conditions, remains a subject of great interest with 30,000 studies published on these aspects. In the cerebral circulation, PKC plays a role in the regulation of myogenic tone by sensitization of myofilaments to calcium. Protein kinase C phosphorylates various ion channels including augmenting voltage-dependent Ca2+ channels and inhibiting K+ channels, which both lead to vessel contraction. These actions of PKC amplify vascular reactivity to different agonists and may be critical in the regulation of cerebral artery tone during vasospasm. Evidence accumulated during at least the last decade suggest that activation of PKC in cerebral vasospasm results in a delayed but prolonged contraction of major arteries after subarachnoid hemorrhage. Most of the experimental results in vitro or in animal models support the view that PKC is involved in cerebral vasospasm. Implication of PKC in cerebral vasospasm helps explain increased arterial narrowing at the signal transduction level and alters current perceptions that the pathophysiology is caused by a combination of multiple receptor activation, hemoglobin toxicity, and damaged neurogenic control. Activation of protein kinase C also interacts with other signaling pathways such as myosin light chain kinase, nitric oxide, intracellular Ca2+, protein tyrosine kinase, and its substrates such as mitogen-activated protein kinase. Even though identifying PKC revolutionized the understanding of cerebral vasospasm, clinical advances are hampered by the lack of clinical trials using selective PKC inhibitors.
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Wong, Aaron K. F., Jacqueline Howie, John R. Petrie, and Chim C. Lang. "AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease." Clinical Science 116, no. 8 (March 16, 2009): 607–20. http://dx.doi.org/10.1042/cs20080066.
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AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKB1 and CaMK (Ca2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease.
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Cereijido, M., L. Shoshani, and R. G. Contreras. "Molecular Physiology and Pathophysiology of Tight Junctions I. Biogenesis of tight junctions and epithelial polarity." American Journal of Physiology-Gastrointestinal and Liver Physiology 279, no. 3 (September 1, 2000): G477—G482. http://dx.doi.org/10.1152/ajpgi.2000.279.3.g477.
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The tight junction (TJ) was first noticed through its ability to control permeation across the paracellular route, but the homologies of its molecular components with peptides that participate in tumor suppression, nuclear addressing, and cell proliferation indicate that it may be involved in many other fundamental functions. TJs are formed by a dozen molecular species that assemble through PDZ and other protein-protein clustering promoting sequences, in response to the activation of E-cadherin. The TJ occupies a highly specific position between the apical and the basolateral domains. Its first molecular components seem to be delivered to such a position by addressing signals in their molecule and, once anchored, serve as a clustering nucleus for further TJ-associated molecules. Although in mature epithelial cells TJs and E-cadherin do not colocalize, a complex chain of reactions goes from one to the other that involves α-, β-, and γ-catenins, two different G proteins, phospholipase C, protein kinase C, calmodulin, mitogen-activated protein kinase, and molecules pertaining to the cytoskeleton, which keep the TJ sensitive to physiological requirements and local conditions (notably to Ca2+-dependent cell-cell contacts) throughout the life of the epithelium.
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Baroudi, Ghayath, Yongxia Qu, Omar Ramadan, Mohamed Chahine, and Mohamed Boutjdir. "Protein kinase C activation inhibits Cav1.3 calcium channel at NH2-terminal serine 81 phosphorylation site." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 4 (October 2006): H1614—H1622. http://dx.doi.org/10.1152/ajpheart.00095.2006.
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The Cav1.3 (α1D) variant of L-type Ca2+ channels plays a vital role in the function of neuroendocrine and cardiovascular systems. In this article, we report on the molecular and functional basis of α1D Ca2+ channel modulation by protein kinase C (PKC). Specifically, we show that the serine 81 (S81) phosphorylation site at the NH2-terminal region plays a critical role in α1D Ca2+ channel modulation by PKC. The introduction of a negatively charged residue at position 81, by converting serine to aspartate, mimicked the PKC phosphorylation effect on α1D Ca2+ channel. The modulation of α1D Ca2+ channel by PKC was prevented by dialyzing cells with a 35-amino acid peptide mimicking the α1D NH2-terminal region comprising S81. In addition, the data revealed that only βII- and εPKC isozymes are implicated in this regulation. These novel findings have significant implications in the pathophysiology of α1D Ca2+ channel and in the development of PKC isozyme-targeted therapeutics.
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Mika, Delphine, Wito Richter, and Marco Conti. "A CaMKII/PDE4D negative feedback regulates cAMP signaling." Proceedings of the National Academy of Sciences 112, no. 7 (February 2, 2015): 2023–28. http://dx.doi.org/10.1073/pnas.1419992112.
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cAMP production and protein kinase A (PKA) are the most widely studied steps in β-adrenergic receptor (βAR) signaling in the heart; however, the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is also activated in response to βAR stimulation and is involved in the regulation of cardiac excitation-contraction coupling. Its activity and expression are increased during cardiac hypertrophy, in heart failure, and under conditions that promote arrhythmias both in animal models and in the human heart, underscoring the clinical relevance of CaMKII in cardiac pathophysiology. Both CaMKII and PKA phosphorylate a number of protein targets critical for Ca2+ handling and contraction with similar, but not always identical, functional consequences. How these two pathways communicate with each other remains incompletely understood, however. To maintain homeostasis, cyclic nucleotide levels are regulated by phosphodiesterases (PDEs), with PDE4s predominantly responsible for cAMP degradation in the rodent heart. Here we have reassessed the interaction between cAMP/PKA and Ca2+/CaMKII signaling. We demonstrate that CaMKII activity constrains basal and βAR-activated cAMP levels. Moreover, we show that these effects are mediated, at least in part, by CaMKII regulation of PDE4D. This regulation establishes a negative feedback loop necessary to maintain cAMP/CaMKII homeostasis, revealing a previously unidentified function for PDE4D as a critical integrator of cAMP/PKA and Ca2+/CaMKII signaling.
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Ridefelt, Peter, Peter Nygren, Per Hellman, Rolf Larsson, Jonas Rastad, Göran Åkerström, and Erik Gylfe. "Regulation of parathyroid hormone release in normal and pathological parathyroid cells exposed to modulators of protein kinase C." Acta Endocrinologica 126, no. 6 (June 1992): 505–9. http://dx.doi.org/10.1530/acta.0.1260505.
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Effects of the protein kinase C activating phorbol ester 12-O-tetradecanoyl phorbol 13-acetate and the inhibitor 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7) on parathyroid hormone (PTH) release were studied in normal bovine and pathological human parathyroid cells. An increase of extracellular Ca2+ from 0.5 to 3.0 mmol/l inhibited PTH release by 60% in the bovine cells with half maximal effect (ED50) at 1.31 mmol/l. This inhibition reached less than 50% in the cells from patients with primary and uremic hyperparathyroidism, and the ED50 values were 1.49 and 1.42 mmol/l, respectively. The phorbol ester (0.1 μmol/l) made secretion insensitive to changes of extracellular Ca2+, an action counteracted by H-7 (50 μmol/l) in the bovine cells, whereas H-7 alone had no effects. The phorbol ester and H-7 had opposite actions on regulation of PTH release also from cells from patients with hyperparathyroidism. However, in pathological cells H-7 alone improved Ca2+ inhibition of secretion by stimulating release in low Ca2+ concentrations and decreasing the ED50 values. The magnitude of changes in ED50 values by H-7 increased with the severity of the secretory disturbance of the pathological cells. The results indicate that increased protein kinase C activity may be a factor of importance in the pathophysiology of hyperparathyroidism.
