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J. Biol. Chem., Vol. 281, Issue 36, 26633-26644, September 8, 2006

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Nck in a Complex Containing the Catalytic Subunit of Protein Phosphatase 1 Regulates Eukaryotic Initiation Factor 2 Signaling and Cell Survival to Endoplasmic Reticulum Stress^*

From the Polypeptide Hormone Laboratory, Department of Medicine, McGill University, Montreal, Quebec H3A 2B2, Canada

Stress imposed on the endoplasmic reticulum (ER) induces the phosphorylation of the -subunit of the eukaryotic initiation factor 2 (eIF2) on Ser⁵¹. This results in transient inhibition of general translation initiation while concomitantly activating a signaling pathway that promotes the expression of genes whose products improve ER function. Conversely, dephosphorylation of eIF2Ser⁵¹ is accomplished by protein phosphatase 1 (PP1c) complexes containing either the protein CReP or GADD34, which target PP1c to eIF2. Here, we demonstrate that the Src homology (SH) domain-containing adaptor Nck is a key component of a molecular complex that controls eIF2 phosphorylation and signaling in response to ER stress. We show that overexpression of Nck decreases basal and ER stress-induced eIF2 phosphorylation and the attendant induction of ATF4 and CHOP. In contrast, we demonstrate that the mouse embryonic fibroblasts lacking both isoforms of Nck (Nck1^-/-Nck2^-/-) show higher levels of eIF2 phosphorylation and premature induction of ATF4, CHOP, and GADD34 in response to ER stress and finally, are more resistant to cell death induced by prolonged ER stress conditions. We establish that a significant amount of Nck protein localizes at the ER and is in a complex with eIF2 subunits. Further analysis of this complex revealed that it also contains the Ser/Thr phosphatase PP1c, its regulatory subunit CReP, and dephosphorylates eIF2 on Ser⁵¹ in vitro. Overall, we demonstrate that Nck as a component of the CReP/PP1c holophosphatase complex contributes to maintain eIF2 in a hypophosphorylated state. In this manner, Nck modulates translation and eIF2 signaling in response to ER stress.

Received for publication, December 21, 2005 , and in revised form, July 10, 2006.

^* This work was supported by a grant (to L. L.) from the Canadian Diabetes Association in honor of the late Lilian I. Dale. 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.

¹ Supported by a fellowship from Fond de la Recherche en Santé du Québec.

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

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