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Proc Natl Acad Sci U S A
1999 Mar 30;967:3859-63. doi: 10.1073/pnas.96.7.3859.
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Ubiquitin-dependent degradation of IkappaBalpha is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1.
Hatakeyama S
,
Kitagawa M
,
Nakayama K
,
Shirane M
,
Matsumoto M
,
Hattori K
,
Higashi H
,
Nakano H
,
Okumura K
,
Onoé K
,
Good RA
,
Nakayama K
.
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Activation of the transcription factor nuclear factor kappa B (NF-kappaB) is controlled by proteolysis of its inhibitory subunit (IkappaB) via the ubiquitin-proteasome pathway. Signal-induced phosphorylation of IkappaBalpha by a large multisubunit complex containing IkappaB kinases is a prerequisite for ubiquitination. Here, we show that FWD1 (a mouse homologue of Slimb/betaTrCP), a member of the F-box/WD40-repeat proteins, is associated specifically with IkappaBalpha only when IkappaBalpha is phosphorylated. The introduction of FWD1 into cells significantly promotes ubiquitination and degradation of IkappaBalpha in concert with IkappaB kinases, resulting in nuclear translocation of NF-kappaB. In addition, FWD1 strikingly evoked the ubiquitination of IkappaBalpha in the in vitro system. In contrast, a dominant-negative form of FWD1 inhibits the ubiquitination, leading to stabilization of IkappaBalpha. These results suggest that the substrate-specific degradation of IkappaBalpha is mediated by a Skp1/Cull 1/F-box protein (SCF) FWD1 ubiquitin-ligase complex and that FWD1 serves as an intracellular receptor for phosphorylated IkappaBalpha. Skp1/Cullin/F-box protein FWD1 might play a critical role in transcriptional regulation of NF-kappaB through control of IkappaB protein stability.
Aberle,
beta-catenin is a target for the ubiquitin-proteasome pathway.
1997, Pubmed
Aberle,
beta-catenin is a target for the ubiquitin-proteasome pathway.
1997,
Pubmed
Bai,
SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box.
1996,
Pubmed
Baldwin,
The NF-kappa B and I kappa B proteins: new discoveries and insights.
1996,
Pubmed
Cohen,
IKAP is a scaffold protein of the IkappaB kinase complex.
1998,
Pubmed
DiDonato,
A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB.
1997,
Pubmed
Drury,
The Cdc4/34/53 pathway targets Cdc6p for proteolysis in budding yeast.
1997,
Pubmed
Elledge,
The role of protein stability in the cell cycle and cancer.
1998,
Pubmed
Feldman,
A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p.
1997,
Pubmed
Hatakeyama,
Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases.
1997,
Pubmed
Henchoz,
Phosphorylation- and ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor Far1p in budding yeast.
1997,
Pubmed
Hershko,
The ubiquitin system for protein degradation.
1992,
Pubmed
Ikeda,
Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin.
1998,
Pubmed
Jiang,
Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb.
1998,
Pubmed
Kirkpatrick,
Not just glue: cell-cell junctions as cellular signaling centers.
1995,
Pubmed
Kominami,
Fission yeast WD-repeat protein pop1 regulates genome ploidy through ubiquitin-proteasome-mediated degradation of the CDK inhibitor Rum1 and the S-phase initiator Cdc18.
1997,
Pubmed
Krek,
Proteolysis and the G1-S transition: the SCF connection.
1998,
Pubmed
Malinin,
MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1.
1997,
Pubmed
Margottin,
A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif.
1998,
Pubmed
May,
Signal transduction through NF-kappa B.
1998,
Pubmed
Mercurio,
IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation.
1997,
Pubmed
Michel,
Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A.
1998,
Pubmed
Miller,
Signal transduction through beta-catenin and specification of cell fate during embryogenesis.
1996,
Pubmed
Nakano,
Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1.
1998,
Pubmed
Orford,
Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin.
1997,
Pubmed
Palombella,
The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B.
1994,
Pubmed
Paul,
Phosphorylation of both phosphoacceptor sites in the HIV-1 Vpu cytoplasmic domain is essential for Vpu-mediated ER degradation of CD4.
1997,
Pubmed
Peifer,
Beta-catenin as oncogene: the smoking gun.
1997,
Pubmed
Piatti,
Activation of S-phase-promoting CDKs in late G1 defines a "point of no return" after which Cdc6 synthesis cannot promote DNA replication in yeast.
1996,
Pubmed
Rothwarf,
IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.
1998,
Pubmed
Régnier,
Identification and characterization of an IkappaB kinase.
1997,
Pubmed
Schubert,
Differential activities of the human immunodeficiency virus type 1-encoded Vpu protein are regulated by phosphorylation and occur in different cellular compartments.
1994,
Pubmed
Skowyra,
F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex.
1997,
Pubmed
Spevak,
Saccharomyces cerevisiae cdc15 mutants arrested at a late stage in anaphase are rescued by Xenopus cDNAs encoding N-ras or a protein with beta-transducin repeats.
1993,
Pubmed
,
Xenbase
Verma,
Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation.
1995,
Pubmed
Weissman,
Regulating protein degradation by ubiquitination.
1997,
Pubmed
Wigler,
Transfer of purified herpes virus thymidine kinase gene to cultured mouse cells.
1977,
Pubmed
Woronicz,
IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK.
1997,
Pubmed
Yamaoka,
Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation.
1998,
Pubmed
Yaron,
Inhibition of NF-kappa-B cellular function via specific targeting of the I-kappa-B-ubiquitin ligase.
1997,
Pubmed
Zandi,
The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation.
1997,
Pubmed
Zandi,
Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate.
1998,
Pubmed
