Tribbles in inflammation

2015 ◽  
Vol 43 (5) ◽  
pp. 1069-1074 ◽  
Author(s):  
Jessica Johnston ◽  
Shaghayegh Basatvat ◽  
Zabran Ilyas ◽  
Sheila Francis ◽  
Endre Kiss-Toth
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Innate Immune ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Disease Development ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Inflammatory Signalling

Inflammation is part of the physiological innate immune response to invading pathogens and tissue injury. However, unresolved inflammation leads to human disease. The tribbles (TRIB) family of pseudokinase proteins has been shown to modulate key inflammatory signalling pathways, including the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) networks. This review summarizes our current knowledge on TRIBs in the context of inflammation, both at the level of molecular mechanisms and in disease development.

Parkinson´s related protein DJ-1 is involved in aberrant cell cycle re-entry through Cdk5

2020 ◽  
Author(s):  
Mª José López-Grueso ◽  
Carmen Alicia Padilla ◽  
José Antonio Bárcena ◽  
Raquel Requejo-Aguilar
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cortical Neurons ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoints ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Multifunctional Protein ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Abstract DJ-1 is a multifunctional protein involved in Parkinson disease (PD) that can act as antioxidant, molecular chaperone, protease, glyoxalase and transcriptional regulator. However, the exact mechanism by which DJ-1 dysfunction contributes to development of Parkinson´s disease remains elusive. Here, using a comparative proteomic analysis between normal cortical neurons and neurons lacking DJ-1, we show that this protein is involved in cell cycle checkpoints disruption as a consequence of increased amount of p-Tau and a-synuclein proteins, altered signalling pathways, as the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK), and deregulation of cyclin-dependent kinase 5 (Cdk5). Cdk5 is normally involved in dendritic growth, axon formation and the establishment of synapses, but can also contribute to cell cycle progression, as in our case, in pathological conditions. In addition, we observed a decrease in proteasomal activity, probably due to Tau phosphorylation that can also lead to activation of mitogenic signalling pathways. Taken together, our findings indicate, for the first time, that aborted cell cycle re-entry could be at the onset of DJ-1 associated PD. Thereby, new approaches targeting cell cycle re-entry can be envisaged to improve current therapeutic strategies.

scholarly journals Insulin stimulation of pyruvate dehydrogenase in adipocytes involves two distinct signalling pathways

2003 ◽  
Vol 369 (2) ◽  
pp. 351-356 ◽  
Author(s):  
Sam A. JOHNSON ◽  
Richard M. DENTON
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Maximal Effect ◽  
Insulin Stimulation ◽  
Rat Adipocytes ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Stimulation Of

In isolated rat adipocytes, the insulin stimulation of pyruvate dehydrogenase can be partially inhibited by inhibitors of PI3K (phosphoinositide 3-kinase) and MEK1/2 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase). In combination, U0126 and wortmannin completely block the insulin stimulation of pyruvate dehydrogenase. It is concluded that the effect of insulin on pyruvate dehydrogenase in rat adipocytes involves two distinct signalling pathways: one is sensitive to wortmannin and the other to U0126. The synthetic phosphoinositolglycan PIG41 can activate pyruvate dehydrogenase but the activation is only approx. 30% of the maximal effect of insulin. This modest activation can be completely blocked by wortmannin alone, suggesting that PIG41 acts through only one of the pathways leading to the activation of pyruvate dehydrogenase.

Signalling pathways and the regulation of SUMO modification

2007 ◽  
Vol 35 (6) ◽  
pp. 1414-1418 ◽  
Author(s):  
B. Guo ◽  
S.-H. Yang ◽  
J. Witty ◽  
A.D. Sharrocks
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Protein Protein Interactions ◽  
E3 Ligases ◽  
Sumo Modification ◽  
Mitogen Activated Protein ◽  
The Impact ◽  
Protein Sumoylation

The modification of proteins by SUMO (small ubiquitin-related modifier) conjugation is becoming increasingly recognized as an important regulatory event. Protein SUMOylation can control a whole range of activities, including subcellular localization, protein–protein interactions and enzymatic activity. However, the SUMOylation process can itself be controlled. In the present review, the mechanisms through which protein SUMOylation is regulated are discussed, with particular emphasis on the impact of signalling pathways. A major point of regulation of the SUMO pathway is through targeting the E3 ligases, and a number of different ways to achieve this have been identified. More generally, the MAPK (mitogen-activated protein kinase) pathways represent one way through which SUMOylation of specific proteins is controlled, by using molecular mechanisms that at least in part also function by modifying the activity of SUMO E3 ligases. Further intricacies in signalling pathway interactions are hinted at through the growing number of examples of cross-talk between different post-translational modifications and SUMO modification.