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Berry, C., R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns. "Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 6 (December 1, 2001): H2337—H2365. http://dx.doi.org/10.1152/ajpheart.2001.281.6.h2337.
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Angiotensin II (ANG II) is a pleiotropic vasoactive peptide that binds to two distinct receptors: the ANG II type 1 (AT1) and type 2 (AT2) receptors. Activation of the renin-angiotensin system (RAS) results in vascular hypertrophy, vasoconstriction, salt and water retention, and hypertension. These effects are mediated predominantly by AT1 receptors. Paradoxically, other ANG II-mediated effects, including cell death, vasodilation, and natriuresis, are mediated by AT2 receptor activation. Our understanding of ANG II signaling mechanisms remains incomplete. AT1receptor activation triggers a variety of intracellular systems, including tyrosine kinase-induced protein phosphorylation, production of arachidonic acid metabolites, alteration of reactive oxidant species activities, and fluxes in intracellular Ca2+concentrations. AT2 receptor activation leads to stimulation of bradykinin, nitric oxide production, and prostaglandin metabolism, which are, in large part, opposite to the effects of the AT1 receptor. The signaling pathways of ANG II receptor activation are a focus of intense investigative effort. We critically appraise the literature on the signaling mechanisms whereby AT1 and AT2 receptors elicit their respective actions. We also consider the recently reported interaction between ANG II and ceramide, a lipid second messenger that mediates cytokine receptor activation. Finally, we discuss the potential physiological cross talk that may be operative between the angiotensin receptor subtypes in relation to health and cardiovascular disease. This may be clinically relevant, inasmuch as inhibitors of the RAS are increasingly used in treatment of hypertension and coronary heart disease, where activation of the RAS is recognized.
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Vepa, Suryanarayana, William M. Scribner, Narasimham L. Parinandi, Denis English, Joe G. N. Garcia, and Viswanathan Natarajan. "Hydrogen peroxide stimulates tyrosine phosphorylation of focal adhesion kinase in vascular endothelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 277, no. 1 (July 1, 1999): L150—L158. http://dx.doi.org/10.1152/ajplung.1999.277.1.l150.
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Reactive oxygen species (ROS) are implicated in the pathophysiology of several vascular disorders including atherosclerosis. Although the mechanism(s) of ROS-induced vascular damage remains unclear, there is increasing evidence for ROS-mediated modulation of signal transduction pathways. Exposure of bovine pulmonary artery endothelial cells to hydrogen peroxide (H2O2) enhanced tyrosine phosphorylation of 60- to 80- and 110- to 130-kDa cellular proteins, which were determined by immunoprecipitation with specific antibodies focal adhesion kinase (p125FAK) and paxillin (p68). Brief exposure of cells to a relatively high concentration of H2O2(1 mM) resulted in a time- and dose-dependent tyrosine phosphorylation of FAK, which reached maximum levels within 10 min (290% of basal levels). Cytoskeletal reorganization as evidenced by the appearance of actin stress fibers preceded H2O2-induced tyrosine phosphorylation of FAK, and the microfilament disruptor cytochalasin D also attenuated the tyrosine phosphorylation of FAK. Treatment of BPAECs with 1,2-bis(2-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid-AM attenuated H2O2-induced increases in intracellular Ca2+but did not show any consistent effect on H2O2-induced tyrosine phosphorylation of FAK. Several tyrosine kinase inhibitors, including genistein, herbimycin, and tyrphostin, had no detectable effect on tyrosine phosphorylation of FAK but attenuated the H2O2-induction of mitogen-activated protein kinase activity. We conclude that H2O2-induced increases in FAK tyrosine phosphorylation may be important in H2O2-mediated endothelial cell activation.
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Tsiokas, Leonidas. "Function and regulation of TRPP2 at the plasma membrane." American Journal of Physiology-Renal Physiology 297, no. 1 (July 2009): F1—F9. http://dx.doi.org/10.1152/ajprenal.90277.2008.
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The vast majority (∼99%) of all known cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by naturally occurring mutations in two separate, but genetically interacting, loci, pkd1 and pkd2. pkd1 encodes a large multispanning membrane protein (PKD1) of unknown function, while pkd2 encodes a protein (TRPP2, polycystin-2, or PKD2) of the transient receptor potential (TRP) superfamily of ion channels. Biochemical, functional, and genetic studies support a model in which PKD1 physically interacts with TRPP2 to form an ion channel complex that conveys extracellular stimuli to ionic currents. However, the molecular identity of these extracellular stimuli remains elusive. Functional studies in cell culture show that TRPP2 can be activated in response to mechanical cues (fluid shear stress) and/or receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR) activation at the cell surface. Recent genetic studies in Chlamydomonas reinhardtii show that CrPKD2 functions in a pathway linking cell-cell adhesion and Ca2+ signaling. The mode of activation depends on protein-protein interactions with other channel subunits and auxiliary proteins. Therefore, understanding the mechanisms underlying the molecular makeup of TRPP2-containing complexes is critical in delineating the mechanisms of TRPP2 activation and, most importantly, the mechanisms by which naturally occurring mutations in pkd1 or pkd2 lead not only to ADPKD, but also to other defects reported in model organisms lacking functional TRPP2. This review focuses on the molecular assembly, function, and regulation of TRPP2 as a cell surface cation channel and discusses its potential role in Ca2+ signaling and ADPKD pathophysiology.
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Tsai, Wen-Chin, Liang-Yo Yang, Yao-Chang Chen, Yu-Hsun Kao, Yung-Kuo Lin, Shih-Ann Chen, Ching-Feng Cheng, and Yi-Jen Chen. "Ablation of the Androgen Receptor Gene Modulates Atrial Electrophysiology and Arrhythmogenesis With Calcium Protein Dysregulation." Endocrinology 154, no. 8 (August 1, 2013): 2833–42. http://dx.doi.org/10.1210/en.2012-2265.
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Abstract Androgen deficiency is important in the pathophysiology of atrial fibrillation. Androgen regulates cardiac electrophysiology and calcium (Ca2+) homeostasis. The purpose of this study is to evaluate whether androgen receptor knockout (ARKO) can modulate atrial electrophysiology and arrhythmogenesis with modulation of Ca2+ homeostasis proteins. We used conventional microelectrodes to study the action potential (AP) in left atrium (LA) tissues prepared from wild-type (WT) and ARKO mice (aged 6–10 months) before and after the administration of isoproterenol, hypocalcemic/hypercalcemic solutions, and ouabain. Echocardiography and Western blots were used to evaluate the cardiac function and expression levels of ionic channel proteins in WT and ARKO LAs. ARKO LAs had larger LA diameter with decreased LA fractional shortening than did WT LAs. In the current study, we found that ARKO LAs had a lower negative resting membrane potential and a greater 90% AP duration (APD) than did WT LAs. Isoproterenol increased the incidence and amplitude of delayed afterdepolarizations (DADs) in ARKO LAs but not in WT LAs. Hypocalcemic solutions prolonged APD in WT and ARKO LAs but increased DAD amplitude only in ARKO LAs. Hypercalcemic solutions shortened APD in ARKO LAs but not in WT LAs. Ouabain increased DAD amplitude in ARKO LAs but not in WT LAs. ARKO LAs expressed higher amounts of Ca2+/calmodulin-dependent protein kinase II, Na+/Ca2+ exchanger, and phosphorylated phospholamban (Ser-16/Thr-17 site) and less Cav1.2, Kir2.1, Kir3.1, and Kv7.1 than WT LAs. These observations indicate that ARKO alters atrial electrophysiology with increased atrial arrhythmogenesis.
