Nck-dependent Activation of Extracellular Signal-regulated Kinase-1 and Regulation of Cell Survival during Endoplasmic Reticulum Stress

Nguyen, Doan Trang; Kebache, Sem; Fazel, Ali; Wong, Hetty N.; Jenna, Sarah; Emadali, Anouk; Lee, Eun-hye; Bergeron, John J.M.; Kaufman, Randal J.; Larose, Louise; Chevet, Éric

doi:10.1091/mbc.e03-11-0851

Cited by 152 publications

(128 citation statements)

References 57 publications

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“…NF-B and p38 MAPK may not be the upstream signal for the ATF6 pathway, because the induction of GRP78 by ER stress was not affected by the inhibitors for p38 MAPK and NF-B. Recently, pp38 activation was reported to be mediated through IRE1 because ER stress-induced pp38 activation was attenuated in IRE1-deficient cells (51). Therefore, IRE1-dependent activation of NF-B may also partly mediated through the p38 MAPK pathway (Fig.…”

Section: Fig 3 Activation Of Nf-b During Er Stressmentioning

confidence: 97%

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Hung

Lei³

et al. 2004

Journal of Biological Chemistry

238

215

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Expression of mutant proteins or viral infection mayinterfere with proper protein folding activity in the endoplasmic reticulum (ER). Several pathways that maintain cellular homeostasis were activated in response to these ER disturbances. Here we investigated which of these ER stress-activated pathways induce COX-2 and potentially oncogenesis. Tunicamycin and brefeldin A, two ER stress inducers, increased the expression of COX-2 in ML-1 or MCF-7 cells. Nuclear translocation of NF-B and activation of pp38 MAPK were observed during ER stress. I B␣ kinase inhibitor Bay 11-7082 or I B␣ kinase dominant negative mutant significantly inhibited the induction of COX-2. pp38 MAPK inhibitor SB203580 or eIF2␣ phosphorylation inhibitor 2-aminopurine attenuated the nuclear NF-B DNA binding activity and COX-2 induction. Expression of mutant hepatitis B virus (HBV) large surface proteins, inducers of ER stress, enhanced the expression of COX-2 in ML-1 and HuH-7 cells. Transgenic mice showed higher expression of COX-2 protein in liver and kidney tissue expressing mutant HBV large surface protein in vivo. Similarly, increased expression of COX-2 mRNA was observed in human hepatocellular carcinoma tissue expressing mutant HBV large surface proteins. In ML-1 cells expressing mutant HBV large surface protein, anchorage-independent growth was enhanced, and the enhancement was abolished by the addition of specific COX-2 inhibitors. Thus, ER stress due either to expression of viral surface proteins or drugs can stimulate the expression of COX-2 through the NF-B and pp38 kinase pathways. Our results provide important insights into cellular carcinogenesis associated with latent endoplasmic reticulum stress.

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Section: Fig 3 Activation Of Nf-b During Er Stressmentioning

confidence: 97%

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Hung

Lei³

et al. 2004

Journal of Biological Chemistry

238

215

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“…The glucosamine-induced dedifferentiation of INS-1E cells is mediated by activation of the mitogen-activated protein kinase/ERK kinase-ERK pathway To obtain insights into the signal transmission pathway linking glucosamineinduced ER stress and beta cell dedifferentiation, we analysed the effect of specific inhibitors of pathways emanating from the stressed ER [28]. We began by using SB203580 to inhibit p38 mitogen-activated protein kinase (MAPK).…”

Section: Glucosamine-induced Er Stress Inhibits Differentiation Of Inmentioning

confidence: 99%

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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Aims/hypothesis Beta cell failure is caused by loss of cell mass, mostly by apoptosis, but also by simple dysfunction (decline of glucose-stimulated insulin secretion, downregulation of specific gene expression). Apoptosis and dysfunction are caused, at least in part, by lipoglucotoxicity. The mechanisms implicated are oxidative stress, increase in the hexosamine biosynthetic pathway (HBP) flux and endoplasmic reticulum (ER) stress. Oxidative stress plays a role in glucotoxicity-induced beta cell dedifferentiation, while glucotoxicity-induced ER stress has been mostly linked to beta cell apoptosis. We sought to clarify whether ER stress caused by increased HBP flux participates in a dedifferentiating response of beta cells, in the absence of relevant apoptosis. Methods We used INS-1E cells and murine islets. We analysed the unfolded protein response and the expression profile of beta cells by real-time RT-PCR and western blot. The signal transmission pathway elicited by ER stress was investigated by real-time RT-PCR and immunofluorescence. Results Glucosamine and high glucose induced ER stress, but did not decrease cell viability in INS-1E cells. ER stress caused dedifferentiation of beta cells, as shown by downregulation of beta cell markers and of the transcription factor, pancreatic and duodenal homeobox 1. Glucose-stimulated insulin secretion was inhibited. These effects were prevented by the chemical chaperone, 4-phenyl butyric acid. The extracellular signal-regulated kinase (ERK) signal transmission pathway was implicated, since its inhibition prevented the effects induced by glucosamine and high glucose. Conclusions/interpretation Glucotoxic ER stress dedifferentiates beta cells, in the absence of apoptosis, through a transcriptional response. These effects are mediated by the activation of ERK1/2.

