Nck‐1 selectively modulates eIF2αSer51 phosphorylation by a subset of eIF2α‐kinases

Cardin, Éric; Latreille, Mathieu; Khoury, Chamel; Greenwood, Michael T.; Larose, Louise

doi:10.1111/j.1742-4658.2007.06110.x

Cited by 15 publications

(13 citation statements)

References 38 publications

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“…Nck is an adapter protein that has been reported interact with and directly limit activation of three of the eIF2a kinases PKR, PERK, and HRI, but not GCN2 and specifically modulate eIF2a phosphorylation under various stress conditions (Cardin et al, 2007). Nck binds to only the inactive form of PKR.…”

Section: Resultsmentioning

confidence: 99%

“…Nck can form a complex with phosphorylated eIF2a and recruit PP1a to dephosphorylate eIF2a (Latreille and Larose, 2006). The absence of Nck has been reported to increase the sensitivity of PKR, PERK and HRI kinase activation and also to reduce the efficiency of eIF2a phosphorylation by PP1a (Cardin et al, 2007). Consistent with the higher level of eIF2a phosphorylation in Nck1,2−/− MEFs, viral yields from these cells were decreased by about 10 fold (data not shown).…”

Section: Resultsmentioning

confidence: 99%

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West Nile virus infection does not induce PKR activation in rodent cells

2011

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dsRNA-activated protein kinase (PKR) is activated by viral dsRNAs and phosphorylates eIF2a reducing translation of host and viral mRNA. Although infection with a chimeric West Nile virus (WNV) efficiently induced PKR and eIF2a phosphorylation, infections with natural lineage 1 or 2 strains did not. Investigation of the mechanism of suppression showed that among the cellular PKR inhibitor proteins tested, only Nck, known to interact with inactive PKR, colocalized and co-immunoprecipitated with PKR in WNV-infected cells and PKR phosphorylation did not increase in infected Nck1,2−/− cells. Several WNV stem-loop RNAs efficiently activated PKR in vitro but not in infected cells. WNV infection did not interfere with intracellular PKR activation by poly(I:C) and similar virus yields were produced by control and PKR−/− cells. The results indicate that PKR phosphorylation is not actively suppressed in WNV-infected cells but that PKR is not activated by the viral dsRNA in infected cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

West Nile virus infection does not induce PKR activation in rodent cells

2011

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“…However, a successful homeostatic response should result in modulation of the UPR and resumption of normal cellular function. To do this several UPR induced proteins such as p58IPK [13], NCK1 [9,10] and GADD34 [7,8] feed-back to relieve the inhibition of protein synthesis mediated by PERK. These act by recruiting phosphatases that dephosphorylate eIF2α.…”

Section: Discussionmentioning

confidence: 99%

“…The proteins GADD34 [7,8], Nck1 [9,10] and p58iPK ([11,12] and reviewed by [13] recruit protein phosphatases that dephosphorylate eIF2a restoring protein synthesis. The protein Xbp1u, dimerizes with Xbp1s and ATF6 and targets them for proteasomal degradation [14,15].…”

Section: Introductionmentioning

confidence: 99%

Zhangfei/CREB-ZF – A Potential Regulator of the Unfolded Protein Response

et al. 2013

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Cells respond to perturbations in the microenvironment of the endoplasmic reticulum (ER), and to the overloading of its capacity to process secretory and membrane-associate proteins, by activating the Unfolded Protein Response (UPR). Genes that mediate the UPR are regulated by three basic leucine-zipper (bLZip) motif-containing transcription factors – Xbp1s, ATF4 and ATF6. A failure of the UPR to achieve homeostasis and its continued stimulation leads to apoptosis. Mechanisms must therefore exist to turn off the UPR if it successfully restores normalcy. The bLZip protein Zhangfei/CREBZF/SMILE is known to suppress the ability of several, seemingly structurally unrelated, transcription factors. These targets include Luman/CREB3 and CREBH, ER-resident bLZip proteins known to activate the UPR in some cell types. Here we show that Zhangfei had a suppressive effect on most UPR genes activated by the calcium ionophore thapsigargin. This effect was at least partially due to the interaction of Zhangfei with Xbp1s. The leucine zipper of Zhangfei was required for this interaction, which led to the subsequent proteasomal degradation of Xbp1s. Zhangfei suppressed the ability of Xbp1s to activate transcription from a promoter containing unfolded protein response elements and significantly reduced the ability to Xbp1s to activate the UPR as measured by RNA and protein levels of UPR-related genes. Finally, specific suppression of endogenous Zhangfei in thapsigargin-treated primary rat sensory neurons with siRNA directed to Zhangfei transcripts, led to a significant increase in transcripts and proteins of UPR genes, suggesting a potential role for Zhangfei in modulating the UPR.

