scholarly journals Protein kinase-dependent oxidative regulation of the cardiac Na+-K+pump: evidence fromin vivoandin vitromodulation of cell signalling

2013 ◽  
Vol 591 (12) ◽  
pp. 2999-3015 ◽  
Author(s):  
Keyvan Karimi Galougahi ◽  
Chia-Chi Liu ◽  
Alvaro Garcia ◽  
Natasha A. S. Fry ◽  
Elisha J. Hamilton ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Signalling ◽  
Oxidative Regulation

scholarly journals The Double-Edged Sword in Pathogenic Trypanosomatids: The Pivotal Role of Mitochondria in Oxidative Stress and Bioenergetics

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Rubem Figueiredo Sadok Menna-Barreto ◽  
Solange Lisboa de Castro
Keyword(s):  
Trypanosoma Brucei ◽  
Cell Signalling ◽  
Oxygen Species ◽  
Kinetoplast Dna ◽  
Excellent Candidate ◽  
Causative Agents ◽  
Parasite Biology ◽  
Oxidative Regulation ◽  
Single Mitochondrion

The pathogenic trypanosomatidsTrypanosoma brucei,Trypanosoma cruzi, andLeishmaniaspp. are the causative agents of African trypanosomiasis, Chagas disease, and leishmaniasis, respectively. These diseases are considered to be neglected tropical illnesses that persist under conditions of poverty and are concentrated in impoverished populations in the developing world. Novel efficient and nontoxic drugs are urgently needed as substitutes for the currently limited chemotherapy. Trypanosomatids display a single mitochondrion with several peculiar features, such as the presence of different energetic and antioxidant enzymes and a specific arrangement of mitochondrial DNA (kinetoplast DNA). Due to mitochondrial differences between mammals and trypanosomatids, this organelle is an excellent candidate for drug intervention. Additionally, during trypanosomatids’ life cycle, the shape and functional plasticity of their single mitochondrion undergo profound alterations, reflecting adaptation to different environments. In an uncoupling situation, the organelle produces high amounts of reactive oxygen species. However, these species role in parasite biology is still controversial, involving parasite death, cell signalling, or even proliferation. Novel perspectives on trypanosomatid-targeting chemotherapy could be developed based on better comprehension of mitochondrial oxidative regulation processes.

Cannabinoid-receptor-independent cell signalling by N-acylethanolamines

2001 ◽  
Vol 360 (1) ◽  
pp. 67-75 ◽  
Author(s):  
Evgueni V. BERDYSHEV ◽  
Patricia C. SCHMID ◽  
Randy J. KREBSBACH ◽  
Cecilia J. HILLARD ◽  
Chuanshu HUANG ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transcriptional Activity ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Cell Signalling ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Mitochondrial Energy Metabolism ◽  
Erk Phosphorylation

Anandamide and other polyunsaturated N-acylethanolamines (NAEs) exert biological activity by binding to cannabinoid receptors. These receptors are linked to Gi/o proteins and their activation leads to extracellular-signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAP kinase) activation, inhibition of cAMP-dependent signalling and complex changes in the expression of various genes. Saturated and monounsaturated NAEs cannot bind to cannabinoid receptors and may thus mediate cell signalling through other targets. Here we report that both saturated/monounsaturated NAEs and anandamide (20:4n-6 NAE) stimulate cannabinoid-receptor-independent ERK phosphorylation and activator protein-1 (AP-1)-dependent transcriptional activity in mouse epidermal JB6 cells. Using a clone of JB6 P+ cells with an AP-1 collagen–luciferase reporter construct, we found that 16:0, 18:1n-9, 18:1n-7, 18:2n-6 and 20:4n-6 NAEs stimulated AP-1-dependent transcriptional activity up to 2-fold, with maximal stimulation at approx. 10–15μM. Higher NAE concentrations had toxic effects mediated by alterations in mitochondrial energy metabolism. The AP-1 stimulation appeared to be mediated by ERK but not JNK or p38 signalling pathways, because all NAEs stimulated ERK1/ERK2 phosphorylation without having any effect on JNK or p38 kinases. Also, overexpression of dominant negative ERK1/ERK2 kinases completely abolished NAE-induced AP-1 activation. In contrast with 18:1n-9 NAE and anandamide, the cannabinoid receptor agonist WIN 55,212-2 did not stimulate AP-1 activity and inhibited ERK phosphorylation. The NAE-mediated effects were not attenuated by pertussis toxin and appeared to be NAE-specific, as a close structural analogue, oleyl alcohol, failed to induce ERK phosphorylation. The data support our hypothesis that the major saturated and monounsaturated NAEs are signalling molecules acting through intracellular targets without participation of cannabinoid receptors.