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Chang, Lingling, Zhijun Wang, Fenfen Ma, Bahieu Tran, Rui Zhong, Ying Xiong, Tao Dai, et al. "ZYZ-803 Mitigates Endoplasmic Reticulum Stress-Related Necroptosis after Acute Myocardial Infarction through Downregulating the RIP3-CaMKII Signaling Pathway." Oxidative Medicine and Cellular Longevity 2019 (June 2, 2019): 1–18. http://dx.doi.org/10.1155/2019/6173685.
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Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide, and both cardiac necroptosis and endoplasmic reticulum stress (ERS) have been involved in the pathophysiology of AMI. ZYZ-803 is a hybrid molecule of a dual donor for gasotransmitters H2S and NO. The aim of the present study is to investigate the antinecroptosis role and potential mechanisms of ZYZ-803 in the setting of ERS during AMI injury. In vivo, ZYZ-803 preserves cardiac function and reduces infarct size significantly after 24-hour left coronary artery ligation through revising H2S and NO imbalance. In addition, ZYZ-803 relieves ERS and necroptosis in an AMI heart. In vitro, ZYZ-803 ameliorates ERS-related necroptosis induced by tunicamycin, and such effect has been depending on the receptor-interacting protein 3- (RIP3-) Ca2+-calmodulin-dependent protein kinase (CaMKII) signaling pathway. These findings have identified a novel antinecroptosis potential of ZYZ-803, providing a valuable candidate for cardioprotection in acute myocardial ischemia.
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Pinna, Lorenzo A. "Protein kinase CK2." International Journal of Biochemistry & Cell Biology 29, no. 4 (April 1997): 551–54. http://dx.doi.org/10.1016/s1357-2725(96)00142-2.
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Montgomery, David E., Veronica L. M. Rundell, Paul H. Goldspink, Dalia Urboniene, David L. Geenen, Pieter P. de Tombe, and Peter M. Buttrick. "Protein kinase Cε induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 5 (November 2005): H1881—H1888. http://dx.doi.org/10.1152/ajpheart.00454.2005.
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Myofilament dysfunction is a common point of convergence for many forms of heart failure. Recently, we showed that cardiac overexpression of PKCε initially depresses myofilament activity and then leads to a progression of changes characteristic of human heart failure. Here, we examined the effects of PKCε on contractile reserve, Starling mechanism, and myofilament activation in this model of end-stage dilated cardiomyopathy. Pressure-volume loop analysis and echocardiography showed that the PKCε mice have markedly compromised systolic function and increased end-diastolic volumes. Dobutamine challenge resulted in a small increase in contractility in PKCε mice but failed to enhance cardiac output. The PKCε mice showed a normal length-dependent tension development in skinned cardiac muscle preparations, although Frank-Starling mechanism appeared to be compromised in the intact animal. Simultaneous measurement of tension and ATPase demonstrated that the maximum tension and ATPase were markedly lower in the PKCε mice at any length or Ca2+ concentration. However, the tension cost was also lower indicating less energy expenditure. We conclude 1) that prolonged overexpression of PKCε ultimately leads to a dilated cardiomyopathy marked by exhausted contractile reserve, 2) that PKCε does not compromise the Frank-Starling mechanism at the myofilament level, and 3) that the Starling curve excursion is limited by the inotropic state of the heart. These results reflect the significance of the primary myofilament contractilopathy induced by phosphorylation and imply a role for PKCε-mediated phosphorylation in myofilament physiology and the pathophysiology of decompensated cardiac failure.
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Akimoto, Tatsuyuki, Ichiro Kusumi, Katsuji Suzuki, and Tsukasa Koyama. "Effects of calmodulin and protein kinase C modulators on transient Ca2+ increase and capacitative Ca2+ entry in human platelets: Relevant to pathophysiology of bipolar disorder." Progress in Neuro-Psychopharmacology and Biological Psychiatry 31, no. 1 (January 2007): 136–41. http://dx.doi.org/10.1016/j.pnpbp.2006.08.008.
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Levin, Mark D., Gautam K. Singh, Hai Xia Zhang, Keita Uchida, Beth A. Kozel, Phyllis K. Stein, Atilla Kovacs, et al. "KATP channel gain-of-function leads to increased myocardial L-type Ca2+ current and contractility in Cantu syndrome." Proceedings of the National Academy of Sciences 113, no. 24 (May 31, 2016): 6773–78. http://dx.doi.org/10.1073/pnas.1606465113.
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Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) KATP channel subunits. We show that patients with CS, as well as mice with constitutive (cGOF) or tamoxifen-induced (icGOF) cardiac-specific Kir6.1 GOF subunit expression, have enlarged hearts, with increased ejection fraction and increased contractility. Whole-cell voltage-clamp recordings from cGOF or icGOF ventricular myocytes (VM) show increased basal L-type Ca2+ current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascular-specific expression (vGOF) show left ventricular dilation as well as less-markedly increased LTCC. Increased LTCC in KATP GOF models is paralleled by changes in phosphorylation of the pore-forming α1 subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928, suggesting enhanced protein kinase activity as a potential link between increased KATP current and CS cardiac pathophysiology.
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Saksena, Seema, Ravinder K. Gill, Sangeeta Tyagi, Waddah A. Alrefai, Krishnamurthy Ramaswamy, and Pradeep K. Dudeja. "Role of Fyn and PI3K in H2O2-induced inhibition of apical Cl−/OH− exchange activity in human intestinal epithelial cells." Biochemical Journal 416, no. 1 (October 28, 2008): 99–108. http://dx.doi.org/10.1042/bj20070960.
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H2O2 is a highly reactive oxygen metabolite that has been implicated as an important mediator of inflammation-induced intestinal injury associated with ischaemia/reperfusion, radiation and inflammatory bowel disease. Previous studies have shown that H2O2 inhibits NaCl absorption and activates Cl− secretion in the rat and rabbit colon. To date, however, almost no information is available with respect to its effect on the human intestinal apical anion exchanger Cl−/OH− (HCO3−). The present studies were, therefore, undertaken to examine the direct effects of H2O2 on OH− gradient-driven DIDS (4,4′-di-isothiocyanostilbene-2,2′-disulfonate)-sensitive 36Cl− uptake utilizing a post-confluent transformed human intestinal epithelial cell line, Caco-2. Our results demonstrate that H2O2 (1 mM for 60 min) significantly inhibited (approx. 60%; P<0.05) Cl−/OH− exchange activity in Caco-2 cells. H2O2-mediated inhibition of Cl−/OH− exchange activity involved the Src kinase Fyn and PI3K (phosphoinositide 3-kinase)-dependent pathways. H2O2 also induced phosphorylation of Fyn and p85 (the regulatory subunit of PI3K) in Caco-2 cells. Moreover, an increased association of Fyn and p85 was observed in response to H2O2, resulting in the activation of the downstream target PLCγ1 (phospholipase Cγ1). Elevated intracellular Ca2+ levels and PKCα (protein kinase Cα) functioned as downstream effectors of H2O2-induced PLCγ1 activation. Our results, for the first time, provide evidence for H2O2-induced Src kinase Fyn/PI3K complex association. This complex association resulted in the subsequent activation of PLCγ1 and Ca2+-dependent PKCα, resulting in the inhibition of Cl−/OH− exchange activity. These findings suggest that H2O2-induced inhibition of the Cl−/OH− exchange process may play an important role in the pathophysiology of diarrhoea associated with inflammatory disorders, where the amount of reactive oxygen species is markedly elevated.
