Phosphorylation of the alpha-subunit of the eukaryotic initiation factor 2 (eIF2) on Ser51 is an early event associated with the down-regulation of protein synthesis at the level of translation and initiation of a transcriptional program. This constitutes a potent mechanism to overcome various stress conditions. In mammals, four eIF2alpha-kinases [PKR-like endoplasmic reticulum kinase (PERK), dsRNA-activated protein kinase (PKR), heme regulated inhibitor (HRI) and general control nonderepressible-2 (GCN2)], activated following specific stresses, have been shown to be involved in this process. In this article, we report that the ubiquitously expressed adaptor protein Nck, composed only of Src homology domains and classically implicated in cell signaling by activated plasma membrane receptor tyrosine kinases, modulates eIF2alpha-kinase-mediated eIF2alphaSer51 phosphorylation in a specific manner. Our results show that Nck not only prevents eIF2alpha phosphorylation upon PERK activation, as reported previously, but also reduces eIF2alpha phosphorylation in conditions leading to PKR and HRI activation. By contrast, the overexpression of Nck in mammalian cells fails to attenuate eIF2alphaSer51 phosphorylation in response to amino acid starvation, a stress well known to activate GCN2. This observation is further confirmed by showing that Nck fails to alter eIF2alphaSer51 phosphorylation in Saccharomyces cerevisiae, for which the sole eIF2alpha-kinase is Gcn2p. Our results suggest the existence of a novel mechanism that specifically modulates the phosphorylation of eIF2alpha on Ser51 under various stress conditions.
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Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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Site | Modification | Modifier | Source | Reference |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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