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Activation of apoptosis signal‐regulating kinase 1 by the stress‐induced activating phosphorylation of pre‐formed oligomer
Author(s) -
Tobiume Kei,
Saitoh Masao,
Ichijo Hidenori
Publication year - 2002
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10080
Subject(s) - ask1 , thioredoxin , microbiology and biotechnology , kinase , map kinase kinase kinase , cyclin dependent kinase 9 , cyclin dependent kinase 2 , phosphorylation , mitogen activated protein kinase kinase , autophosphorylation , protein kinase a , chemistry , biology , biochemistry , oxidative stress
Apoptosis signal‐regulating kinase 1 (ASK1) is a MAPKKK family member which activates c‐Jun N‐terminal kinase (JNK) and p38. In non‐stressed cells, ASK1 exists as an inactive complex with the reduced form of thioredoxin. Oxidative stress such as hydrogen peroxide (H 2 O 2 ) disrupts the ASK1‐thioredoxin complex by oxidization of thioredoxin and thereby activates ASK1. The precise mechanism by which ASK1 is activated after its release from thioredoxin is unknown. Here we show that phosphorylation of Thr845 at the activation loop is essential for ASK1 to be activated by H 2 O 2 . ASK1 appears to form a silent homo‐oligomer through its C‐terminal coiled‐coil region in non‐stressed cells. Following H 2 O 2 treatment, pre‐existing ASK1 oligomer undergoes conformational change and creates a new interface within an oligomer, which ultimately leads to trans‐autophosphorylation of Thr845. Thus, direct interaction via the coiled‐coil region is required for self‐scaffolding but not sufficient for activation of ASK1. Importantly, Thr845 of ASK1 can also be trans‐phosphorylated by an unidentified Thr845 kinase in response to H 2 O 2 treatment. We propose that this potential Thr845 kinase may be an ignition kinase that triggers Thr845 phosphorylation in oligomerized and activation‐competent forms of ASK1. J. Cell. Physiol. 191: 95–104, 2002. © 2002 Wiley‐Liss, Inc.