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“…RNA was converted to cDNA using oligo(dT) 20 and the Thermoscript reverse transcription-PCR system (Invitrogen). Aliquots of the cDNA synthesis reaction were used for PCR analysis of EDEM, XBP1, and glyceraldehyde-3-phosphate dehydrogenase mRNA expression by amplification with Taq DNA polymerase (MBI Fermentas).…”

Section: Methodsmentioning

confidence: 99%

Calnexin Phosphorylation Attenuates the Release of Partially Misfolded α1-Antitrypsin to the Secretory Pathway

Cameron

Chevet

Pluquet

et al. 2009

Journal of Biological Chemistry

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Calnexin is a type I integral membrane phosphoprotein resident of the endoplasmic reticulum. Its intraluminal domain has been deduced to function as a lectin chaperone coordinating the timing of folding of newly synthesized N-linked glycoproteins of the secretory pathway. Its C-terminal cytosolic oriented extension has an ERK1 phosphorylation site at Ser 563 affecting calnexin association with the translocon. Here we find an additional function for calnexin phosphorylation at Ser 563 in endoplasmic reticulum quality control. A low dose of the misfolding agent L-azetidine 2-carboxylic acid slows glycoprotein maturation and diminishes the extent and rate of secretion of newly synthesized secretory ␣1-antitrypsin. Under these conditions the phosphorylation of calnexin is enhanced at Ser 563 . Inhibition of this phosphorylation by the MEK1 inhibitor PD98059 enhanced the extent and rate of ␣1-antitrypsin secretion comparable with that achieved by inhibiting ␣-mannosidase activity with kifunensine. This is the first report in which the phosphorylation of calnexin is linked to the efficiency of secretion of a cargo glycoprotein.It has generally been accepted that the quality control system of the endoplasmic reticulum (ER) 3 prevents the exit of newly synthesized misfolded proteins to the secretory pathway (1). The calnexin cycle (1-3) has been extensively studied to deduce the mechanisms that regulate the selection and sorting of misfolded glycoproteins for their targeting to the proteasome for ER-associated degradation (ERAD). A prolonged time of association of constituents of the calnexin cycle with misfolded glycoproteins coincides with their targeting to ERAD (4). Similar to entry into the calnexin cycle for productive folding, entry to ERAD appears to be based on a sugar code for misfolded glycoproteins with the former being glucose-based and the latter being mannose-based (4 -6).The mannosidase EDEM/Htm1p (7, 8), whose expression is induced by the unfolded protein response (9 -11), selectively processes Man 8 GlcNAc 2 glycans on misfolded glycoproteins. This yields glycans containing a terminal ␣1,6-linked mannose residue. It is this sugar linkage that is recognized by the lectin Yos9p (12) for retrotranslocation of misfolded glycoproteins out of the ER and their degradation by the proteasome (see as well the work of Christianson et al. (13) for mammalian OS-9). An association between calnexin and EDEM facilitates the efficient presentation of misfolded glycoproteins to ERAD (9).The dogma that ER quality control is highly efficient at preventing the access of newly synthesized misfolded proteins to the cargo exit machinery has been challenged by observations indicating that misfolded variants of transthyretin were efficiently secreted after expression in baby hamster kidney cells or murine hepatocytes (14). These authors further formalized a hypothesis for quality control in which competition of a misfolded protein for the folding machineries of the ER (ER-assisted folding) or the degradation machineries (ER...

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Nck-dependent Activation of Extracellular Signal-regulated Kinase-1 and Regulation of Cell Survival during Endoplasmic Reticulum Stress

Cited by 152 publications

References 57 publications

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Calnexin Phosphorylation Attenuates the Release of Partially Misfolded α1-Antitrypsin to the Secretory Pathway

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