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c‐jun N‐terminal kinase hyperphosphorylates R406W tau at the PHF‐1 site during mitosis
Author(s) -
Tatebayashi Yoshitaka,
Planel Emmanuel,
Chui DeHua,
Sato Shinji,
Miyasaka Tomohiro,
Sahara Naruhiko,
Murayama Miyuki,
Kikuchi Naomi,
Yoshioka Katsuji,
Rivka Ravid,
Takashima Akihiko
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4362fje
Subject(s) - hyperphosphorylation , tauopathy , phosphorylation , gsk 3 , kinase , mitosis , chemistry , gsk3b , microbiology and biotechnology , cyclin dependent kinase 5 , tau protein , biology , alzheimer's disease , protein kinase a , cyclin dependent kinase 2 , neurodegeneration , medicine , disease
Tauopathies such as Alzheimer disease (AD) probably involve a type of phosphorylation imbalance causing the accumulation of abnormally hyperphosphorylated tau in neurons and/or glias. Investigation of R406W tau mutation may provide insight into such abnormal tau hyperphosphorylation, since this mutation causes AD‐like dementia and tauopathy in humans and because it has the unique ability to reduce tau phosphorylation in vitro and in cultured cells. Here we show that R406W mutation primarily disrupts tau phosphorylation at Ser404, a priming phosphorylation site of glycogen synthase kinase‐3β (GSK‐3β), thereby reducing subsequent GSK‐3β‐mediated phosphorylation at the PHF‐1 site (mostly Ser396). In contrast, c‐jun N‐terminal kinase (JNK) as activated in the mitotic phase directly hyperphosphorylates R406W tau at the PHF‐1 site. This was confirmed by PHF‐1 hyperphosphorylation of R406W tau in mitotic cells, its association with cytoplasmic JNK activation, and its inhibition by a JNK inhibitor, SP600125. These data unveil the unknown mechanisms of physiological tau phosphorylation at the PHF‐1 site and suggest that cytoplasmic JNK activation may play an important role in the abnormal tau hyperphosphorylation associated with R406W tau mutation and in AD.