Modulation of signal-transduction pathways by chemopreventive agents

2000 ◽  
Vol 28 (2) ◽  
pp. 7-12 ◽  
Author(s):  
M. M. Manson ◽  
K. A. Holloway ◽  
L. M. Howells ◽  
E. A. Hudson ◽  
S. M. Plummer ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Function ◽  
Cell Signalling ◽  
Growth Factor Receptor ◽  
Disease Process ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Chemopreventive Agents ◽  
Mitogen Activated Protein

For a disease such as cancer, where a number of alterations to normal cell function accumulate over time, there are several opportunities to inhibit, slow down or even reverse the process. Many of the changes which drive the disease process occur in cell-signalling pathways that regulate proliferation and apoptosis. As our knowledge of these complicated signalling networks improves, it is becoming clear that many molecules, both drugs and naturally occurring dietary constituents, can interact beneficially with deregulated pathways. Aspirin and other non-steroidal anti-inflammatory drugs, as well as natural compounds present in plants such as green vegetables and tea, can modulate signalling by affecting kinase activity and therefore phosphorylation of key molecules. Examples of pathways which can be modulated by these agents include activation of the transcription factor nuclear factor κB by tumour promoters or cytokines, signalling by growth factors through the growth-factor receptor/extracellular-regulated protein kinase pathways and by a number of other molecules through the stress-activated c-Jun N-terminal kinase and p38 pathways. These mitogen-activated protein kinase pathways regulate a number of transcription factors including c-Fos and c-Jun. Evidence exists, at least from in vitro experiments, that by targeting such pathways, certain dietary compounds may be able to restore abnormal rates of apoptosis and proliferation to more normal levels.

scholarly journals How treatments with endocrine and metabolic drugs influence pituitary cell function

2020 ◽  
Vol 9 (2) ◽  
pp. R14-R27 ◽  
Author(s):  
Giovanni Tulipano
Keyword(s):  
Protein Kinase ◽  
Mammalian Cells ◽  
Cell Function ◽  
Cell Metabolism ◽  
Cell Signalling ◽  
Pituitary Cell ◽  
Pituitary Cells ◽  
Transduction Mechanisms ◽  
Amp Activated Protein Kinase

A variety of endocrine and metabolic signals regulate pituitary cell function acting through the hypothalamus-pituitary neuroendocrine axes or directly at the pituitary level. The underlying intracellular transduction mechanisms in pituitary cells are still debated. AMP-activated protein kinase (AMPK) functions as a cellular sensor of low energy stores in all mammalian cells and promotes adaptive changes in response to calorie restriction. It is also regarded as a target for therapy of proliferative disorders. Various hormones and drugs can promote tissue-specific activation or inhibition of AMPK by enhancing or inhibiting AMPK phosphorylation, respectively. This review explores the preclinical studies published in the last decade that investigate the role of AMP-activated protein kinase in the intracellular transduction pathways downstream of endocrine and metabolic signals or drugs affecting pituitary cell function, and its role as a target for drug therapy of pituitary proliferative disorders. The effects of the hypoglycemic agent metformin, which is an indirect AMPK activator, are discussed. The multiple effects of metformin on cell metabolism and cell signalling and ultimately on cell function may be either dependent or independent of AMPK. The in vitro effects of metformin may also help highlighting differences in metabolic requirements between pituitary adenomatous cells and normal cells.

