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Compromised MAPK signaling in human diseases: an update

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Abstract

The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine–threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras–Raf–MEK–ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.

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Abbreviations

RAGE:

Receptors for advanced glycation end products

PrPc :

Cellular prion protein

FcγRIIb:

The immunoglobulin G Fcγ receptor II-b

IRAK4:

Interleukin receptor-associated kinase 4

MLK3:

Mixed lineage kinase 3

SHP-1:

SH2 domain-containing phosphatase 1

HtrA2:

High temperature requirement A2

CDK5:

Cyclin-dependent kinase 5

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

TDP-43:

TAR DNA-binding protein 43

FUS:

Fused in sarcoma

TLS:

Translocated in liposarcoma

C9orf72:

Chromosome 9 open reading frame 72

AMPAR:

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor

NMDA:

N-methyl-d-aspartate

GHS-R:

Growth hormone secretagogue receptor

VEGF:

Vascular endothelial growth factor

mTOR:

Mammalian target of rapamycin

MEK:

Mitogen-activated protein/extracellular signal-regulated kinase

ERK:

Extracellular signal-regulated kinase

PI3K:

Phosphatidylinositol-3-kinase

GTP:

Guanosine triphosphate

PLC-γ:

Phospholipase C-γ

P-REX1:

Phosphatidylinositol-3,4,5-triphosphate (PIP3)-dependent Rac exchange factor-1

PTEN:

Phosphatase and tensin homolog

EGFR:

Epidermal growth factor receptor

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Acknowledgments

This work was supported by a NRF grant (2013R1A1A3011404) (E.K.K.) and by a NRF grant (2006-0093855) through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (MEST) of the Korea (E.-J.C.).

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The authors declare that they have no conflict of interest.

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Kim, E.K., Choi, EJ. Compromised MAPK signaling in human diseases: an update. Arch Toxicol 89, 867–882 (2015). https://doi.org/10.1007/s00204-015-1472-2

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  • DOI: https://doi.org/10.1007/s00204-015-1472-2

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