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PMID:10228155

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Citation

Kitagawa, M, Hatakeyama, S, Shirane, M, Matsumoto, M, Ishida, N, Hattori, K, Nakamichi, I, Kikuchi, A, Nakayama, K and Nakayama, K (1999) An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. EMBO J. 18:2401-10

Abstract

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.

Links

PubMed PMC1171323 Online version:10.1093/emboj/18.9.2401

Keywords

Adenomatous Polyposis Coli Protein; Animals; Axin Protein; Carrier Proteins/metabolism; Cytoskeletal Proteins/genetics; Cytoskeletal Proteins/metabolism; GTP-Binding Proteins/genetics; GTP-Binding Proteins/metabolism; Mice; Models, Biological; Mutation; Neoplasm Proteins/metabolism; Peptide Synthases/metabolism; Protein Binding; Proteins/isolation & purification; Recombinant Proteins/metabolism; Repressor Proteins; SKP Cullin F-Box Protein Ligases; Trans-Activators; Ubiquitins/metabolism; beta Catenin; beta-Transducin Repeat-Containing Proteins

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:AXIN1

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P18266

F

Seeded From UniProt

complete

RAT:AXIN1

part_of

GO:0030877: beta-catenin destruction complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:AXIN1

involved_in

GO:2000060: positive regulation of ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:GSK3B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O70239

F

Seeded From UniProt

complete

MOUSE:FBW1A

enables

GO:0008013: beta-catenin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:FBW1A

involved_in

GO:0000209: protein polyubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FBW1A

enables

GO:0045309: protein phosphorylated amino acid binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:FBW1A

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:Q02248)

Seeded From UniProt

complete

RAT:GSK3B

part_of

GO:0030877: beta-catenin destruction complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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