biostudies-literatureCantoria MJHHS | NIH | National Institute of Diabetes and Digestive and Kidney DiseasesHHS | NIH | National Institute of General Medical SciencesNIDDK NIH HHSHHS | NIH | National Cancer InstituteNCI NIH HHSWelch FoundationNIGMS NIH HHSe2208787120https://www.ebi.ac.uk/biostudies/studies/S-EPMC9926258biostudies-literatureUnknown120(2)Wnt ligands are considered classical morphogens, for which the strength of the cellular response is proportional to the concentration of the ligand. Herein, we show an emergent property of bistability arising from feedback among the Wnt destruction complex proteins that target the key transcriptional co-activator β-catenin for degradation. Using biochemical reconstitution, we identified positive feedback between the scaffold protein Axin and the kinase glycogen synthase kinase 3 (GSK3). Theoretical modeling of this feedback between Axin and GSK3 suggested that the activity of the destruction complex exhibits bistable behavior. We experimentally confirmed these predictions by demonstrating that cellular cytoplasmic β-catenin concentrations exhibit an "all-or-none" response with sustained memory (hysteresis) of the signaling input. This bistable behavior was transformed into a graded response and memory was lost through inhibition of GSK3. These findings provide a mechanism for establishing decisive, switch-like cellular response and memory upon Wnt pathway stimulation.Proceedings of the National Academy of Sciences of the United States of AmericaFeedback in the β-catenin destruction complex imparts bistability and cellular memory.PMC9926258K99 DK103126R35 GM136233R01 GM134207GM122516P30 DK058404T32 CA009213R00 DK103126GM147128CA224188I-1950-20180324DK103126R35 GM147128CAT32009213-40GM134207R01 CA244188R35 GM122516R35 GM119455GM136233GM119455Ahmed YKettenbach ANAlizadeh EPaek ALPond KWLee EBunnag NCantoria MJVarghese RPTyson JJRavi JThorne CADoubrovinski KfalseFeedback in the β-catenin destruction complex imparts bistability and cellular memory.Wnt ligands are considered classical morphogens, for which the strength of the cellular response is proportional to the concentration of the ligand. Herein, we show an emergent property of bistability arising from feedback among the Wnt destruction complex proteins that target the key transcriptional co-activator β-catenin for degradation. Using biochemical reconstitution, we identified positive feedback between the scaffold protein Axin and the kinase glycogen synthase kinase 3 (GSK3). Theoretical modeling of this feedback between Axin and GSK3 suggested that the activity of the destruction complex exhibits bistable behavior. We experimentally confirmed these predictions by demonstrating that cellular cytoplasmic β-catenin concentrations exhibit an "all-or-none" response with sustained memory (hysteresis) of the signaling input. This bistable behavior was transformed into a graded response and memory was lost through inhibition of GSK3. These findings provide a mechanism for establishing decisive, switch-like cellular response and memory upon Wnt pathway stimulation.2023-01-01T00:00:00Z2023 Jan2025-04-21T22:10:10.968Z2025-04-21T22:10:10.968ZS-EPMC99262583659893710.1073/pnas.2208787120