scholarly journals Oxidative Stress in Cardiovascular Diseases and Obesity: Role of p66Shc and Protein Kinase C

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Elena De Marchi ◽  
Federica Baldassari ◽  
Angela Bononi ◽  
Mariusz R. Wieckowski ◽  
Paolo Pinton
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase C ◽  
Cardiovascular Diseases ◽  
Protein Kinase ◽  
Cell Signalling ◽  
Redox Balance ◽  
Kinase C ◽  
Antioxidant Defence System ◽  
Normal Metabolism

Reactive oxygen species (ROS) are a byproduct of the normal metabolism of oxygen and have important roles in cell signalling and homeostasis. An imbalance between ROS production and the cellular antioxidant defence system leads to oxidative stress. Environmental factors and genetic interactions play key roles in oxidative stress mediated pathologies. In this paper, we focus on cardiovascular diseases and obesity, disorders strongly related to each other; in which oxidative stress plays a fundamental role. We provide evidence of the key role played byp66Shcprotein and protein kinase C (PKC) in these pathologies by their intracellular regulation of redox balance and oxidative stress levels. Additionally, we discuss possible therapeutic strategies aimed at attenuating the oxidative damage in these diseases.

scholarly journals Enzyme activity effects of N-terminal His-tag attached to catalytic sub-unit of phosphoinositide-3-kinase

2013 ◽  
Vol 33 (6) ◽  
Author(s):  
James M. J. Dickson ◽  
Woo-Jeong Lee ◽  
Peter R. Shepherd ◽  
Christina M. Buchanan
Keyword(s):  
Protein Kinase ◽  
Kinase Activity ◽  
Catalytic Domain ◽  
Cell Signalling ◽  
Protein Kinase Activity ◽  
Lipid Kinase ◽  
His Tag ◽  
The Impact

NTT (N-terminal tags) on the catalytic (p110) sub-unit of PI 3-K (phosphoinositol 3-kinase) have previously been shown to increase cell signalling and oncogenic transformation. Here we test the impact of an NT (N-terminal) His-tag on in vitro lipid and protein kinase activity of all class-1 PI 3-K isoforms and two representative oncogenic mutant forms (E545K and H1047R), in order to elucidate the mechanisms behind this elevated signalling and transformation observed in vivo. Our results show that an NT His-tag has no impact on lipid kinase activity as measured by enzyme titration, kinetics and inhibitor susceptibility. Conversely, the NT His-tag did result in a differential effect on protein kinase activity, further potentiating the elevated protein kinase activity of both the helical domain and catalytic domain oncogenic mutants with relation to p110 phosphorylation. All other isoforms also showed elevated p110 phosphorylation (although not statistically significant). We conclude that the previously reported increase in cell signalling and oncogenic-like transformation in response to p110 NTT is not mediated via an increase in the lipid kinase activity of PI 3-K, but may be mediated by increased p110 autophosphorylation and/or other, as yet unidentified, intracellular protein/protein interactions. We further observe that tagged recombinant protein is suitable for use in in vitro lipid kinase screens to identify PI 3-K inhibitors; however, we recommend that in vivo (including intracellular) experiments and investigations into the protein kinase activity of PI 3-K should be conducted with untagged constructs.

scholarly journals Inactive membrane protein kinase Cs: a possible target for receptor signalling

1994 ◽  
Vol 304 (3) ◽  
pp. 809-816 ◽  
Author(s):  
B R Chakravarthy ◽  
J F Whitfield ◽  
J P Durkin
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Cell Signalling ◽  
Interleukin 2 ◽  
Substrate Protein ◽  
Low Concentrations ◽  
Extracellular Stimuli ◽  
Epidermal Growth ◽  
Cytosolic Enzymes ◽  
Hydrolysis Of

