Feedback in the β-catenin destruction complex imparts bistability and cellular memory.

Autor: Cantoria MJ; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721.; University of Arizona Cancer Center, Tucson, AZ 85724., Alizadeh E; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721.; University of Arizona Cancer Center, Tucson, AZ 85724., Ravi J; Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061., Varghese RP; University of Arizona Cancer Center, Tucson, AZ 85724., Bunnag N; Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755., Pond KW; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721.; University of Arizona Cancer Center, Tucson, AZ 85724., Kettenbach AN; Department of Biochemistry and Cell Biology and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Lebanon, NH 03756., Ahmed Y; Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755., Paek AL; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721., Tyson JJ; Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061., Doubrovinski K; Department of Biophysics, UT Southwestern Medical Center, Dallas, TX 75390., Lee E; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232.; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232., Thorne CA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721.; University of Arizona Cancer Center, Tucson, AZ 85724.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jan 10; Vol. 120 (2), pp. e2208787120. Date of Electronic Publication: 2023 Jan 04.
DOI: 10.1073/pnas.2208787120
Abstrakt: 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.
Databáze: MEDLINE
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