scholarly journals Negative regulation of defence signalling pathways by the EDR1 protein kinase

2011 ◽  
Vol 12 (8) ◽  
pp. 746-758 ◽  
Author(s):  
KATY M. CHRISTIANSEN ◽  
YANGNAN GU ◽  
NATALIE RODIBAUGH ◽  
ROGER W. INNES
Keyword(s):  
Protein Kinase ◽  
Negative Regulation ◽  
Signalling Pathways ◽  
Defence Signalling

A novel vasculo-angiogenic effect of cilostazol mediated by cross-talk between multiple signalling pathways including the ERK/p38 MAPK signalling transduction cascade

2012 ◽  
Vol 123 (3) ◽  
pp. 147-159 ◽  
Author(s):  
Ting-Hsing Chao ◽  
Shih-Ya Tseng ◽  
Yi-Heng Li ◽  
Ping-Yen Liu ◽  
Chung-Lung Cho ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
No Production ◽  
Angiogenic Effect

Cilostazol is an anti-platelet agent with vasodilatory activity that acts by increasing intracellular concentrations of cAMP. Recent reports have suggested that cilostazol may promote angiogenesis. In the present study, we have investigated the effect of cilostazol in promoting angiogenesis and vasculogenesis in a hindlimb ischaemia model and have also examined its potential mechanism of action in vitro and in vivo. We found that cilostazol treatment significantly increased colony formation by human early EPCs (endothelial progenitor cells) through a mechanism involving the activation of cAMP/PKA (protein kinase A), PI3K (phosphoinositide 3-kinase)/Akt/eNOS (endothelial NO synthase) and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) signalling pathways. Cilostazol also enhanced proliferation, chemotaxis, NO production and vascular tube formation in HUVECs (human umbilical vein endothelial cells) through activation of multiple signalling pathways downstream of PI3K/Akt/eNOS. Cilostazol up-regulated VEGF (vascular endothelial growth factor)-A165 expression and secretion of VEGF-A in HUVECs through activation of the PI3K/Akt/eNOS pathway. In a mouse hindlimb ischaemia model, recovery of blood flow ratio (ipsilateral/contralateral) 14 days after surgery was significantly improved in cilostazol-treated mice (10 mg/kg of body weight) compared with vehicle-treated controls (0.63±0.07 and 0.43±0.05 respectively, P<0.05). Circulating CD34+ cells were also increased in cilostazol-treated mice (3614±670 compared with 2151±608 cells/ml, P<0.05). Expression of VEGF and phosphorylation of PI3K/Akt/eNOS and ERK/p38 MAPK in ischaemic muscles were significantly enhanced by cilostazol. Our data suggest that cilostazol produces a vasculo-angiogenic effect by up-regulating a broad signalling network that includes the ERK/p38 MAPK, VEGF-A165, PI3K/Akt/eNOS and cAMP/PKA pathways.

Ranscriptome Analysis Reveals the Molecular Mechanism of Yiqi Rougan Decoction in Reducing CCl4-induced Liver Fibrosis in Rats

2021 ◽  
Author(s):  
Yu Xiong ◽  
Jinyuan Hu ◽  
Chen Xuan ◽  
Jiayu Tian ◽  
Kaiyue Tan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Liver Fibrosis ◽  
Liver Injury ◽  
Molecular Mechanism ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
High Dose ◽  
Peroxisome Proliferator

Abstract BackgroundLiver fibrosis develops from various chronic liver diseases, and there is currently a lack of specific treatment strategies. Yiqi Rougan decoction (YQRG) is a traditional Chinese medicine that has shown durative effects in the treatment of liver fibrosis; however, the mechanism associated with YQRG-related improvements in liver fibrosis remains to be experimentally determined. This study evaluated the therapeutic effect of YQRG on carbon tetrachloride (CCl4)-induced liver fibrosis in rats and its molecular mechanism. MethodsWe used low-, medium-, and high-dose YQRG to treat CCl4-induced liver fibrosis in rats, followed by assessment of liver injury and fibrosis according to liver appearance, body weight, liver mass index, histopathologic examination, and serum testing. Additionally, we performed transcriptome analysis using RNA-sequencing (RNA-seq) technology, including cluster, Gene Ontology (GO), and pathway analyses, to identify differentially expressed genes (DEGs), and protein and gene expression were detected by immunofluorescence (IFC), western blot, and real-time quantitative PCR. ResultsThe results showed that YQRG effectively alleviated CCl4-induced liver injury and fibrosis in rats, including observations of improved liver function, decreased activity of hepatic stellate cells (HSCs), and decreased extracellular matrix (ECM) deposition. Moreover, we identified downregulated and upregulated DEGs in the model group relative to the control and YQRG-treated groups, with GO analysis revealing their enrichment in biological processes, such as endoplasmic reticulum stress (ERS), apoptosis, and autophagy. Furthermore, pathway analysis showed that YQRG treatment downregulated the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/Akt (PI3K/AKT) signalling pathways and upregulated other signalling pathways, including those related to peroxisome proliferator-activated receptors(PPAR) and AMP-activated protein kinase(AMPK), with these finding subsequently verified experimentally. ConclusionThese findings showed that YQRG improved CCl4-induced liver fibrosis through multiple mechanisms and pathways, offering critical insight into the YQRG-related therapeutic mechanism and promoting further research into its potential application.

Growth factor-induced activation of a kinase activity which causes regulatory phosphorylation of p42/microtubule-associated protein kinase

1992 ◽  
Vol 12 (5) ◽  
pp. 2222-2229
Author(s):  
G L'Allemain ◽  
J H Her ◽  
J Wu ◽  
T W Sturgill ◽  
M J Weber
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Growth Control ◽  
Signalling Pathways ◽  
3T3 Cells ◽  
Regulatory Phosphorylation ◽  
Enzymatic Activation

p42/microtubule-associated protein kinase (p42mapk) is activated by tyrosine and threonine phosphorylation, and its regulatory phosphorylation is likely to be important in signalling pathways involved in growth control, secretion, and differentiation. Here we show that treatment of quiescent 3T3 cells with diverse agonists results in the appearance of an activity capable of causing the in vitro phosphorylation of p42mapk on the regulatory tyrosine and to a lesser extent on the regulatory threonine, resulting in enzymatic activation of the p42mapk. This p42mapk-activating activity is capable of phosphorylating a kinase-defective p42mapk mutant, thus confirming its activity as a kinase.

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 Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide

2007 ◽  
Vol 404 (2) ◽  
pp. 179-190 ◽  
Author(s):  
Mark Windheim ◽  
Christine Lang ◽  
Mark Peggie ◽  
Lorna A. Plater ◽  
Philip Cohen
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Muramyl Dipeptide ◽  
Dominant Negative ◽  
Signalling Pathways ◽  
Dominant Negative Mutant ◽  
Protein Kinase Activity ◽  
P38α Mapk

MDP (muramyl dipeptide), a component of peptidoglycan, interacts with NOD2 (nucleotide-binding oligomerization domain 2) stimulating the NOD2–RIP2 (receptor-interacting protein 2) complex to activate signalling pathways important for antibacterial defence. Here we demonstrate that the protein kinase activity of RIP2 has two functions, namely to limit the strength of downstream signalling and to stabilize the active enzyme. Thus pharmacological inhibition of RIP2 kinase with either SB 203580 [a p38 MAPK (mitogen-activated protein kinase) inhibitor] or the Src family kinase inhibitor PP2 induces a rapid and drastic decrease in the level of the RIP2 protein, which may explain why these RIP2 inhibitors block MDP-stimulated downstream signalling and the production of IL-1β (interleukin-1β) and TNFα (tumour necrosis factor-α). We also show that RIP2 induces the activation of the protein kinase TAK1 (transforming-growth-factor-β-activated kinase-1), that a dominant-negative mutant of TAK1 inhibits RIP2-induced activation of JNK (c-Jun N-terminal kinase) and p38α MAPK, and that signalling downstream of NOD2 or RIP2 is reduced by the TAK1 inhibitor (5Z)-7-oxozeaenol or in TAK1-deficient cells. We also show that MDP activates ERK1 (extracellular-signal-regulated kinase 1)/ERK2 and p38α MAPK in human peripheral-blood mononuclear cells and that the activity of both MAPKs and TAK1 are required for MDP-induced signalling and production of IL-1β and TNFα in these cells. Taken together, our results indicate that the MDP–NOD2/RIP2 and LPS (lipopolysaccharide)–TLR4 (Toll-like receptor 4) signalling pathways converge at the level of TAK1 and that many subsequent events that lead to the production of pro-inflammatory cytokines are common to both pathways.

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