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Originally published as MBC in Press, 10.1091/mbc.E03-11-0851 on June 16, 2004

Vol. 15, Issue 9, 4248-4260, September 2004

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Nck-dependent Activation of Extracellular Signal-regulated Kinase-1 and Regulation of Cell Survival during Endoplasmic Reticulum Stress{boxd}

Duc Thang Nguyên *, Sem Kebache {dagger}, Ali Fazel {ddagger}, Hetty N. Wong §, Sarah Jenna ||, Anouk Emadali *, Eun-hye Lee ||, John J.M. Bergeron {ddagger} ||, Randal J. Kaufman §, Louise Larose {dagger}, and Eric Chevet * {ddagger} || ¶

* Department of Surgery, McGill University, Montreal, Quebec, H3A 1A1 Canada; {dagger} Department of Experimental Medicine, McGill University, Montreal, Quebec, H3A 1A1 Canada; {ddagger} Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, H3A 1A1 Canada; || Department of Montreal Proteomic Network, McGill University, Montreal, Quebec, H3A 1A1 Canada; and § Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109-0650

Submitted November 26, 2003; Revised May 21, 2004; Accepted June 7, 2004
Monitoring Editor: Jennifer Lippincott-Schwartz

In response to stress, the endoplasmic reticulum (ER) signaling machinery triggers the inhibition of protein synthesis and up-regulation of genes whose products are involved in protein folding, cell cycle exit, and/or apoptosis. We demonstrate that the misfolding agents azetidine-2-carboxylic acid (Azc) and tunicamycin initiate signaling from the ER, resulting in the activation of Jun-N-terminal kinase, p44MAPK/extracellular signal-regulated kinase-1 (ERK-1), and p38MAPK through IRE1{alpha}-dependent mechanisms. To characterize the ER proximal signaling events involved, immuno-isolated ER membranes from rat fibroblasts treated with ER stress inducers were used to reconstitute the activation of the stress-activated protein kinase/mitogen-activate protein kinase (MAPK) pathways in vitro. This allowed us to demonstrate a role for the SH2/SH3 domain containing adaptor Nck in ERK-1 activation after Azc treatment. We also show both in vitro and in vivo that under basal conditions ER-associated Nck represses ERK-1 activation and that upon ER stress this pool of Nck dissociates from the ER membrane to allow ERK-1 activation. Moreover, under the same conditions, Nck-null cells elicit a stronger ERK-1 activation in response to Azc stress, thus, correlating with an enhanced survival phenotype. These data delineate a novel mechanism for the regulation of ER stress signaling to the MAPK pathway and demonstrate a critical role for Nck in ER stress and cell survival.

Article published online ahead of print. Mol. Biol. Cell 10.1091/mbc.E03–11–0851. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E03–11–0851.

Abbreviations used: Azc, azetidine-2-carboxylic acid; CNX, calnexin; ER, endoplasmic reticulum; MAPK, mitogen-activated protein kinase; RLC, rat liver cytosol; SAPK, stress-activated protein kinase; Tun, tunicamycin; UPR, unfolded protein response.

{boxd} Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.

Corresponding author. E-mail address: eric.chevet{at}mcgill.ca.




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