Activation mechanism of c-Jun amino-terminal kinase in the course of neural differentiation of P19 embryonic carcinoma cells

Shoko Akiyama, Takayuki Yonezawa, Tada Aki Kudo, Ming Guang Li, Hong Wang, Michihiko Ito, Katsuji Yoshioka, Jun Ninomiya-Tsuji, Kunihiro Matsumoto, Ryunosuke Kanamaru, Shinri Tamura, Takayasu Kobayashi

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

P19 embryonic carcinoma cells, a model system for studying early development and differentiation, can differentiate into neurons and primitive endoderm-like cells depending on the culture conditions. We have previously reported that the activation of c-Jun amino-terminal kinase (JNK) is required for the retinoic acid-induced neural differentiation of P19 cells. However, the signaling pathway(s) responsible for the activation of JNK has not been known. In this study, we demonstrated that activities of MAPK kinase 4 (MKK4) and TAK1, one of the upstream kinases of MKK4, were enhanced in the neurally differentiating cells. Inhibition of the neural differentiation by an overexpression of protein phosphatase 2C∈, an inactivator of TAK1, suggested a critical role of the TAK1 signaling pathway during the differentiation. Confocal microscopic analysis indicated that TAK1, phospho-MKK4, and phospho-JNK were colocalized with tubulin in the neurites and localized also in the nuclei of the differentiating cells. In contrast, two TAK1-binding proteins, TAB1 and TAB2, which are involved in the activation of TAK1, were localized in the neurites and the nuclei of the differentiating cells, respectively. These results suggest that two distinct TAK1-MKK4-JNK signaling pathways are independently activated at the different intracellular locations and may participate in the regulation of the neural differentiation of P19 cells.

Original languageEnglish
Pages (from-to)36616-36620
Number of pages5
JournalJournal of Biological Chemistry
Volume279
Issue number35
DOIs
Publication statusPublished - 2004 Aug 27

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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