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Science 287 (5453): 664-666

Copyright © 2000 by the American Association for the Advancement of Science

Coupling of Stress in the ER to Activation of JNK Protein Kinases by Transmembrane Protein Kinase IRE1

Fumihiko Urano, XiaoZhong Wang, Anne Bertolotti, Yuhong Zhang, Peter Chung, Heather P. Harding, David Ron *

Malfolded proteins in the endoplasmic reticulum (ER) induce cellular stress and activate c-Jun amino-terminal kinases (JNKs or SAPKs). Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha -/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. Dominant-negative TRAF2 inhibited activation of JNK by IRE1. Activation of JNK by endogenous signals initiated in the ER proceeds by a pathway similar to that initiated by cell surface receptors in response to extracellular signals.

Skirball Institute of Biomolecular Medicine, Departments of Medicine, Cell Biology and the Kaplan Cancer Center, New York University Medical School, New York, NY 10016, USA.
*   To whom correspondence should be addressed: E-mail: ron{at}saturn.med.nyu.edu

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M. Flores-Diaz, J.-C. Higuita, I. Florin, T. Okada, P. Pollesello, T. Bergman, M. Thelestam, K. Mori, and A. Alape-Giron (2004)
J. Biol. Chem. 279, 21724-21731
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TRAF Family Proteins Link PKR with NF-{kappa}B Activation.
J. Gil, M. A. Garcia, P. Gomez-Puertas, S. Guerra, J. Rullas, H. Nakano, J. Alcami, and M. Esteban (2004)
Mol. Cell. Biol. 24, 4502-4512
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Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and A{beta}-induced cell death.
J. Hitomi, T. Katayama, Y. Eguchi, T. Kudo, M. Taniguchi, Y. Koyama, T. Manabe, S. Yamagishi, Y. Bando, K. Imaizumi, et al. (2004)
J. Cell Biol. 165, 347-356
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Role of Herp in the endoplasmic reticulum stress response.
O. Hori, F. Ichinoda, A. Yamaguchi, T. Tamatani, M. Taniguchi, Y. Koyama, T. Katayama, M. Tohyama, D. M. Stern, K. Ozawa, et al. (2004)
Genes Cells 9, 457-469
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