TY - JOUR
T1 - Phosphorylation-dependent Lys63-linked polyubiquitination of Daxx is essential for sustained TNF-α-induced ASK1 activation
AU - Fukuyo, Yayoi
AU - Kitamura, Tetsuya
AU - Inoue, Masahiro
AU - Horikoshi, Nobuko T.
AU - Higashikubo, Ryuji
AU - Hunt, Clayton R.
AU - Usheva, Anny
AU - Horikoshi, Nobuo
PY - 2009/10/1
Y1 - 2009/10/1
N2 - Apoptosis signal-regulating kinase 1 (ASK1) is a key regulatory kinase in the proapoptotic response to various stresses. ASK1 phosphorylation of Daxx, an ASK1 activator protein, increases Daxx accumulation in cells and further enhances ASK1 activity through a positive feedback mechanism. Here, we show that ASK1-dependent phosphorylation of Daxx induces Lys63 (K63)-linked polyubiquitination on Lys122 of Daxx. Polyubiquitination is dispensable for Daxx accumulation or Daxx interaction with ASK1 because mutant Daxx deficient in polyubiquitin still exhibits ASK1-dependent accumulation and interaction with cellular ASK1. However, K63-linked Daxx polyubiquitination is required for tumor necrosis factor-α (TNF-α)-induced activation of ASK1. Therefore, K63-linked polyubiquitination of Daxx functions as a molecular switch to initiate and amplify the stress kinase response in the TNF-α signaling pathway.
AB - Apoptosis signal-regulating kinase 1 (ASK1) is a key regulatory kinase in the proapoptotic response to various stresses. ASK1 phosphorylation of Daxx, an ASK1 activator protein, increases Daxx accumulation in cells and further enhances ASK1 activity through a positive feedback mechanism. Here, we show that ASK1-dependent phosphorylation of Daxx induces Lys63 (K63)-linked polyubiquitination on Lys122 of Daxx. Polyubiquitination is dispensable for Daxx accumulation or Daxx interaction with ASK1 because mutant Daxx deficient in polyubiquitin still exhibits ASK1-dependent accumulation and interaction with cellular ASK1. However, K63-linked Daxx polyubiquitination is required for tumor necrosis factor-α (TNF-α)-induced activation of ASK1. Therefore, K63-linked polyubiquitination of Daxx functions as a molecular switch to initiate and amplify the stress kinase response in the TNF-α signaling pathway.
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U2 - 10.1158/0008-5472.CAN-09-2148
DO - 10.1158/0008-5472.CAN-09-2148
M3 - Article
C2 - 19789334
AN - SCOPUS:70350227321
SN - 0008-5472
VL - 69
SP - 7512
EP - 7517
JO - Cancer Research
JF - Cancer Research
IS - 19
ER -