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

Abstract

Perturbations in endoplasmic reticulum (ER) homeostasis, including depletion of Ca(2+) 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.

Baicalin Augments Hyperthermia-Induced Apoptosis in U937 Cells and Modulates the MAPK Pathway via ROS Generation

“…The MAPK pathway is involved in the regulation of cell cycle progression, cell survival, and death responses after exposure to a variety of stimuli [30]. Therefore, we analyzed the activated or phosphorylated forms of the members of the subfamilies of the MAPK path-way, including JNK, ERK1/2, and p38.…”

“…Activation of JNK usually occurs from the activation of ASK1, which is a target of Akt inhibitory phosphorylation, and provides the direct link between Akt and JNK [34, 53, 54]. Sometimes induction of apoptosis is done by following the pathway of RAF1-ERK or ASK1-JNK signals, especially in the presence of any kind of stress [30]. However, some reports also reflect that Akt signals exist side by side with the MAPK pathway and play a role in the induction of apoptosis [55, 56].…”

Endoplasmic reticulum stress and its effects on renal tubular cells apoptosis in ischemic acute kidney injury

“…CHOP promotes hyperoxidation of the ER and promotes IP3-induced Ca2 þ release from the ER lumen. 38 Ca2 þ leaked from the ER lumen enters the mitochondria and generates mitochondrial reactive oxygen species (ROS), triggering a vicious cycle of oxidative stress both in the ER and mitochondria. 39 In addition, CHOP decreases the expression of pro-survival protein BCL-2.…”

PI3K-Akt-mTOR signal inhibition affects expression of genes related to endoplasmic reticulum stress

“…In order to restore ER homeostasis, liver cells down-regulate the overall protein synthesis through an adaptive protective response termed the unfolded protein response (UPR) signaling system, which involves enhancement of protein folding and degradation in the ER (Shen et al, 2004). Perturbations in the environment within the ER lumen, for example a reduction in the luminal Ca 2+ concentration or altered redox status, can affect protein folding and processing (Darling and Cook, 2014).…”