title: Wnt/Wingless Pathway Activation Is Promoted by a Critical Threshold of Axin Maintained by the Tumor Suppressor APC and the ADP-Ribose Polymerase Tankyrase.
abstract: Wnt/β-catenin signal transduction directs metazoan development and is deregulated in numerous human congenital disorders and cancers. In the absence of Wnt stimulation, a multiprotein "destruction complex," assembled by the scaffold protein Axin, targets the key transcriptional activator β-catenin for proteolysis. Axin is maintained at very low levels that limit destruction complex activity, a property that is currently being exploited in the development of novel therapeutics for Wnt-driven cancers. Here, we use an in vivo approach in Drosophila to determine how tightly basal Axin levels must be controlled for Wnt/Wingless pathway activation, and how Axin stability is regulated. We find that for nearly all Wingless-driven developmental processes, a three- to fourfold increase in Axin is insufficient to inhibit signaling, setting a lower-limit for the threshold level of Axin in the majority of in vivo contexts. Further, we find that both the tumor suppressor adenomatous polyposis coli (APC) and the ADP-ribose polymerase Tankyrase (Tnks) have evolutionarily conserved roles in maintaining basal Axin levels below this in vivo threshold, and we define separable domains in Axin that are important for APC- or Tnks-dependent destabilization. Together, these findings reveal that both APC and Tnks maintain basal Axin levels below a critical in vivo threshold to promote robust pathway activation following Wnt stimulation.
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755.
authors.forename: Zhenghan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755.
authors.forename: Ofelia
authors.initials: O
authors.lastname: Tacchelly-Benites
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755.
authors.forename: Eungi
authors.initials: E
authors.lastname: Yang
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Thorne
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nojima
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 Vanderbilt Ingram Cancer Center and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755 yfa@dartmouth.edu.
authors.forename: Yashi
authors.initials: Y
authors.lastname: Ahmed
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D008938:Mitosis; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D038501:Tankyrases / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D014981:Xenopus
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D051153:Wnt Proteins; D038501:Tankyrases
keywords: APC; Axin; Tankyrase; Wingless