Common pathway for the ubiquitination of IκBα, Iκbβ, and IκBε mediated by the F-box protein FWD1

Michiko Shirane, Shigetsugu Hatakeyama, Kimihiko Hattori, Keiko Nakayama, Kei Ichi Nakayama

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71 Citations (Scopus)


FWD1 (the mouse homolog of Drosophila Slimb and Xenopus βTrCP, a member of the F-box- and WD40 repeat-containing family of proteins, and a component of the SCF ubiquitin ligase complex) was recently shown to interact with IκBα and thereby to promote its ubiquitination and degradation. This protein has now been shown also to bind to IκBβ and IκBε as well as to induce their ubiquitination and proteolysis. FWD1 was shown to recognize the conserved DSGψXS motif (where ψ represents the hydrophobic residue) present in the NH2-terminal regions of these three IκB proteins only when the component serine residues are phosphorylated. However, in contrast to IκBα and IκBβ, the recognition site in IκBε for FWD1 is not restricted to the DSGψXS motif; FWD1 also interacts with other sites in the NH2-terminal region of IκBε. Substitution of the critical setine residues in the NH2- terminal regions of IκBα, IκBβ, and IκBε with alanines also markedly reduced the extent of FWD1-mediated ubiquitination of these proteins and increased their stability. These data indicate that the three IκB proteins, despite their substantial structural and functional differences, all undergo ubiquitination mediated by the SCF(FWD1) complex. FWD1 may thus play an important role in NF-κB signal transduction through regulation of the stability of multiple IκB proteins.

Original languageEnglish
Pages (from-to)28169-28174
Number of pages6
JournalJournal of Biological Chemistry
Issue number40
Publication statusPublished - Oct 1 1999

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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