Consequences of feedback in signal transduction for targeted therapies

2014 ◽  
Vol 42 (4) ◽  
pp. 770-775 ◽  
Author(s):  
Bertram Klinger ◽  
Nils Blüthgen
Keyword(s):  
Signal Transduction ◽  
Clinical Trials ◽  
Protein Kinase ◽  
Mathematical Modelling ◽  
Drug Sensitivity ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Targeted Therapeutics ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Over the last two decades, many small-molecule inhibitors that target kinase signalling have been developed. More than 20 of these inhibitors are FDA (U.S. Food and Drug Administration)-approved and are now being used in the clinics to treat tumours; even more have entered clinical trials. However, resistance to these inhibitors, either intrinsic to the tumour or acquired during treatment, remains a major problem in targeted therapeutics. One of the mechanisms by which tumours become resistant is the rewiring of the signalling networks via feedback, by which the tumour cells re-activate signalling or activate alternative signalling pathways. In the present article, we review insights from recent quantitative signalling studies combining mathematical modelling and experiments that revealed how feedback rewires MAPK (mitogen-activated protein kinase)/PI3K (phosphoinositide 3-kinase) signalling upon treatment and how that affects drug sensitivity.

scholarly journals Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies

2019 ◽  
Vol 8 (4) ◽  
pp. 520 ◽  
Author(s):  
Chia-Jung Li ◽  
Chien-Sheng Chen ◽  
Giou-Teng Yiang ◽  
Andy Po-Yi Tsai ◽  
Wan-Ting Liao ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Interventions ◽  
High Morbidity ◽  
Biomechanical Stress ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Systolic And Diastolic Function

Cardiomyopathy is a group of heterogeneous cardiac diseases that impair systolic and diastolic function, and can induce chronic heart failure and sudden cardiac death. Cardiomyopathy is prevalent in the general population, with high morbidity and mortality rates, and contributes to nearly 20% of sudden cardiac deaths in younger individuals. Genetic mutations associated with cardiomyopathy play a key role in disease formation, especially the mutation of sarcomere encoding genes and ATP kinase genes, such as titin, lamin A/C, myosin heavy chain 7, and troponin T1. Pathogenesis of cardiomyopathy occurs by multiple complex steps involving several pathways, including the Ras-Raf-mitogen-activated protein kinase-extracellular signal-activated kinase pathway, G-protein signaling, mechanotransduction pathway, and protein kinase B/phosphoinositide 3-kinase signaling. Excess biomechanical stress induces apoptosis signaling in cardiomyocytes, leading to cell loss, which can induce myocardial fibrosis and remodeling. The clinical features and pathophysiology of cardiomyopathy are discussed. Although several basic and clinical studies have investigated the mechanism of cardiomyopathy, the detailed pathophysiology remains unclear. This review summarizes current concepts and focuses on the molecular mechanisms of cardiomyopathy, especially in the signaling from mutation to clinical phenotype, with the aim of informing the development of therapeutic interventions.

scholarly journals Interleukin-6 signalling in health and disease

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1013
Author(s):  
Stefan Rose-John
Keyword(s):  
Neural Development ◽  
Interleukin 6 ◽  
Molecular Mechanisms ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Interleukin 6 Receptor ◽  
A Cell ◽  
Health And Disease ◽  
Phosphoinositide 3 Kinase

