Review
The role of MAPK signalling pathways in the response to endoplasmic reticulum stress

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Highlights

  • MAPK signalling acts as an effector and modulator for the unfolded protein response.

  • MAPK signalling promotes cell cycle progression or arrest and survival or death.

  • Cell fate determination following ER stress and MAPK signalling is context-specific.

  • Cross-talk between MAPKs and UPR is evident in cancer, atherosclerosis and ischemia.

  • UPR inhibitors have potential as single and combined therapies with MAPK inhibitors.

Abstract

Perturbations in endoplasmic reticulum (ER) homeostasis, including depletion of Ca2 + or altered redox status, induce ER stress due to protein accumulation, misfolding and oxidation. This activates the unfolded protein response (UPR) to re-establish the balance between ER protein folding capacity and protein load, resulting in cell survival or, following chronic ER stress, promotes cell death. The mechanisms for the transition between adaptation to ER stress and ER stress-induced cell death are still being understood. However, the identification of numerous points of cross-talk between the UPR and mitogen-activated protein kinase (MAPK) signalling pathways may contribute to our understanding of the consequences of ER stress. Indeed, the MAPK signalling network is known to regulate cell cycle progression and cell survival or death responses following a variety of stresses. In this article, we review UPR signalling and the activation of MAPK signalling pathways in response to ER stress. In addition, we highlight components of the UPR that are modulated in response to MAPK signalling and the consequences of this cross-talk. We also describe several diseases, including cancer, type II diabetes and retinal degeneration, where activation of the UPR and MAPK signalling contribute to disease progression and highlight potential avenues for therapeutic intervention. This article is part of a Special Issue entitled: Calcium Signaling In Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.

Abbreviations

Akt
Ak mouse thymoma oncogene, also known as protein kinase B, PKB
ANF
atrial natriuretic factor
AP
activator protein
ASK1
apoptosis signal-regulating kinase 1
ATF6
activating transcription factor 6
bZIP
basic leucine zipper
C/EBP
CCAAT/enhancer-binding protein
CaMKII
Ca2 +/calmodulin-dependent protein kinase II
CDK
cyclin dependent kinase
CHOP
C/EBP homologous protein
DR5
death receptor 5
eIF
eukaryotic initiation factor
ER
endoplasmic reticulum
ERK
extracellular signal-regulated kinase
ERO1α
ER oxidase 1α
FOXO3
forkhead box O3
GADD34
growth arrest and DNA damage 34
GRP
glucose regulated protein
IL-6
interleukin-6
IP3
inositol 1,4,5-triphosphate
IP3R1
IP3 receptor type 1
IRE1
inositol requiring protein 1
IRES
internal ribosome entry site
IRS1
insulin receptor substrate 1
JNK
c-Jun N-terminal kinase
Keap
Kelch-like ECH associating protein
MAPK
mitogen-activated protein kinase
MEFs
mouse embryonic fibroblast cells
MEK
MAPK or ERK kinase
MK-2
MAPK-activated protein kinase-2
MKK
MAPK kinase
MKKK
MAPK kinase kinases
NGF
nerve growth factor
Nrf2
nuclear factor (erythroid-derived 2)-like 2
PERK
PKR-like ER kinase
Rb
retinoblastoma-associated protein
RIDD
regulated IRE1 dependent-decay
SERCA
sarco/endoplasmic reticulum Ca2 + ATPase
Tg
thapsigargin
TNF
tumour necrosis factor
TRAF
TNF receptor-associated factor
UPR
unfolded protein response
XBP1
x-box binding protein 1

Keywords

Endoplasmic reticulum stress
Unfolded protein response
ERK1/2
JNK
p38

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This article is part of a Special Issue entitled: Calcium Signaling In Health and Disease.