Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1.
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.
Urano
F
F
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.
Wang
X
X
Bertolotti
A
A
Zhang
Y
Y
Chung
P
P
Harding
H P
HP
Ron
D
D
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D018390:Gene Targeting; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2; D019284:Thapsigargin / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D019892:eIF-2 Kinase / Q000378:metabolism
D004722:Endoribonucleases; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D009097:Multienzyme Complexes; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011993:Recombinant Fusion Proteins; D047992:TNF Receptor-Associated Factor 2; D019284:Thapsigargin; D019892:eIF-2 Kinase; C575026:Ern1 protein, rat; C403982:ERN2 protein, human; C486557:Ern2 protein, rat; C528229:ERN1 protein, human