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J. Biol. Chem., Vol. 279, Issue 10, 9662-9671, March 5, 2004

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Nck-1 Antagonizes the Endoplasmic Reticulum Stress-induced Inhibition of Translation^*

Sem Kebache, Eric Cardin, Duc Thang Nguyên, Eric Chevet, and Louise Larose¶

From the Polypeptide Laboratory, Division of Endocrinology, Department of Experimental Medicine, Faculty of Medicine, Organelle Signaling Laboratory, Department of Surgery, McGill University, Montreal, Quebec H3A 2B2, Canada

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 2 (eIF2) 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 eIF2 kinase PERK and consequently the phosphorylation of eIF2 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.

Received for publication, September 23, 2003 , and in revised form, December 12, 2003.

^* This work was supported by Canadian Institutes for Health Research Grant MOT-53357 (to E. C.), the Canadian Diabetes Association, and the Natural Sciences and Engineering Research Council of Canada (to L. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Scholar from the Fond de Recherche en Santé du Québec. To whom correspondence should be addressed: Polypeptide Laboratory, McGill University, Strathcona Bldg., 3640 University St., Rm. W315, Montreal, Quebec H3A 2B2, Canada. Tel.: 514-398-5844; Fax: 514-398-3923; E-mail: louise.larose{at}mcgill.ca.

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