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Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress
Author(s) -
Morita Keiichi,
Saitoh Masao,
Tobiume Kei,
Matsuura Hiroshi,
Enomoto Shoji,
Nishitoh Hideki,
Ichijo Hidenori
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.21.6028
Subject(s) - ask1 , map kinase kinase kinase , biology , cyclin dependent kinase 9 , c raf , mitogen activated protein kinase kinase , map2k7 , p38 mitogen activated protein kinases , microbiology and biotechnology , cyclin dependent kinase 2 , kinase , protein kinase a , biochemistry
Apoptosis signal‐regulating kinase 1 (ASK1) is a MAP kinase kinase kinase (MAPKKK) that activates the JNK and p38 MAP kinase cascades and is activated in response to oxidative stress such as hydrogen peroxide (H 2 O 2 ). A yeast two‐hybrid screening identified a serine/threonine protein phosphatase 5 (PP5) as a binding partner of ASK1. PP5 directly dephosphorylated an essential phospho‐threonine residue within the kinase domain of ASK1 and thereby inactivated ASK1 activity in vitro and in vivo . The interaction between PP5 and ASK1 was induced by H 2 O 2 treatment and was followed by the decrease in ASK1 activity. PP5 inhibited not only H 2 O 2 ‐induced sustained activation of ASK1 but also ASK1‐dependent apoptosis. Thus, PP5 appears to act as a physiological inhibitor of ASK1–JNK/p38 pathways by negative feedback.