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Jefferson, D. M., J. D. Valentich, F. C. Marini, S. A. Grubman, M. C. Iannuzzi, H. L. Dorkin, M. Li, K. W. Klinger, and M. J. Welsh. "Expression of normal and cystic fibrosis phenotypes by continuous airway epithelial cell lines." American Journal of Physiology-Lung Cellular and Molecular Physiology 259, no. 6 (December 1, 1990): L496—L505. http://dx.doi.org/10.1152/ajplung.1990.259.6.l496.
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Continuous epithelial cell lines from individuals with cystic fibrosis (CF) and normal controls are required to understand the genetic and cellular defects in CF. We used retroviruses to transduce SV40 large T antigen into nasal epithelial cells. Transformed continuous cell lines were isolated that expressed epithelial markers, cytokeratin, and tight junctions. Northern blot analysis shows that all of the cell lines express the putative CF gene mRNA. Studies of transepithelial electrolyte transport show that CF and normal cell lines develop a transepithelial electrical resistance. Normal but not CF cell lines secreted Cl- in response to agonists that increase cellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) (isoproterenol, forskolin, and a membrane-permeant analogue of cAMP) or in response to a tumor-promoting phorbol ester that activates protein kinase C. In contrast, the Ca2(+)-elevating agonist bradykinin and the Ca2+ ionophore A23187 stimulated secretion in both normal and CF cell lines. The continuous cell lines we have produced maintain their proper phenotypes and will serve as useful tools in understanding the pathophysiology of CF.
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Al, Z., and C. M. Cohen. "Phorbol 12-myristate 13-acetate-stimulated phosphorylation of erythrocyte membrane skeletal proteins is blocked by calpain inhibitors: possible role of protein kinase M." Biochemical Journal 296, no. 3 (December 15, 1993): 675–83. http://dx.doi.org/10.1042/bj2960675.
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Human erythrocytes contain cytosolic protein kinase C (PKC) which, when activated by phorbol 12-myristate 13-acetate (PMA), induces the phosphorylation of the membrane skeletal proteins band 4.1, band 4.9 and adducin. We found that brief treatments of erythrocytes with PMA resulted in a decrease in cytosolic PKC content and in the transient appearance in the cytosol of a Ca(2+)- and phospholipid-independent 55 kDa fragment of PKC, called PKM. Prolonged treatment with PMA resulted in the complete and irreversible loss of erythrocyte PKC. To investigate the possible role of calpain in this process, the calpain inhibitors leupeptin and E-64 were sealed inside erythrocytes by reversible haemolysis. Both inhibitors prolonged the lifetime of PKC in PMA-treated cells, and leupeptin was shown to block the PMA-stimulated appearance of PKM in the cytosol. Significantly, leupeptin also completely blocked PMA-stimulated phosphorylation of membrane and cytosolic substrates. This effect was mimicked by other calpain inhibitors (MDL-28170 and calpain inhibitor I), but did not occur when other protease inhibitors such as phenylmethanesulphonyl fluoride, pepstatin A or chymostatin were used. In addition, the phosphorylation of exogenous histone sealed inside erythrocytes was also blocked by leupeptin. Immunoblotting showed that leupeptin did not prevent the PMA-induced translocation of PKC to the erythrocyte membrane. Thus inhibition of PKC phosphorylation of membrane skeletal proteins by calpain inhibitors was not due to inhibition of PKC translocation to the membrane. Our results suggest that PMA treatment of erythrocytes results in the translocation of PKC to the plasma membrane, followed by calpain-mediated cleavage of PKC to PKM. This cleavage, or some other leupeptin-inhibitable process, is a necessary step for the phosphorylation of membrane skeletal substrates, suggesting that the short-lived PKM may be responsible for membrane skeletal phosphorylation. Our results suggest a potential mechanism whereby erythrocyte PKC may be subject to continual down-regulation during the lifespan of the erythrocyte due to repeated activation events, possibly related to transient Ca2+ influx. Such down-regulation may play an important role in erythrocyte survival or pathophysiology.
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Kume, Hiroaki, Ryuki Yamada, Yuki Sato, and Ryuichi Togawa. "Airway Smooth Muscle Regulated by Oxidative Stress in COPD." Antioxidants 12, no. 1 (January 6, 2023): 142. http://dx.doi.org/10.3390/antiox12010142.
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Since COPD is a heterogeneous disease, a specific anti-inflammatory therapy for this disease has not been established yet. Oxidative stress is recognized as a major predisposing factor to COPD related inflammatory responses, resulting in pathological features of small airway fibrosis and emphysema. However, little is known about effects of oxidative stress on airway smooth muscle. Cigarette smoke increases intracellular Ca2+ concentration and enhances response to muscarinic agonists in human airway smooth muscle. Cigarette smoke also enhances proliferation of these cells with altered mitochondrial protein. Hydrogen peroxide and 8-isoprostans are increased in the exhaled breath condensate in COPD. These endogenous oxidants cause contraction of tracheal smooth muscle with Ca2+ dynamics through Ca2+ channels and with Ca2+ sensitization through Rho-kinase. TNF-α and growth factors potentiate proliferation of these cells by synthesis of ROS. Oxidative stress can alter the function of airway smooth muscle through Ca2+ signaling. These phenotype changes are associated with manifestations (dyspnea, wheezing) and pathophysiology (airflow limitation, airway remodeling, airway hyperresponsiveness). Therefore, airway smooth muscle is a therapeutic target against COPD; oxidative stress should be included in treatable traits for COPD to advance precision medicine. Research into Ca2+ signaling related to ROS may contribute to the development of a novel agent for COPD.
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Kumamaru, Emi, Tadahiro Numakawa, Naoki Adachi, Yuki Yagasaki, Aiko Izumi, Madinyet Niyaz, Motoshige Kudo, and Hiroshi Kunugi. "Glucocorticoid Prevents Brain-Derived Neurotrophic Factor-Mediated Maturation of Synaptic Function in Developing Hippocampal Neurons through Reduction in the Activity of Mitogen-Activated Protein Kinase." Molecular Endocrinology 22, no. 3 (March 1, 2008): 546–58. http://dx.doi.org/10.1210/me.2007-0264.
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Abstract An increased level of glucocorticoid may be related to the pathophysiology of depressive disorder. The involvement of brain-derived neurotrophic factor (BDNF) in the antidepressive effect has also been suggested; however, the possible influence of glucocorticoid on the action of BDNF in the developing central nervous system has not been elucidated. In this study, we investigated the effect of glucocorticoid (dexamethasone, DEX) on synaptic maturation and function enhanced by BDNF in early developing hippocampal neurons. In the immature stage, BDNF increased the outgrowth of dendrites and the expression of synaptic proteins including glutamate receptors and presynaptic proteins. Pretreatment with DEX significantly inhibited the BDNF-dependent up-regulation of both dendritic outgrowth and synaptic proteins. In the more mature stage, the BDNF-reinforced postsynaptic Ca2+ influx was decreased by DEX. BDNF-enhanced presynaptic glutamate release was also suppressed. RU486, a glucocorticoid receptor antagonist, canceled the DEX-dependent blocking effect on the action of BDNF. After down-regulation of glucocorticoid receptor by small interfering RNA application, no inhibitory effect of DEX on the BDNF-increased synaptic proteins was observed. Interestingly, the BDNF-activated MAPK/ERK pathway, which is an essential intracellular signaling pathway for the BDNF-increased synaptic proteins, was reduced by DEX. These results suggest that BDNF-mediated synaptic maturation is disturbed after neurons are exposed to high-level glucocorticoid in their development stage.
