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Modulation of eIF2alpha Phosphorylation and PKR Activation by Nck
Author(s) -
Cardin Eric,
Larose Louise
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.294
Subject(s) - protein kinase r , phosphorylation , eif2 , microbiology and biotechnology , kinase , eif 2 kinase , integrated stress response , signal transduction , signal transducing adaptor protein , protein kinase a , biology , translation (biology) , mitogen activated protein kinase kinase , biochemistry , cyclin dependent kinase 2 , messenger rna , gene
Phosphorylation of the α‐subunit of the eukaryotic initiation factor 2 (eIF2) on Ser 51 is an early event associated with downregulation of protein synthesis at the level of translation and constitutes a potent mechanism to overcome various stress conditions. In mammals, four eIF2α‐kinases PERK, PKR, HRI and GCN2, activated following specific stresses, have been involved in this process. In a first study, we demonstrated that the adaptor protein Nck, classically implicated in receptor tyrosine kinases signal transduction, modulates eIF2α‐kinases‐mediated eIF2αSer 51 phosphorylation in a specific manner. In fact, we showed that Nck reduces eIF2α phosphorylation in conditions activating PKR or HRI as we reported for PERK, but fails to do so in conditions activating GCN2. Herein, we report that Nck reduces PKR activation in response to dsRNA. In addition, we found that Nck reduces dsRNA‐induced activation of p38MAPK, a PKR‐downstream substrate, and cell death. Finally, we show that Nck interacts with inactive PKR. All together, these results suggest that Nck could regulate threshold levels of PKR activation. Our study reveals the existence of a novel mechanism regulating phosphorylation of eIF2α on Ser 51 under various stress conditions and identifies Nck as a regulator of the tumor suppressor and antiviral protein kinase PKR. Supported by the Natural Sciences and Engineering Research Council of Canada (NSERC).