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Vol. 13, No. 3, pp. 284-294, February 1, 1999

RESEARCH PAPER
Signal-induced ubiquitination of Ikappa Balpha by the F-box protein Slimb/beta -TrCP

Erika Spencer,1 Jin Jiang,2 and Zhijian J. Chen1,3

1 Department of Molecular Biology and Oncology, 2 Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9148 USA

Signal-induced phosphorylation of Ikappa Balpha targets this inhibitor of NF-kappa B for ubiquitination and subsequent degradation, thus allowing NF-kappa B to enter the nucleus to turn on its target genes. We report here the identification of an Ikappa B-ubiquitin (Ub) ligase complex containing the F-box/WD40-repeat protein, beta -TrCP, a vertebrate homolog of Drosophila Slimb. beta -TrCP binds to Ikappa Balpha only when the latter is specifically phosphorylated by an Ikappa B kinase complex. Moreover, immunopurified beta -TrCP ubiquitinates phosphorylated Ikappa Balpha at specific lysines in the presence of Ub-activating (E1) and -conjugating (Ubch5) enzymes. A beta -TrCP mutant lacking the F-box inhibits the signal-induced degradation of Ikappa Balpha and subsequent activation of NF-kappa B-dependent transcription. Furthermore, Drosophila embryos deficient in slimb fail to activate twist and snail, two genes known to be regulated by the NF-kappa B homolog, Dorsal. These biochemical and genetic data strongly suggest that Slimb/beta -TrCP is the specificity determinant for the signal-induced ubiquitination of Ikappa Balpha .

[Key Words: Phosphorylation; NF-kappa B; Ikappa B; ubiquitin; SCF; Slimb; beta -TrCP]


GENES & DEVELOPMENT 13:284-294 © 1999 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/99 $5.00

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