Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutation

Yasuhito Hayashi, Toshihide Iwashita, Hideki Murakamai, Yutaka Kato, Kumi Kawai, Kei Kurokawa, Iwai Tohnai, Minoru Ueda, Masahide Takahashi

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Big mitogen-activated protein kinase 1 (BMK1) is a new member of mitogen-activated protein kinase (MAPK) family. In the present study, we investigated whether glial cell line-derived neurotrophic factor (GDNF) can induce activation of BMK1 through RET tyrosine kinase. Its activation reached a maximal level at 30 min and continued at least for 120 min after GDNF stimulation. In addition, we detected BMK1 activation in NIH3T3 cells expressing RET with a multiple endocrine neoplasia (MEN) 2A mutation. The level of BMK1 activation markedly decreased by replacement of tyrosine 1062 with phenylalanine (designated Y1062F) in RET, indicating the importance of down-stream signaling via tyrosine 1062. However, although both RAS/MAPK and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways are activated via tyrosine 1062, BMK1 activation by GDNF was not significantly impaired by treatment with an MEK1 inhibitor, PD98059, or two distinct PI3-K inhibitors, LY294002 and wortmannin, suggesting that the RAS and PI3-K signaling pathways are not crucial for BMK1 activation by GDNF. Moreover, luciferase reporter assays revealed that RET-MEN2A mutant proteins can activate the MEF2C transcription factor that is known to be a cellular target for BMK1, and that its activation is impaired by the Y1062F mutation or by expression of a dominant negative form of MEK5.

Original languageEnglish
Pages (from-to)682-689
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume281
Issue number3
DOIs
Publication statusPublished - 01-01-2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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