Biochemically, interleukin-6 belongs to the class of four-helical cytokines. The cytokine can be synthesised and secreted by many cells. It acts via a cell surface-expressed interleukin-6 receptor, which is not signalling competent. This receptor, when complexed with interleukin-6, associates with the signalling receptor glycoprotein 130 kDa (gp130), which becomes dimerised and initiates intracellular signalling via the Janus kinase/signal transducer and activator of transcription and rat sarcoma proto oncogene/mitogen-activated protein kinase/phosphoinositide-3 kinase pathways. Physiologically, interleukin-6 is involved in the regulation of haematopoiesis and the coordination of the innate and acquired immune systems. Additionally, interleukin-6 plays an important role in the regulation of metabolism, in neural development and survival, and in the development and maintenance of various cancers. Although interleukin-6 is mostly regarded as a pro-inflammatory cytokine, there are numerous examples of protective and regenerative functions of this cytokine. This review will explain the molecular mechanisms of the, in part opposing, activities of the cytokine interleukin-6.

Tetraspanin CD9 in cell migration

2011 ◽  
Vol 39 (2) ◽  
pp. 563-567 ◽  
Author(s):  
Dale Powner ◽  
Petra M. Kopp ◽  
Susan J. Monkley ◽  
David R. Critchley ◽  
Fedor Berditchevski
Keyword(s):  
Cell Migration ◽  
Focal Adhesion ◽  
Breast Cancer Cells ◽  
Focal Adhesions ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Migration And Invasion ◽  
Mitogen Activated Protein ◽  
Dependent Cell ◽  
Phosphoinositide 3 Kinase

Tetraspanin CD9 is associated with integrin adhesion receptors and it was reported that CD9 regulates integrin-dependent cell migration and invasion. Pro- and anti-migratory effects of CD9 have been linked to adhesion-dependent signalling pathways, including phosphorylation of FAK (focal adhesion kinase) and activation of phosphoinositide 3-kinase, p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). In the present paper, we describe a novel mechanism whereby CD9 specifically controls localization of talin1, one of the critical regulators of integrin activation, to focal adhesions: CD9-deficiency leads to impaired localization of talin1 to focal adhesions and correlates with increased motility of breast cancer cells.

scholarly journals Bacillus anthracis Spores Stimulate Cytokine and Chemokine Innate Immune Responses in Human Alveolar Macrophages through Multiple Mitogen-Activated Protein Kinase Pathways

2006 ◽  
Vol 74 (8) ◽  
pp. 4430-4438 ◽  
Author(s):  
Kaushik Chakrabarty ◽  
Wenxin Wu ◽  
J. Leland Booth ◽  
Elizabeth S. Duggan ◽  
K. Mark Coggeshall ◽  
...  
Keyword(s):  
Immune System ◽  
Bacillus Anthracis ◽  
Alveolar Macrophages ◽  
Innate Immune System ◽  
Innate Immune ◽  
Mitogen Activated Protein Kinase ◽  
Tnf Α ◽  
Human Alveolar Macrophages ◽  
Mitogen Activated Protein ◽  
Multiple Signaling

ABSTRACT Contact with the human alveolar macrophage plays a key role in the innate immune response to Bacillus anthracis spores. Because there is a significant delay between the initial contact of the spore with the host and clinical evidence of disease, there appears to be temporary containment of the pathogen by the innate immune system. Therefore, the early macrophage response to Bacillus anthracis exposure is important in understanding the pathogenesis of this disease. In this paper, we studied the initial events after exposure to spores, beginning with the rapid internalization of spores by the macrophages. Spore exposure rapidly activated the mitogen-activated protein kinase signaling pathways extracellular signal-regulated kinase, c-Jun-NH2-terminal kinase, and p38. This was followed by the transcriptional activation of cytokine and primarily monocyte chemokine genes as determined by RNase protection assays. Transcriptional induction is reflected at the translational level, as interleukin-1α (IL-1α), IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) cytokine protein levels were markedly elevated as determined by enzyme-linked immunosorbent assay. Induction of IL-6 and TNF-α, and, to a lesser extent, IL-1α and IL-1β, was partially inhibited by the blockade of individual mitogen-activated protein kinases, while the complete inhibition of cytokine induction was achieved when multiple signaling pathway inhibitors were used. Taken together, these data clearly show activation of the innate immune system in human alveolar macrophages by Bacillus anthracis spores. The data also show that multiple signaling pathways are involved in this cytokine response. This report is the first comprehensive examination of this process in primary human alveolar macrophages.

Sign in / Sign up

Export Citation Format

Share Document