The effects of metabotropic glutamate receptor 7 allosteric agonist N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride on developmental sevoflurane neurotoxicity: role of extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase signaling pathway

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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Ras Mutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes

Molecular Biology of the Cell ◽

10.1091/mbc.e05-04-0294 ◽

2005 ◽

Vol 16 (12) ◽

pp. 5538-5550 ◽

Cited By ~ 30

Author(s):

James M. Mullin ◽

James M. Leatherman ◽

Mary Carmen Valenzano ◽

Erika Rendon Huerta ◽

Jon Verrechio ◽

...

Keyword(s):

Tight Junctions ◽

Mitogen Activated Protein Kinase ◽

Epithelial Barrier ◽

Epithelial Barrier Function ◽

Downstream Effects ◽

Extracellular Signal ◽

Wide Range ◽

Mitogen Activated Protein ◽

Protein Kinase Signaling ◽

Kinase Signaling Pathway

Although ras mutations have been shown to affect epithelial architecture and polarity, their role in altering tight junctions remains unclear. Transfection of a valine-12 mutated ras construct into LLC-PK1 renal epithelia produces leakiness of tight junctions to certain types of solutes. Transepithelial permeability of d-mannitol increases sixfold but transepithelial electrical resistance increases >40%. This indicates decreased paracellular permeability to NaCl but increased permeability to nonelectrolytes. Permeability increases to d-mannitol (Mr 182), polyethylene glycol (Mr 4000), and 10,000-Mr methylated dextran but not to 2,000,000-Mr methylated dextran. This implies a “ceiling” on the size of solutes that can cross a ras-mutated epithelial barrier and therefore that the increased permeability is not due to loss of cells or junctions. Although the abundance of claudin-2 declined to undetectable levels in the ras-overexpressing cells compared with vector controls, levels of occludin and claudins 1, 4, and 7 increased. The abundance of claudins-3 and -5 remained unchanged. An increase in extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein kinase signaling pathway. These selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier.

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Role of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways downstream molecules, phosphorylated extracellular signal–regulated kinase, and phosphorylated AKT in colorectal cancer—A tissue microarray–based approach☆

Human Pathology ◽

10.1016/j.humpath.2006.03.002 ◽

2006 ◽

Vol 37 (8) ◽

pp. 1022-1031 ◽

Cited By ~ 33

Author(s):

A LUGLI ◽

I ZLOBEC ◽

P MINOO ◽

K BAKER ◽

L TORNILLO ◽

...

Keyword(s):

Colorectal Cancer ◽

Protein Kinase ◽

Tissue Microarray ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Phosphorylated Akt ◽

Mitogen Activated Protein ◽

Phosphoinositide 3 Kinase

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Impact of ERK5 on the Hallmarks of Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20061426 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1426 ◽

Cited By ~ 11

Author(s):

Barbara Stecca ◽

Elisabetta Rovida

Keyword(s):

Mitogen Activated Protein Kinase ◽

Extracellular Signal Regulated Kinase ◽

Biological Features ◽

Promising Strategy ◽

Biological Responses ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Relevant Role ◽

Almost All

Extracellular signal-regulated kinase 5 (ERK5) belongs to the mitogen-activated protein kinase (MAPK) family that consists of highly conserved enzymes expressed in all eukaryotic cells and elicits several biological responses, including cell survival, proliferation, migration, and differentiation. In recent years, accumulating lines of evidence point to a relevant role of ERK5 in the onset and progression of several types of cancer. In particular, it has been reported that ERK5 is a key signaling molecule involved in almost all the biological features of cancer cells so that its targeting is emerging as a promising strategy to suppress tumor growth and spreading. Based on that, in this review, we pinpoint the hallmark-specific role of ERK5 in cancer in order to identify biological features that will potentially benefit from ERK5 targeting.

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