Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line
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Cells, Cultured
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Endoplasmic Reticulum / metabolism*
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Endoribonucleases / genetics
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Endoribonucleases / metabolism*
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Enzyme Activation
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Gene Targeting
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Humans
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JNK Mitogen-Activated Protein Kinases
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Membrane Proteins*
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Mitogen-Activated Protein Kinases / metabolism*
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Multienzyme Complexes / genetics
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Multienzyme Complexes / metabolism*
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proteins / chemistry
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Proteins / genetics
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Proteins / metabolism*
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Rats
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Recombinant Fusion Proteins / metabolism
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TNF Receptor-Associated Factor 2
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Thapsigargin / pharmacology
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Two-Hybrid System Techniques
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eIF-2 Kinase / metabolism
Substances
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Ern1 protein, rat
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Membrane Proteins
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Multienzyme Complexes
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Proteins
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Recombinant Fusion Proteins
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TNF Receptor-Associated Factor 2
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Thapsigargin
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Protein Kinases
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ERN2 protein, human
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Ern2 protein, rat
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ERN1 protein, human
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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Endoribonucleases