A novel mechanism of nuclear factor κB activation through the binding between inhibitor of nuclear factor-κBα and the processed NH2-terminal region of Mig-6

Toshiyuki Tsunoda, Junichi Inokuchi, Iwai Baba, Koji Okumura, Seiji Naito, Senji Shirasawa

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Mitogene-inducible gene-6 (Mig-6), an adaptor molecule containing the Cdc42/Rac interaction and binding (CRIB) domain, is rapidly induced by mitogenic and stressful stimuli, and sustained mig-6 expression is observed in chronic pathological conditions. The function of this molecule has remained elusive. We find that mig-6 is constitutively expressed in many human cancer cell lines, and Mig-6 is cleaved into the NH2-terminal region containing the CRIB domain and the remainder of the COOH-terminal region by limited proteolytic processing. We report here that full-length Mig-6, but not CRIB domain-deleted Mig-6 (ΔMig-6) or uncleavable mutant of Mig-6 (Mig-6-S38A), induces transcriptional activation of nuclear factor of κB (NFκB), which is inhibited by inhibitor of κBα (IκBα), and that the processed NH2-terminal region of Mig-6 but not the full length is bound with IκBα through its NFκB binding region. These findings suggest that the processed CRIB domain of Mig-6 will compete with NFκB for IκBα and result in NFκB activation. This novel NFκB activation pathway provides new insights regarding tumorigenesis, and the specific inhibition of the cleavage of Mig-6 may be a target for clinical treatment.

Original languageEnglish
Pages (from-to)5668-5671
Number of pages4
JournalCancer Research
Volume62
Issue number20
Publication statusPublished - Oct 15 2002

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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