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“…Par l'intermédiaire des intégrines, ces structures servent de domaines d'adhésion, mais elles sont surtout caractérisées par la présence de métalloprotéases dégradant la matrice extracellulaire. Contrairement aux podosomes, la formation d'invadopodes est restreinte aux cellu- atténuant la phosphorylation de sa sous-unité α par certaines protéi-nes kinases activées en réponse à différents stress cellulaires [25]. Par exemple, Nck module la phosphorylation d'eIF2 par PERK (PKR-related endoplasmic reticulum kinase), protéine kinase de la membrane du RE activée en réponse à un stress causé par l'accumulation de protéines mal conformées dans le RE, en recrutant dans un même complexe eIF2 et la phosphatase PP1c [9].…”

Section: La Traduction Et La Réponse Au Stressunclassified

Une protéine uNick en son genre

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Larose

2011

Med Sci (Paris)

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> Nck, représenté par Nck1 et Nck2, est un adaptateur à domaines homologues de Src (SH2 et SH3), unique compte tenu de la diversité des processus cellulaires morphogéniques et mitogé-niques auxquels il participe et de ses modes atypiques de signalisation. Son rôle-clé au centre de plusieurs voies de signalisation laisse présager qu'une variation de ses niveaux d'expression pourrait altérer l'homéostasie des cellules. En accord avec cette hypothèse, une augmentation de l'expression de Nck1 et Nck2 a été observée dans de nombreux types de cancer. Nous décri-vons ici certains des complexes signalétiques associés à Nck, en mettant l'accent sur les méca-nismes moléculaires par lesquels cet adaptateur unique peut contribuer au cancer. < kinase) est unique car non seulement elle possède un domaine SH2, mais, de plus, elle présente trois domaines SH3 fonctionnellement différents qui lui confèrent un caractère polyvalent pour assembler une grande diversité de complexes moléculaires. Cette synthèse a pour but de souligner le caractère unique de Nck en faisant état des complexes moléculaires qu'il assemble et des modes particuliers de signalisation qu'il utilise, et en insistant sur sa participation à la progression du cancer. (Figure 1) [1,4]. Des études génétiques chez la souris ont révélé que les gènes Nck sont essentiels au développement embryonnaire et fonctionnellement redondants [5]. Cette redondance pourrait s'expliquer parce que de nombreux partenaires d'interaction sont communs aux deux Nck (Figure 1). Néanmoins, on leur attribue aussi des fonctions uniques comme le suggèrent leur interaction avec des partenaires différents, leur expression simultanée dans certains types cellulaires et leurs profils d'expression tissulaire distincts [1,5]. Le mode classique de signalisation signal/pY-SH2/SH3-effecteurs utilisé en général par les adaptateurs contenant des domaines SH est le mécanisme principal par lequel Nck propage l'information aux effecteurs intracellulaires suivant l'activation de récepteurs membranaires de type tyrosine kinase (RTK : receptor tyrosine kinases) (Figure 2) [1]. Cependant, Nck transmet aussi le signal selon un mode de signalisation inversé où l'information perçue par les domaines SH3 est transmise à Laboratoire des polypeptides, L'adaptateur Nck

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Nck‐1 selectively modulates eIF2αSer51 phosphorylation by a subset of eIF2α‐kinases

Cited by 15 publications

References 38 publications

West Nile virus infection does not induce PKR activation in rodent cells

West Nile virus infection does not induce PKR activation in rodent cells

Zhangfei/CREB-ZF – A Potential Regulator of the Unfolded Protein Response

Une protéine uNick en son genre

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