title: Nck-1 antagonizes the endoplasmic reticulum stress-induced inhibition of translation.
abstract: Eukaryotic cells have developed specific mechanisms to overcome environmental stress. Here we show that the Src homology 2/3 (SH2/SH3) domain-containing protein Nck-1 prevents the unfolded protein response normally induced by pharmacological endoplasmic reticulum (ER) stress agents. Overexpression of Nck-1 enhances protein translation, whereas it abrogates eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation and inhibition of translation in response to tunicamycin or thapsigargin treatment. Nck-1 overexpression also attenuates induction of the ER chaperone, the immunoglobulin heavy chain-binding protein (BiP), and impairs cell survival in response to thapsigargin. We provided evidence that in these conditions, the effects of Nck on the unfolded protein response (UPR) involve its second SH3 domain and a calyculin A-sensitive phosphatase activity. In addition, we demonstrated that protein translation is reduced in mouse embryonic fibroblasts lacking both Nck isoforms and is enhanced in similar cells expressing high levels of Nck-1. In these various mouse embryonic fibroblasts, we also provided evidence that Nck modulates the activation of the ER resident eIF2alpha kinase PERK and consequently the phosphorylation of eIF2alpha on Ser-51 in response to stress. Our study establishes that Nck is required for optimal protein translation and demonstrates that, in addition to its adaptor function in mediating signaling from the plasma membrane, Nck also mediates signaling from the ER membrane compartment.
authors.affiliation: Polypeptide Laboratory, Division of Endocrinology, Department of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec H3A 2B2, Canada.
authors.forename: Sem
authors.initials: S
authors.lastname: Kebache
authors.forename: Eric
authors.initials: E
authors.lastname: Cardin
authors.forename: Duc Thang
authors.initials: DT
authors.lastname: Nguyên
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
authors.forename: Louise
authors.initials: L
authors.lastname: Larose
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006801:Humans; D015513:Oncogene Proteins / Q000502:physiology*; D014176:Protein Biosynthesis / Q000502:physiology*; D015398:Signal Transduction; D013314:Stress, Mechanical
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C078332:Nck protein; D015513:Oncogene Proteins