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Di Buduo, Christian A., Vittorio Abbonante, Caroline Marty, Francesco Moccia, Elisa Rumi, Daniela Pietra, Paolo M. Soprano, et al. "Defective interaction of mutant calreticulin and SOCE in megakaryocytes from patients with myeloproliferative neoplasms." Blood 135, no. 2 (January 9, 2020): 133–44. http://dx.doi.org/10.1182/blood.2019001103.
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Abstract Approximately one-fourth of patients with essential thrombocythemia or primary myelofibrosis carry a somatic mutation of the calreticulin gene (CALR), the gene encoding for calreticulin. A 52-bp deletion (type I mutation) and a 5-bp insertion (type II mutation) are the most frequent genetic lesions. The mechanism(s) by which a CALR mutation leads to a myeloproliferative phenotype has been clarified only in part. We studied the interaction between calreticulin and store-operated calcium (Ca2+) entry (SOCE) machinery in megakaryocytes (Mks) from healthy individuals and from patients with CALR-mutated myeloproliferative neoplasms (MPNs). In Mks from healthy subjects, binding of recombinant human thrombopoietin to c-Mpl induced the activation of signal transducer and activator of transcription 5, AKT, and extracellular signal-regulated kinase 1/2, determining inositol triphosphate–dependent Ca2+ release from the endoplasmic reticulum (ER). This resulted in the dissociation of the ER protein 57 (ERp57)-mediated complex between calreticulin and stromal interaction molecule 1 (STIM1), a protein of the SOCE machinery that leads to Ca2+ mobilization. In Mks from patients with CALR-mutated MPNs, defective interactions between mutant calreticulin, ERp57, and STIM1 activated SOCE and generated spontaneous cytosolic Ca2+ flows. In turn, this resulted in abnormal Mk proliferation that was reverted using a specific SOCE inhibitor. In summary, the abnormal SOCE regulation of Ca2+ flows in Mks contributes to the pathophysiology of CALR-mutated MPNs. In perspective, SOCE may represent a new therapeutic target to counteract Mk proliferation and its clinical consequences in MPNs.
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Li, Pei-Feng, Jincheng Li, Eva-Christina Müller, Albrecht Otto, Rainer Dietz, and Rüdiger von Harsdorf. "Phosphorylation by Protein Kinase CK2." Molecular Cell 10, no. 2 (August 2002): 247–58. http://dx.doi.org/10.1016/s1097-2765(02)00600-7.
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Wirkner, U., H. Voss, P. Lichter, W. Ansorge, and W. Pyerin. "Human protein kinase CK2 genes." Journal of Cancer Research and Clinical Oncology 121, S1 (January 1995): A14. http://dx.doi.org/10.1007/bf02572021.
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Montenarh, Mathias. "Protein Kinase CK2 and Angiogenesis." Advances in Clinical and Experimental Medicine 23, no. 2 (2014): 153–58. http://dx.doi.org/10.17219/acem/37040.
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Baier, Andrea, Ryszard Szyszka, and Monika Elżbieta Jach. "Yeast Protein Asf1 Possesses Modulating Activity towards Protein Kinase CK2." International Journal of Molecular Sciences 23, no. 24 (December 12, 2022): 15764. http://dx.doi.org/10.3390/ijms232415764.
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Protein kinase CK2 plays an important role in cell survival and protects regulatory proteins from caspase-mediated degradation during apoptosis. The consensus sequence of proteins phosphorylated by CK2 contains a cluster of acidic amino acids around the phosphorylation site. The poly-acidic sequence in yeast protein Asf1 is similar to the acidic loop in CK2β, which possesses a regulatory function. We observed that the overexpression of Asf1 in yeast cells influences cell growth. Experiments performed in vitro and in vivo indicate that yeast protein Asf1 inhibits protein kinase CK2. Our data suggest that each CK2 isoform might be regulated in a different way. Deletion of the amino or carboxyl end of Asf1 reveals that the acidic cluster close to the C-terminus is responsible for the activation or inhibition of CK2 activity.
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Montenarh, Mathias, Friedrich A. Grässer, and Claudia Götz. "Protein Kinase CK2 and Epstein–Barr Virus." Biomedicines 11, no. 2 (January 26, 2023): 358. http://dx.doi.org/10.3390/biomedicines11020358.
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Protein kinase CK2 is a pleiotropic protein kinase, which phosphorylates a number of cellular and viral proteins. Thereby, this kinase is implicated in the regulation of cellular signaling, controlling of cell proliferation, apoptosis, angiogenesis, immune response, migration and invasion. In general, viruses use host signaling mechanisms for the replication of their genome as well as for cell transformation leading to cancer. Therefore, it is not surprising that CK2 also plays a role in controlling viral infection and the generation of cancer cells. Epstein–Barr virus (EBV) lytically infects epithelial cells of the oropharynx and B cells. These latently infected B cells subsequently become resting memory B cells when passing the germinal center. Importantly, EBV is responsible for the generation of tumors such as Burkitt’s lymphoma. EBV was one of the first human viruses, which was connected to CK2 in the early nineties of the last century. The present review shows that protein kinase CK2 phosphorylates EBV encoded proteins as well as cellular proteins, which are implicated in the lytic and persistent infection and in EBV-induced neoplastic transformation. EBV-encoded and CK2-phosphorylated proteins together with CK2-phosphorylated cellular signaling proteins have the potential to provide efficient virus replication and cell transformation. Since there are powerful inhibitors known for CK2 kinase activity, CK2 might become an attractive target for the inhibition of EBV replication and cell transformation.
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MEGGIO, Flavio, Alessandro NEGRO, Stefania SARNO, Maria RUZZENE, Alessandro BERTOLI, M. Catia SORGATO, and Lorenzo A. PINNA. "Bovine prion protein as a modulator of protein kinase CK2." Biochemical Journal 352, no. 1 (November 7, 2000): 191–96. http://dx.doi.org/10.1042/bj3520191.
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On the basis of far-Western blot and plasmon resonance (BIAcore) experiments, we show here that recombinant bovine prion protein (bPrP) (25–242) strongly interacts with the catalytic α/α´ subunits of protein kinase CK2 (also termed ‘casein kinase 2’). This association leads to increased phosphotransferase activity of CK2α, tested on calmodulin or specific peptides as substrate. We also show that bPrP counteracts the inhibition of calmodulin phosphorylation promoted by the regulatory β subunits of CK2. A truncated form of bPrP encompassing the C-terminal domain (residues 105–242) interacts with CK2 but does not affect its catalytic activity. The opposite is found with the N-terminal fragment of bPrP (residues 25–116), although the stimulation of catalysis is less efficient than with full-size bPrP. These results disclose the potential of the PrP to modulate the activity of CK2, a pleiotropic protein kinase that is particularly abundant in the brain.
