PMID- 10228155
OWN - NLM
STAT- MEDLINE
DCOM- 19990628
LR  - 20181113
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 18
IP  - 9
DP  - 1999 May 4
TI  - An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin.
PG  - 2401-10
AB  - beta-catenin plays an essential role in the Wingless/Wnt signaling cascade and is
      a component of the cadherin cell adhesion complex. Deregulation of beta-catenin
      accumulation as a result of mutations in adenomatous polyposis coli (APC) tumor
      suppressor protein is believed to initiate colorectal neoplasia. beta-catenin
      levels are regulated by the ubiquitin-dependent proteolysis system and
      beta-catenin ubiquitination is preceded by phosphorylation of its N-terminal
      region by the glycogen synthase kinase-3beta (GSK-3beta)/Axin kinase complex.
      Here we show that FWD1 (the mouse homologue of Slimb/betaTrCP), an
      F-box/WD40-repeat protein, specifically formed a multi-molecular complex with
      beta-catenin, Axin, GSK-3beta and APC. Mutations at the signal-induced
      phosphorylation site of beta-catenin inhibited its association with FWD1. FWD1
      facilitated ubiquitination and promoted degradation of beta-catenin, resulting in
      reduced cytoplasmic beta-catenin levels. In contrast, a dominant-negative mutant 
      form of FWD1 inhibited the ubiquitination process and stabilized beta-catenin.
      These results suggest that the Skp1/Cullin/F-box protein FWD1 (SCFFWD1)-ubiquitin
      ligase complex is involved in beta-catenin ubiquitination and that FWD1 serves as
      an intracellular receptor for phosphorylated beta-catenin. FWD1 also links the
      phosphorylation machinery to the ubiquitin-proteasome pathway to ensure prompt
      and efficient proteolysis of beta-catenin in response to external signals.
      SCFFWD1 may be critical for tumor development and suppression through regulation 
      of beta-catenin protein stability.
FAU - Kitagawa, M
AU  - Kitagawa M
AD  - Department of Molecular and Cellular Biology, Medical Institute of Bioregulation,
      Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
FAU - Hatakeyama, S
AU  - Hatakeyama S
FAU - Shirane, M
AU  - Shirane M
FAU - Matsumoto, M
AU  - Matsumoto M
FAU - Ishida, N
AU  - Ishida N
FAU - Hattori, K
AU  - Hattori K
FAU - Nakamichi, I
AU  - Nakamichi I
FAU - Kikuchi, A
AU  - Kikuchi A
FAU - Nakayama, K
AU  - Nakayama K
FAU - Nakayama, K
AU  - Nakayama K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Adenomatous Polyposis Coli Protein)
RN  - 0 (Axin Protein)
RN  - 0 (Btrc protein, mouse)
RN  - 0 (CTNNB1 protein, mouse)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cytoskeletal Proteins)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (Trans-Activators)
RN  - 0 (Ubiquitins)
RN  - 0 (beta Catenin)
RN  - 0 (beta-Transducin Repeat-Containing Proteins)
RN  - EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - EC 6.3.2.- (Peptide Synthases)
SB  - IM
MH  - Adenomatous Polyposis Coli Protein
MH  - Animals
MH  - Axin Protein
MH  - Carrier Proteins/metabolism
MH  - Cytoskeletal Proteins/genetics/*metabolism
MH  - GTP-Binding Proteins/genetics/*metabolism
MH  - Mice
MH  - Models, Biological
MH  - Mutation
MH  - Neoplasm Proteins/metabolism
MH  - Peptide Synthases/metabolism
MH  - Protein Binding
MH  - Proteins/isolation & purification
MH  - Recombinant Proteins/metabolism
MH  - *Repressor Proteins
MH  - SKP Cullin F-Box Protein Ligases
MH  - *Trans-Activators
MH  - Ubiquitins/*metabolism
MH  - beta Catenin
MH  - beta-Transducin Repeat-Containing Proteins
PMC - PMC1171323
EDAT- 1999/05/06 00:00
MHDA- 1999/05/06 00:01
CRDT- 1999/05/06 00:00
PHST- 1999/05/06 00:00 [pubmed]
PHST- 1999/05/06 00:01 [medline]
PHST- 1999/05/06 00:00 [entrez]
AID - 10.1093/emboj/18.9.2401 [doi]
PST - ppublish
SO  - EMBO J. 1999 May 4;18(9):2401-10. doi: 10.1093/emboj/18.9.2401.