The activation of the multifunctional cell signalling enzymes, the protein kinase Cs (PKCs), is generally thought to result from the translocation of inactive cytosolic enzymes to activation sites in cell membranes. However, recent studies suggest that PKCs may also be stimulated in cells by processes independent of translocation. One possible mechanism is the modulation of the activity of PKCs already resident in membranes. A PKC assay that measures enzyme activity directly in isolated native membranes has revealed the presence of an activatable pool of PKCs resident in native membranes of various cells and tissues. In 3T3-L1 cells, some or all of this pool of membrane PKCs was stimulated within 10 min of exposing the cells to 10 ng/ml epidermal growth factor or 100 ng/ml fibroblast growth factor. Similar increases in PKC activity were observed in native membranes isolated from CTLL-2, WEHI-231 and S49 lymphoma cells that had been exposed to interleukin-2. These growth factors all stimulated membrane PKC activity without detectably translocating cytosolic enzymes to the membranes. In intact WEHI cells, low concentrations (5-10 microM) of a diacylglycerol, 1-oleoyl-2-acetyl-sn-glycerol (OAG), or low concentrations (2-10 nM) of phorbol 12-myristate 13-acetate sufficed to activate PKCs already resident in membranes, but much higher concentrations (50-100 microM and 50-100 nM respectively) were needed to detectably stimulate the translocation of cytosolic PKCs. A phosphatidylcholine-specific phospholipase C also selectively stimulated membrane PKCs in WEHI cells at concentrations that were much less than those needed to induce the translocation of cytosolic enzymes. Furthermore, interleukin-2 and low concentrations of OAG both stimulated the phosphorylation of the 85 kDa PKC-selective substrate protein in intact WEHI cells in which translocation of PKCs was not evident. These results suggest that the membranes of some cells maintain a pool of activatable PKCs that respond to lower levels of extracellular stimuli than cytosolic PKCs, and that can be stimulated by signals which produce diacylglycerols through the hydrolysis of phospholipids other than polyphosphoinositides.

scholarly journals Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD

2005 ◽  
Vol 390 (3) ◽  
pp. 729-735 ◽  
Author(s):  
Hemamalini Renganathan ◽  
Hema Vaidyanathan ◽  
Anna Knapinska ◽  
Joe W. Ramos
Keyword(s):  
Protein Kinase ◽  
Cell Signalling ◽  
Death Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Death Domain ◽  
Apoptosis Pathway ◽  
Akt Phosphorylation ◽  
Erk Mapk

Cell signalling pathways that regulate proliferation and those that regulate programmed cell death (apoptosis) are co-ordinated. The proteins and mechanisms that mediate the integration of these pathways are not yet fully described. The phosphoprotein PEA-15 (phosphoprotein enriched in astrocytes) can regulate both the ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) pathway and the death receptor-initiated apoptosis pathway. This is the result of PEA-15 binding to the ERK/MAPK or the proapoptotic protein FADD (Fas-activated death domain protein) respectively. The mechanism by which binding of PEA-15 to these proteins is controlled has not been elucidated. PEA-15 is a phosphoprotein containing a Ser-104 phosphorylated by protein kinase C and a Ser-116 phosphorylated by CamKII (calcium/calmodulin-dependent protein kinase II) or AKT. Phosphorylation of Ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at Ser-116 is required for PEA-15 recruitment to the DISC (death-initiation signalling complex). Moreover, PEA-15 must be phosphorylated at Ser-116 to inhibit apoptosis. In the present study, we report that phosphorylation at Ser-104 blocks ERK binding to PEA-15 in vitro and in vivo, whereas phosphorylation at Ser-116 promotes its binding to FADD. We further characterize phospho-epitope-binding antibodies to these sites. We report that phosphorylation does not influence the distribution of PEA-15 between the cytoplasm and nucleus of the cell since all phosphorylated states are found predominantly in the cytoplasm. We propose that phosphorylation of PEA-15 acts as the switch that controls whether PEA-15 influences proliferation or apoptosis.

Role of the protein kinase CIPK8 in guard cell signalling

2009 ◽  
Vol 153 (2) ◽  
pp. S210
Author(s):  
Deirdre H. McLachlan ◽  
Jorg Kudla ◽  
Alistair M. Hetherington
Keyword(s):  
Protein Kinase ◽  
Guard Cell ◽  
Cell Signalling
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