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Shavit-Stein, Efrat, Shani Berkowitz, Shany Guly Gofrit, Keren Altman, Nitai Weinberg, and Nicola Maggio. "Neurocoagulation from a Mechanistic Point of View in the Central Nervous System." Seminars in Thrombosis and Hemostasis 48, no. 03 (January 20, 2022): 277–87. http://dx.doi.org/10.1055/s-0041-1741569.
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AbstractCoagulation mechanisms are critical for maintaining homeostasis in the central nervous system (CNS). Thrombin, an important player of the coagulation cascade, activates protease activator receptors (PARs), members of the G-protein coupled receptor family. PAR1 is located on neurons and glia. Following thrombin activation, PAR1 signals through the extracellular signal-regulated kinase pathway, causing alterations in neuronal glutamate release and astrocytic morphological changes. Similarly, the anticoagulation factor activated protein C (aPC) can cleave PAR1, following interaction with the endothelial protein C receptor. Both thrombin and aPC are expressed on endothelial cells and pericytes in the blood-brain barrier (BBB). Thrombin-induced PAR1 activation increases cytosolic Ca2+ concentration in brain vessels, resulting in nitric oxide release and increasing F-actin stress fibers, damaging BBB integrity. aPC also induces PAR1 activation and preserves BBB vascular integrity via coupling to sphingosine 1 phosphate receptors. Thrombin-induced PAR1 overactivation and BBB disruption are evident in CNS pathologies. During epileptic seizures, BBB disruption promotes thrombin penetration. Thrombin induces PAR1 activation and potentiates N-methyl-D-aspartate receptors, inducing glutamate-mediated hyperexcitability. Specific PAR1 inhibition decreases status epilepticus severity in vivo. In stroke, the elevation of brain thrombin levels further compromises BBB integrity, with direct parenchymal damage, while systemic factor Xa inhibition improves neurological outcomes. In multiple sclerosis (MS), brain thrombin inhibitory capacity correlates with clinical presentation. Both thrombin inhibition by hirudin and the use of recombinant aPC improve disease severity in an MS animal model. This review presents the mechanisms underlying the effects of coagulation on the physiology and pathophysiology of the CNS.
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Shin, Yong Jae, Yong-Bae Kim, and Jeong-Ho Kim. "Protein kinase CK2 phosphorylates and activates p21-activated kinase 1." Molecular Biology of the Cell 24, no. 18 (September 15, 2013): 2990–99. http://dx.doi.org/10.1091/mbc.e13-04-0204.
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Activation of the p21-activated kinase 1 (PAK1) is achieved through a conformational change that converts an inactive PAK1 dimer to an active monomer. In this paper, we show that this change is necessary but not sufficient to activate PAK1 and that it is, rather, required for CK2-dependent PAK1S223 phosphorylation that converts a monomeric PAK1 into a catalytically active form. This phosphorylation appears to be essential for autophosphorylation at specific residues and overall activity of PAK1. A phosphomimetic mutation (S223E) bypasses the requirement for GTPases in PAK1 activation, whereas the constitutive activity of the PAK1 mutant (PAK1H83,86L), postulated to mimic GTPase-induced structural changes, is abolished by inhibition of S223 phosphorylation. Thus, S223 is likely accessible to CK2 upon conformational changes of PAK1 induced by GTPase-dependent and GTPase-independent stimuli, suggesting that S223 phosphorylation may play a key role in the final step of the PAK1 activation process. The physiological significance of this phosphorylation is reinforced by the observations that CK2 is responsible for epidermal growth factor–induced PAK1 activation and that inhibition of S223 phosphorylation abrogates PAK1-mediated malignant transformation of prostate epithelial cells. Taken together, these findings identify CK2 as an upstream activating kinase of PAK1, providing a novel mechanism for PAK1 activation.
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Heo, Jinho, James M. Larner, and David L. Brautigan. "Protein kinase CK2 phosphorylation of SAPS3 subunit increases PP6 phosphatase activity with Aurora A kinase." Biochemical Journal 477, no. 2 (January 30, 2020): 431–44. http://dx.doi.org/10.1042/bcj20190740.
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Protein Ser/Thr phosphatase-6 (PP6) regulates pathways for activation of NF-kB, YAP1 and Aurora A kinase (AURKA). PP6 is a heterotrimer comprised of a catalytic subunit, one of three different SAPS subunits and one of three different ankyrin-repeat ANKRD subunits. Here, we show FLAG-PP6C expressed in cells preferentially binds endogenous SAPS3, and the complex is active with the chemical substrate DiFMUP. SAPS3 has multiple acidic sequence motifs recognized by protein kinase CK2 (CK2) and SAPS3 is phosphorylated by purified CK2, without affecting its associated PP6 phosphatase activity. However, HA3-SAPS3-PP6 phosphatase activity using pT288 AURKA as substrate is significantly increased by phosphorylation with CK2. The substitution of Ala in nine putative phosphorylation sites in SAPS3 was required to prevent CK2 activation of the phosphatase. Different CK2 chemical inhibitors equally increased phosphorylation of endogenous AURKA in living cells, consistent with reduction in PP6 activity. CRISPR/Cas9 deletion or siRNA knockdown of SAPS3 resulted in highly activated endogenous AURKA, and a high proportion of cells with abnormal nuclei. Activation of PP6 by CK2 can form a feedback loop with bistable changes in substrates.
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Guerra, Barbara, and Olaf-Georg Issinger. "Protein Kinase CK2 in Human Diseases." Current Medicinal Chemistry 15, no. 19 (August 1, 2008): 1870–86. http://dx.doi.org/10.2174/092986708785132933.
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Faust, Michael, and Mathias Montenarh. "Subcellular localization of protein kinase CK2." Cell and Tissue Research 301, no. 3 (August 18, 2000): 329–40. http://dx.doi.org/10.1007/s004410000256.
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Kramerov, Andrei A., and Alexander V. Ljubimov. "Focus on Molecules: Protein kinase CK2." Experimental Eye Research 101 (August 2012): 111–12. http://dx.doi.org/10.1016/j.exer.2010.12.011.
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Montenarh, Mathias. "Cellular regulators of protein kinase CK2." Cell and Tissue Research 342, no. 2 (October 27, 2010): 139–46. http://dx.doi.org/10.1007/s00441-010-1068-3.
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Deshière, Alexandre, Nathalie Theis-Febvre, Véronique Martel, Claude Cochet, and Odile Filhol. "Protein kinase CK2 and cell polarity." Molecular and Cellular Biochemistry 316, no. 1-2 (June 28, 2008): 107–13. http://dx.doi.org/10.1007/s11010-008-9845-y.
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Cozza, Giorgio, Andrea Bortolato, and Stefano Moro. "How druggable is protein kinase CK2?" Medicinal Research Reviews 30, no. 3 (June 12, 2009): 419–62. http://dx.doi.org/10.1002/med.20164.
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Wei, Hairong, Wei Yang, Zhaoqi Yan, Hongwei Qin, and Etty Benveniste. "Protein Kinase CK2 Drives Plasma Cell Differentiation." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 188.1. http://dx.doi.org/10.4049/jimmunol.202.supp.188.1.
