Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin.
Several lines of evidence suggest that accumulation of cytoplasmic beta-catenin transduces an oncogenic signal. We show that beta-catenin is ubiquitinated and degraded by the proteosome and that beta-catenin stability is regulated by a diacylglycerol-independent protein kinase C-like kinase activity, which is required for beta-catenin ubiquitination. We also define a six-amino acid sequence found in both beta-catenin and the NF-kappaB regulatory protein IkappaBalpha, which, upon phosphorylation, targets both proteins for ubiquitination. Mutation of a single serine within the ubiquitination targeting sequence prevents ubiquitination of beta-catenin. Mutations within the ubiquitination targeting sequence of beta-catenin may be oncogenic.
Orford
K
K
Lombardi Cancer Center, Georgetown University Medical Center, Washington, D. C. 20007, USA.
Crockett
C
C
Jensen
J P
JP
Weissman
A M
AM
Byers
S W
SW
D000595:Amino Acid Sequence; D016384:Consensus Sequence; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D017354:Point Mutation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D016415:Sequence Alignment; D012694:Serine; D013379:Substrate Specificity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators; D014452:Ubiquitins / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007211:Indoles; D008301:Maleimides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009281:Naphthalenes; D015534:Trans-Activators; D014452:Ubiquitins; D051176:beta Catenin; D000072000:NF-KappaB Inhibitor alpha; D010768:Phosphoserine; D012694:Serine; D011493:Protein Kinase C; C058819:calphostin C; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate