An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin - PubMed (original) (raw)

An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin

M Kitagawa et al. EMBO J. 1999.

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.

PubMed Disclaimer

Similar articles

• 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. Hatakeyama S, et al. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3859-63. doi: 10.1073/pnas.96.7.3859. Proc Natl Acad Sci U S A. 1999. PMID: 10097128 Free PMC article.
• Targeted degradation of beta-catenin by chimeric F-box fusion proteins.
  Liu J, Stevens J, Matsunami N, White RL. Liu J, et al. Biochem Biophys Res Commun. 2004 Jan 23;313(4):1023-9. doi: 10.1016/j.bbrc.2003.12.035. Biochem Biophys Res Commun. 2004. PMID: 14706645
• The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro.
  Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW. Winston JT, et al. Genes Dev. 1999 Feb 1;13(3):270-83. doi: 10.1101/gad.13.3.270. Genes Dev. 1999. PMID: 9990852 Free PMC article.
• [Ubiquitin-dependent proteolysis by SCF complex].
  Nakayama K, Nakayama K. Nakayama K, et al. Seikagaku. 2000 Feb;72(2):113-7. Seikagaku. 2000. PMID: 10737103 Review. Japanese. No abstract available.
• [Familial adenomatous polyposis syndrome (FAP): pathogenesis and molecular mechanisms].
  Friedrich A, Kullmann F. Friedrich A, et al. Med Klin (Munich). 2003 Dec 15;98(12):776-82. doi: 10.1007/s00063-003-1325-2. Med Klin (Munich). 2003. PMID: 14685680 Review. German.

Cited by

• New insights in ubiquitin-dependent Wnt receptor regulation in tumorigenesis.
  Tsukiyama T. Tsukiyama T. In Vitro Cell Dev Biol Anim. 2024 May;60(5):449-465. doi: 10.1007/s11626-024-00855-w. Epub 2024 Feb 21. In Vitro Cell Dev Biol Anim. 2024. PMID: 38383910 Free PMC article. Review.
• Beta-Transducin Repeats-Containing Proteins as an Anticancer Target.
  Kim DJ, Yi YW, Seong YS. Kim DJ, et al. Cancers (Basel). 2023 Aug 24;15(17):4248. doi: 10.3390/cancers15174248. Cancers (Basel). 2023. PMID: 37686524 Free PMC article. Review.
• Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk.
  Qin K, Yu M, Fan J, Wang H, Zhao P, Zhao G, Zeng W, Chen C, Wang Y, Wang A, Schwartz Z, Hong J, Song L, Wagstaff W, Haydon RC, Luu HH, Ho SH, Strelzow J, Reid RR, He TC, Shi LL. Qin K, et al. Genes Dis. 2023 Mar 24;11(1):103-134. doi: 10.1016/j.gendis.2023.01.030. eCollection 2024 Jan. Genes Dis. 2023. PMID: 37588235 Free PMC article. Review.
• Regulatory changes associated with the head to trunk developmental transition.
  Duarte P, Brattig Correia R, Nóvoa A, Mallo M. Duarte P, et al. BMC Biol. 2023 Aug 8;21(1):170. doi: 10.1186/s12915-023-01675-2. BMC Biol. 2023. PMID: 37553620 Free PMC article.
• Mechanistic Regulation of Wnt Pathway-Related Progression of Chronic Obstructive Pulmonary Disease Airway Lesions.
  Liu M, Huo Y, Cheng Y. Liu M, et al. Int J Chron Obstruct Pulmon Dis. 2023 May 15;18:871-880. doi: 10.2147/COPD.S391487. eCollection 2023. Int J Chron Obstruct Pulmon Dis. 2023. PMID: 37215745 Free PMC article. Review.

References

1. 1. Curr Opin Genet Dev. 1998 Feb;8(1):36-42 - PubMed
2. 1. Mech Dev. 1996 Sep;59(1):3-10 - PubMed
3. 1. Genes Dev. 1996 Oct 15;10(20):2527-39 - PubMed
4. 1. Curr Opin Cell Biol. 1996 Oct;8(5):685-91 - PubMed
5. 1. Science. 1997 Mar 21;275(5307):1784-7 - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Europe PubMed Central
  • Nature Publishing Group
  • PubMed Central

• Other Literature Sources

  • The Lens - Patent Citations

• Molecular Biology Databases

  • Gene Ontology
  • Mouse Genome Informatics (MGI)