Identification of two novel regulated serines in the N terminus of beta-catenin.
Beta-catenin plays a key role in the Wnt signaling cascade. The levels of beta-catenin within a cell are regulated via phosphorylation of the N terminus of beta-catenin by GSK-3beta. The phosphorylation leads to ubiquitination and subsequent degradation of the protein. Thus far three serines (S33, 37, 45) and one threonine (T41) are considered to be the substrates for GSK-3beta phosphorylation. Indeed, these amino acids are regularly mutated in tumors, resulting in beta-catenin molecules with enhanced transcriptional activity. Aligning N-terminal sequences of beta-catenin homologues of different species revealed two other highly conserved serines (S23, 29), which have also been found mutated in tumors. We show that these serines are modified in the same fashion as that of the known regulatory residues. During embryogenesis, the phosphorylation status of S23 and S29 appears to be actively regulated. Nevertheless, constructs harboring the mutations found in tumors fail to show enhanced transcriptional activity or transforming properties.
van Noort
Mascha
M
Department of Immunology, University Medical Center Utrecht, The Netherlands.
van de Wetering
Marc
M
Clevers
Hans
H
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D000911:Antibodies, Monoclonal; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D012694:Serine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride