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MBC in Press, published online ahead of print June 16, 2004
Mol. Biol. Cell 10.1091/mbc.E03-11-0851

A more recent version of this article appeared on September 1, 2004
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Submitted on November 26, 2003
Revised on May 21, 2004
Accepted on June 7, 2004

Nck-dependent Activation of ERK-1 and Regulation of Cell Survival during Endoplasmic Reticulum Stress

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

Departments of *Surgery, {dagger}Experimental Medicine, {ddagger}Anatomy and Cell Biology, ||Montreal Proteomic Network, McGill University, Montreal, Quebec, Canada; {sect}Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI

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 JNK-1, p44MAPK/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 SAPK/MAPK pathways in vitro. This allowed us to demonstrate a role for the SH2/SH3 domain containing adaptor Nck in ERK-1 activation following 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.

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




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