articleNature GeneticsFeb 1, 2026HYBRID OA

Mutational scanning reveals oncogenic CTNNB1 mutations have diverse effects on signaling

AKAnagha KrishnaAMAlison MeynertKSKaramjit Singh DoltMKMartijn KelderAMAgavni Mesropian

Roslin Institute · University of Edinburgh · +15 more institutions

PubMed
Indexed incrossrefpubmed

Abstract

CTNNB1, the gene encoding β-catenin, is a frequent target for oncogenic mutations activating the canonical Wnt signaling pathway, typically through missense mutations within a degron hotspot motif in exon 3. Here, we combine saturation genome editing with a fluorescent reporter assay to quantify signaling phenotypes for all 342 possible missense mutations in the mutation hotspot. Our data define the genetic requirements for β-catenin degron function, refine the consensus motif for substrate recognition by β-TRCP and reveal diverse levels of signal activation among known driver mutations. Tumorigenesis in different human tissues involves selection for CTNNB1 mutations spanning distinct ranges of predicted…

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Topics & keywords

Topics
Keywords
  • Missense mutation
  • Gene
  • Carcinogenesis
  • Phenotype
  • Exon
  • Mutation
  • Wnt signaling pathway
  • Mutant
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