Regulation of IL-6-type cytokine responses by MAPKs

2014 ◽  
Vol 42 (1) ◽  
pp. 59-62 ◽  
Author(s):  
Ana P. Costa-Pereira
Keyword(s):  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Cell Type ◽  
Fully Integrated ◽  
Extracellular Signal Regulated Kinase ◽  
Cellular Environment ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
The Stability

IL-6 (interleukin 6)-type cytokines are pleiotropic molecules, critical for cellular homoeostasis and with well-recognized roles in several human diseases. They all activate JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling and, depending on the particular cytokine, cell type and cellular environment, they can also trigger the activation of MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) cascades. Although it is clear that JAK/STAT and MAPK reciprocally regulate each other, how these signalling pathways are fully integrated remains to be fully understood. Not only do cells have to be able to integrate and conciliate what are often contradictory signalling cues, but they are also subject to complex regulatory mechanisms involving these pathways. More specifically, we have shown recently that ERK2 (extracellular-signal-regulated kinase 2) is required for the transcriptional regulation of gp130 (glycoprotein 130), a key receptor complex component for most IL-6-type cytokines. ERK2 not only binds to the gp130 promoter and is required for full expression of the protein, but it also regulates the stability of gp130 mRNA. This function of ERK2 is not shared by ERK1 and it probably represents an entirely novel function for this prominent kinase.

scholarly journals Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-xiang Wang ◽  
Xu Zhang ◽  
Qing-yang Ma ◽  
Lan-dian Hu ◽  
Xi Zhang ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Selective Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Adaptive Resistance ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Genomic Adaptation ◽  
Phosphoinositide 3 Kinase ◽  
Specific Inhibitors

AbstractPhosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3Kαi like other targeted therapies. To identify genomic adaptation to PI3Kαi, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3Kαi CYH33. Particularly, HRASG12S mutation was found in KYSE180C cells. Overexpression of HRASG12S in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRASG12S restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts. Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3Kαi in ESCC cells and identified combinatorial regimens that may circumvent resistance.

scholarly journals Identification of signalling cascades involved in red blood cell shrinkage and vesiculation

2015 ◽  
Vol 35 (2) ◽  
Author(s):  
Elena B. Kostova ◽  
Boukje M. Beuger ◽  
Thomas R.L. Klei ◽  
Pasi Halonen ◽  
Cor Lieftink ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
Bioactive Molecules ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
G Protein Coupled

After screening two libraries of small bioactive molecules and kinase inhibitors, we identified several signalling pathways to be involved in red blood cell (RBC) shrinkage and vesiculation. These include the Jak (Janus kinase)–STAT (signal transducer and activator of transcription) pathway, phosphoinositide 3-kinase (PI3K)–Akt pathway, the Raf–MEK (mitogen-activated protein kinase kinase)–ERK (extracellular signal-regulated kinase) pathway and GPCR (G protein-coupled receptor) signalling.

ERK5 and its role in tumour development

2012 ◽  
Vol 40 (1) ◽  
pp. 251-256 ◽  
Author(s):  
Pamela A. Lochhead ◽  
Rebecca Gilley ◽  
Simon J. Cook
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Invasion And Migration ◽  
Extracellular Signal Regulated Kinase ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Tumour Cell Invasion ◽  
And Migration

The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the ‘hallmarks of cancer’ as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer.

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