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Abstract Casein kinase 2 (CK2) is a serine/threonine protein kinase composed of three subunits: two catalytic subunits, CK2α and CK2α’, and the regulatory subunit CK2β. It is overexpressed and overactive in B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphomas, leading to inappropriate activation of NF-κB, JAK/STAT and PI3K/AKT/mTOR signaling, but little is known about how CK2 functions in normal B-cell differentiation. Here, we demonstrate that CK2 mRNA and protein expression is induced upon B-cell activation. Using the small molecule inhibitor CX-4945, which targets the catalytic activity of CK2, a significant inhibition of plasma cell differentiation was observed in vitro under T-cell-independent (TI) or T-cell-dependent (TD) conditions via stimulation with lipopolysaccharide (LPS) or CD40L and interleukin 4 (IL-4) +IL-5, respectively. At the cellular level, we found that inhibition of CK2 kinase activity in B-cells resulted in defective mTORC1 signaling upon stimulation with LPS. These results were confirmed in purified mature B-cells from mice with tamoxifen-induced global deletion of CK2α. These data demonstrate that CK2α is an important regulator of B-cell differentiation. Ongoing experiments with B-cell specific deletion of CK2α will further examine the impact of CK2α on B-cell differentiation in vivo.
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POSPÍŠILOVÁ, Šárka, Václav BRÁZDA, Kateřina KUCHAŘÍKOVÁ, M. Gloria LUCIANI, Ted R. HUPP, Petr SKLÁDAL, Emil PALEČEK, and Bořivoj VOJTĚŠEK. "Activation of the DNA-binding ability of latent p53 protein by protein kinase C is abolished by protein kinase CK2." Biochemical Journal 378, no. 3 (March 15, 2004): 939–47. http://dx.doi.org/10.1042/bj20030662.
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p53 is one of the most important regulators of cell proliferation and differentiation and of programmed cell death, triggering growth arrest and/or apoptosis in response to different cellular stress signals. The sequence-specific DNA-binding function of p53 protein can be activated by several different stimuli that modulate the C-terminal domain of this protein. The predominant mechanism of activation of p53 sequence-specific DNA binding is phosphorylation at specific sites. For example, phosphorylation of p53 by PKC (protein kinase C) occurs in undamaged cells, resulting in masking of the epitope recognized by monoclonal antibody PAb421, and presumably promotes steady-state levels of p53 activity in cycling cells. In contrast, phosphorylation by cdk2 (cyclin-dependent kinase 2)/cyclin A and by the protein kinase CK2 are both enhanced in DNA-damaged cells. We determined whether one mechanism to account for this mutually exclusive phosphorylation may be that each phosphorylation event prevents modification by the other kinase. We used non-radioactive electrophoretic mobility shift assays to show that C-terminal phosphorylation of p53 protein by cdk2/cyclin A on Ser315 or by PKC on Ser378 can efficiently stimulate p53 binding to DNA in vitro, as well as binding of the monoclonal antibody Bp53-10, which recognizes residues 371–380 in the C-terminus of p53. Phosphorylation of p53 by CK2 on Ser392 induces its DNA-binding activity to a much lower extent than phosphorylation by cdk2/cyclin A or PKC. In addition, phosphorylation by CK2 strongly inhibits PKC-induced activation of p53 DNA binding, while the activation of p53 by cdk2/cyclin A is not affected by CK2. The presence of CK2-mediated phosphorylation promotes PKC binding to its docking site within the p53 oligomerization domain, but decreases phosphorylation by PKC, suggesting that competition between CK2 and PKC does not rely on the inhibition of PKC–p53 complex formation. These results indicate the crucial role of p53 C-terminal phosphorylation in the regulation of its DNA-binding activity, but also suggest that antagonistic relationships exist between different stress signalling pathways.
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Torrecilla, Ignacio, Elizabeth J. Spragg, Benoit Poulin, Phillip J. McWilliams, Sharad C. Mistry, Andree Blaukat, and Andrew B. Tobin. "Phosphorylation and regulation of a G protein–coupled receptor by protein kinase CK2." Journal of Cell Biology 177, no. 1 (April 2, 2007): 127–37. http://dx.doi.org/10.1083/jcb.200610018.
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We demonstrate a role for protein kinase casein kinase 2 (CK2) in the phosphorylation and regulation of the M3-muscarinic receptor in transfected cells and cerebellar granule neurons. On agonist occupation, specific subsets of receptor phosphoacceptor sites (which include the SASSDEED motif in the third intracellular loop) are phosphorylated by CK2. Receptor phosphorylation mediated by CK2 specifically regulates receptor coupling to the Jun-kinase pathway. Importantly, other phosphorylation-dependent receptor processes are regulated by kinases distinct from CK2. We conclude that G protein–coupled receptors (GPCRs) can be phosphorylated in an agonist-dependent fashion by protein kinases from a diverse range of kinase families, not just the GPCR kinases, and that receptor phosphorylation by a defined kinase determines a specific signalling outcome. Furthermore, we demonstrate that the M3-muscarinic receptor can be differentially phosphorylated in different cell types, indicating that phosphorylation is a flexible regulatory process where the sites that are phosphorylated, and hence the signalling outcome, are dependent on the cell type in which the receptor is expressed.
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Koffa, Maria D., Joy Kean, George Zachos, Stephen A. Rice, and J. Barklie Clements. "CK2 Protein Kinase Is Stimulated and Redistributed by Functional Herpes Simplex Virus ICP27 Protein." Journal of Virology 77, no. 7 (April 1, 2003): 4315–25. http://dx.doi.org/10.1128/jvi.77.7.4315-4325.2003.
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ABSTRACT It has been shown previously (S. Wadd, H. Bryant, O. Filhol, J. E. Scott, T.-T. Hsieh, R. D. Everett, and J. B. Clements, J. Biol. Chem. 274:28991-28998, 2000) that ICP27, an essential and multifunctional herpes simplex virus type 1 (HSV-1) protein, interacts with CK2 and with heterogeneous ribonucleoprotein K (hnRNP K). CK2 is a pleiotropic and ubiquitous protein kinase, and the tetrameric holoenzyme consists of two catalytic α or α′ subunits and two regulatory β subunits. We show here that HSV-1 infection stimulates CK2 activity. CK2 stimulation occurs at early times after infection and correlates with redistribution of the holoenzyme from the nucleus to the cytoplasm. Both CK2 stimulation and redistribution require expression and cytoplasmic accumulation of ICP27. In HSV-1-infected cells, CK2 phosphorylates ICP27 and affects its cytoplasmic accumulation while it also phosphorylates hnRNP K, which is not ordinarily phosphorylated by this kinase, suggesting an alteration of hnRNP K activities. This is the first example of CK2 stimulation by a viral protein in vivo, and we propose that it might facilitate the HSV-1 lytic cycle by, for example, regulating trafficking of ICP27 protein and/or viral RNAs.
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Pagano, M. A., L. Cesaro, F. Meggio, and L. A. Pinna. "Protein kinase CK2: a newcomer in the ‘druggable kinome’." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1303–6. http://dx.doi.org/10.1042/bst0341303.
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The acronym CK2 (derived from the misnomer ‘casein kinase’ 2) denotes one of the most pleiotropic members of the eukaryotic protein kinase superfamily, characterized by an acidic consensus sequence in which a carboxylic acid (or pre-phosphorylated) side chain at position n+3 relative to the target serine/threonine residue plays a crucial role. The latest repertoire of CK2 substrates includes approx. 300 proteins, but the analysis of available phosphopeptide databases from different sources suggests that CK2 alone may be responsible for the generation of a much larger proportion (10–20%) of the eukaryotic phosphoproteome. Although for the time being CK2 is not included among protein kinases whose inhibitors are in clinical practice or in advanced clinical trials, evidence is accumulating that elevated CK2 constitutive activity co-operates to induce a number of pathological conditions, including cancer, infectious diseases, neurodegeneration and cardiovascular pathologies. The development and usage of cell-permeant, selective inhibitors discloses a scenario whereby CK2 plays a global anti-apoptotic role, which under special circumstances may lead to untimely and pathogenic cell survival.
