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Feedback in the ß-catenin destruction complex imparts bistability and cellular memory.
Cantoria, Mary Jo; Alizadeh, Elaheh; Ravi, Janani; Varghese, Reeba P; Bunnag, Nawat; Pond, Kelvin W; Kettenbach, Arminja N; Ahmed, Yashi; Paek, Andrew L; Tyson, John J; Doubrovinski, Konstantin; Lee, Ethan; Thorne, Curtis A.
Afiliación
  • Cantoria MJ; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721.
  • Alizadeh E; University of Arizona Cancer Center, Tucson, AZ 85724.
  • Ravi J; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721.
  • Varghese RP; University of Arizona Cancer Center, Tucson, AZ 85724.
  • Bunnag N; Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
  • Pond KW; University of Arizona Cancer Center, Tucson, AZ 85724.
  • Kettenbach AN; Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755.
  • Ahmed Y; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721.
  • Paek AL; University of Arizona Cancer Center, Tucson, AZ 85724.
  • Tyson JJ; Department of Biochemistry and Cell Biology and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Lebanon, NH 03756.
  • Doubrovinski K; Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755.
  • Lee E; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721.
  • Thorne CA; Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.
Proc Natl Acad Sci U S A ; 120(2): e2208787120, 2023 01 10.
Article en En | MEDLINE | ID: mdl-36598937
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 ß-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 ß-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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Beta Catenina / Complejo de Señalización de la Axina Tipo de estudio: Prognostic_studies Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Beta Catenina / Complejo de Señalización de la Axina Tipo de estudio: Prognostic_studies Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos