Fbxw7 acts as an E3 ubiquitin ligase that targets c-Myb for Nemo-like kinase (NLK)-induced degradation

Chie Kanei-Ishii, Teruaki Nomura, Tsuyoshi Takagi, Nobumoto Watanabe, Keiichi I. Nakayama, Shunsuke Ishii

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

The c-myb proto-oncogene product (c-Myb) is degraded in response to Wnt-1 signaling via a pathway involving TAK1 (transforming growth factor-β- activated kinase 1), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). NLK directly binds to c-Myb, which results in the phosphorylation of c-Myb at multiple sites, and induces its ubiquitination and proteasome-dependent degradation. Here, we report that Fbxw7, the F-box protein of an SCF complex, targets c-Myb for degradation in a Wnt-1- and NLK-dependent manner. Fbxw7α directly binds to c-Myb via its C-terminal WD40 domain and induces the ubiquitination of c-Myb in the presence of NLK in vivo and in vitro. The c-Myb phosphorylation site mutant failed to interact with Fbxw7α, suggesting that the c-Myb/Fbxw7α interaction is enhanced by NLK phosphorylation of c-Myb. Treatment of M1 cells with Fbxw7 small interfering RNA (siRNA) rescued the Wnt-induced c-Myb degradation and also the Wnt-induced inhibition of cell proliferation. NLK bound to Cul1, a component of the SCF complex, while HIPK2 interacted with both Fbxw7α and Cul1, suggesting that both kinases enhance the c-Myb/SCF interaction. In contrast to c-Myb, the v-myb gene product (v-Myb) encoded by the avian myeloblastosis virus was resistant to NLK/Fbxw7α-induced degradation. Thus, Fbxw7 is an E3 ubiquitin ligase of c-Myb, and the increased c-Myb levels may contribute, at least partly, to transformation induced by mutation of Fbxw7.

Original languageEnglish
Pages (from-to)30540-30548
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number45
DOIs
Publication statusPublished - Nov 7 2008

Fingerprint

Ubiquitin-Protein Ligases
Phosphotransferases
Degradation
Phosphorylation
myb Genes
Homeodomain Proteins
Ubiquitination
Protein Kinases
Proto-Oncogene Proteins c-myb
Avian Myeloblastosis Virus
F-Box Proteins
Cell proliferation
Transforming Growth Factors
Proteasome Endopeptidase Complex
Viruses
Small Interfering RNA
Genes
Cell Proliferation
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Fbxw7 acts as an E3 ubiquitin ligase that targets c-Myb for Nemo-like kinase (NLK)-induced degradation. / Kanei-Ishii, Chie; Nomura, Teruaki; Takagi, Tsuyoshi; Watanabe, Nobumoto; Nakayama, Keiichi I.; Ishii, Shunsuke.

In: Journal of Biological Chemistry, Vol. 283, No. 45, 07.11.2008, p. 30540-30548.

Research output: Contribution to journalArticle

Kanei-Ishii, Chie ; Nomura, Teruaki ; Takagi, Tsuyoshi ; Watanabe, Nobumoto ; Nakayama, Keiichi I. ; Ishii, Shunsuke. / Fbxw7 acts as an E3 ubiquitin ligase that targets c-Myb for Nemo-like kinase (NLK)-induced degradation. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 45. pp. 30540-30548.
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