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Chrysanthus, Chukwuma Sr. "The complex interplay in the regulation of cardiac pathophysiologic functionalities by protein kinases and phosphatases." Journal of Cardiology and Cardiovascular Medicine 6, no. 3 (August 26, 2021): 048–54. http://dx.doi.org/10.29328/journal.jccm.1001118.
Full textAbstract:
Protein phosphorylation regulates several dimensions of cell fate and is substantially dysregulated in pathophysiological instances as evident spatiotemporally via intracellular localizations or compartmentalizations with discrete control by specific kinases and phosphatases. Cardiovascular disease manifests as an intricately complex entity presenting as a derangement of the cardiovascular system. Cardiac or heart failure connotes the pathophysiological state in which deficient cardiac output compromises the body burden and requirements. Protein kinases regulate several pathophysiological processes and are emerging targets for drug lead or discovery. The protein kinases are family members of the serine/threonine phosphatases. Protein kinases covalently modify proteins by attaching phosphate groups from ATP to residues of serine, threonine and/or tyrosine. Protein kinases and phosphatases are pivotal in the regulatory mechanisms in the reversible phosphorylation of diverse effectors whereby discrete signaling molecules regulate cardiac excitation and contraction. Protein phosphorylation is critical for the sustenance of cardiac functionalities. The two major contributory ingredients to progressive myocardium derangement are dysregulation of Ca2+ processes and contemporaneous elevated concentrations of reactive oxygen species, ROS. Certain cardiac abnormalities include cardiac myopathy or hypertrophy due to response in untoward haemodynamic demand with concomitant progressive heart failure. The homeostasis or equilibrium between protein kinases and phosphatases influence cardiac morphology and excitability during pathological and physiological processes of the cardiovascular system. Inasmuch as protein kinases regulate numerous dimensions of normal cellular functions, the pathophysiological dysfunctionality of protein kinase signaling pathways undergirds the molecular aspects of several cardiovascular diseases or disorders as related in this study. These have presented protein kinases as essential and potential targets for drug discovery and heart disease therapy.
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Cozza, Giorgio, Marco Mazzorana, Elena Papinutto, Jenny Bain, Matthew Elliott, Giovanni di Maira, Alessandra Gianoncelli, et al. "Quinalizarin as a potent, selective and cell-permeable inhibitor of protein kinase CK2." Biochemical Journal 421, no. 3 (July 15, 2009): 387–95. http://dx.doi.org/10.1042/bj20090069.
Full textAbstract:
Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a moderately potent and poorly selective inhibitor of protein kinase CK2, one of the most pleiotropic serine/threonine protein kinases, implicated in neoplasia and in other global diseases. By virtual screening of the MMS (Molecular Modeling Section) database, we have now identified quinalizarin (1,2,5,8-tetrahydroxyanthraquinone) as an inhibitor of CK2 that is more potent and selective than emodin. CK2 inhibition by quinalizarin is competitive with respect to ATP, with a Ki value of approx. 50 nM. Tested at 1 μM concentration on a panel of 75 protein kinases, quinalizarin drastically inhibits only CK2, with a promiscuity score (11.1), which is the lowest ever reported so far for a CK2 inhibitor. Especially remarkable is the ability of quinalizarin to discriminate between CK2 and a number of kinases, notably DYRK1a (dual-specificity tyrosine-phosphorylated and -regulated kinase), PIM (provirus integration site for Moloney murine leukaemia virus) 1, 2 and 3, HIPK2 (homeodomain-interacting protein kinase-2), MNK1 [MAPK (mitogen-activated protein kinase)-interacting kinase 1], ERK8 (extracellular-signal-regulated kinase 8) and PKD1 (protein kinase D 1), which conversely tend to be inhibited as drastically as CK2 by commercially available CK2 inhibitors. The determination of the crystal structure of a complex between quinalizarin and CK2α subunit highlights the relevance of polar interactions in stabilizing the binding, an unusual characteristic for a CK2 inhibitor, and disclose other structural features which may account for the narrow selectivity of this compound. Tested on Jurkat cells, quinalizarin proved able to inhibit endogenous CK2 and to induce apoptosis more efficiently than the commonly used CK2 inhibitors TBB (4,5,6,7-tetrabromo-1H-benzotriazole) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole).
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Labiuk, Shaunivan L., Lorne A. Babiuk, and Sylvia van Drunen Littel-van den Hurk. "Major tegument protein VP8 of bovine herpesvirus 1 is phosphorylated by viral US3 and cellular CK2 protein kinases." Journal of General Virology 90, no. 12 (December 1, 2009): 2829–39. http://dx.doi.org/10.1099/vir.0.013532-0.
Full textAbstract:
The UL47 gene product, VP8, is one of the major tegument proteins of bovine herpesvirus 1 (BoHV-1) and is subject to phosphorylation. Analysis of protein bands co-immunoprecipitated with VP8 from BoHV-1-infected cells by mass spectroscopy suggested that VP8 interacts with two protein kinases: cellular CK2 and viral US3. CK2 is a highly conserved cellular protein, expressed ubiquitously and known to phosphorylate numerous proteins. The US3 gene product is one of the viral kinases produced by BoHV-1 during infection. Interactions of CK2 and US3 with VP8 were confirmed outside the context of infection when FLAG–VP8 was expressed alone or co-expressed with US3–haemagglutinin tag in Cos-7 cells. Furthermore, VP8 and US3 were found to co-localize in the nucleus during viral infection. To explore the significance of these interactions, an in vitro kinase assay was performed, which demonstrated that VP8 is heavily phosphorylated by CK2. In the presence of the highly specific CK2 kinase inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), phosphorylation of VP8 was significantly reduced. Phosphorylation of VP8 was also inhibited by the presence of kenpaullone, a less specific CK2 inhibitor, but not by protein kinase CK1 or protein kinase C inhibitors. When VP8 and US3 were both included in the kinase assay in the presence of DMAT, phosphorylation of VP8 was again observed. Autophosphorylation of US3 was also detected and was not inhibited by DMAT. Based on these results, it is proposed that VP8 interacts with cellular CK2 and viral US3 in BoHV-1-infected cells, and is in turn subject to kinase activities associated with both of these proteins.
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D'Amore, Claudio, Valentina Salizzato, Christian Borgo, Luca Cesaro, Lorenzo A. Pinna, and Mauro Salvi. "A Journey through the Cytoskeleton with Protein Kinase CK2." Current Protein & Peptide Science 20, no. 6 (May 20, 2019): 547–62. http://dx.doi.org/10.2174/1389203720666190119124846.
Full textAbstract:
Substrate pleiotropicity, a very acidic phosphorylation consensus sequence, and an apparent uncontrolled activity, are the main features of CK2, a Ser/Thr protein kinase that is required for a plethora of cell functions. Not surprisingly, CK2 appears to affect cytoskeletal structures and correlated functions such as cell shape, mechanical integrity, cell movement and division. This review outlines our current knowledge of how CK2 regulates cytoskeletal structures, and discusses involved pathways and molecular mechanisms.