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Genetics
2016 May 01;2031:269-81. doi: 10.1534/genetics.115.183244.
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Wnt/Wingless Pathway Activation Is Promoted by a Critical Threshold of Axin Maintained by the Tumor Suppressor APC and the ADP-Ribose Polymerase Tankyrase.
Wang Z
,
Tacchelly-Benites O
,
Yang E
,
Thorne CA
,
Nojima H
,
Lee E
,
Ahmed Y
.
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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.
Ahmed,
Drosophila Apc1 and Apc2 regulate Wingless transduction throughout development.
2002, Pubmed
Ahmed,
Drosophila Apc1 and Apc2 regulate Wingless transduction throughout development.
2002,
Pubmed
Ahmed,
Regulation of armadillo by a Drosophila APC inhibits neuronal apoptosis during retinal development.
1998,
Pubmed
Akong,
Drosophila APC2 and APC1 play overlapping roles in wingless signaling in the embryo and imaginal discs.
2002,
Pubmed
Baker,
Transcription of the segment-polarity gene wingless in the imaginal discs of Drosophila, and the phenotype of a pupal-lethal wg mutation.
1988,
Pubmed
Bejsovec,
Roles of wingless in patterning the larval epidermis of Drosophila.
1991,
Pubmed
Bischof,
An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases.
2007,
Pubmed
Brand,
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.
1993,
Pubmed
Brunner,
pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila.
1997,
Pubmed
Chen,
Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.
2009,
Pubmed
Chen,
Wingless transduction by the Frizzled and Frizzled2 proteins of Drosophila.
1999,
Pubmed
Chou,
Use of a yeast site-specific recombinase to produce female germline chimeras in Drosophila.
1992,
Pubmed
Clevers,
Wnt/β-catenin signaling and disease.
2012,
Pubmed
Couso,
The wingless signalling pathway and the patterning of the wing margin in Drosophila.
1994,
Pubmed
Cselenyi,
LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of beta-catenin.
2008,
Pubmed
,
Xenbase
Fagotto,
Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization.
1999,
Pubmed
,
Xenbase
Feng,
The Drosophila tankyrase regulates Wg signaling depending on the concentration of Daxin.
2014,
Pubmed
Gerlach,
Wnt signalling induces accumulation of phosphorylated β-catenin in two distinct cytosolic complexes.
2014,
Pubmed
Golic,
The FLP recombinase of yeast catalyzes site-specific recombination in the Drosophila genome.
1989,
Pubmed
Graham,
A new technique for the assay of infectivity of human adenovirus 5 DNA.
1973,
Pubmed
Hamada,
Negative regulation of Wingless signaling by D-axin, a Drosophila homolog of axin.
1999,
Pubmed
Huang,
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.
2009,
Pubmed
Kramps,
Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex.
2002,
Pubmed
Lau,
A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth.
2013,
Pubmed
Lee,
The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway.
2003,
Pubmed
,
Xenbase
Luo,
Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex.
2007,
Pubmed
,
Xenbase
MacDonald,
Wnt/beta-catenin signaling: components, mechanisms, and diseases.
2009,
Pubmed
,
Xenbase
Markstein,
Exploiting position effects and the gypsy retrovirus insulator to engineer precisely expressed transgenes.
2008,
Pubmed
Nolo,
Senseless, a Zn finger transcription factor, is necessary and sufficient for sensory organ development in Drosophila.
2000,
Pubmed
Parks,
Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome.
2004,
Pubmed
Peterson-Nedry,
Unexpectedly robust assembly of the Axin destruction complex regulates Wnt/Wg signaling in Drosophila as revealed by analysis in vivo.
2008,
Pubmed
Rogers,
Culture of Drosophila S2 cells and their use for RNAi-mediated loss-of-function studies and immunofluorescence microscopy.
2008,
Pubmed
Salic,
Control of beta-catenin stability: reconstitution of the cytoplasmic steps of the wnt pathway in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase
Takacs,
Dual positive and negative regulation of wingless signaling by adenomatous polyposis coli.
2008,
Pubmed
Tian,
Regulation of Stem Cell Proliferation and Cell Fate Specification by Wingless/Wnt Signaling Gradients Enriched at Adult Intestinal Compartment Boundaries.
2016,
Pubmed
Tolwinski,
Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity.
2003,
Pubmed
Venken,
Versatile P[acman] BAC libraries for transgenesis studies in Drosophila melanogaster.
2009,
Pubmed
Vincent,
A cell-autonomous, ubiquitous marker for the analysis of Drosophila genetic mosaics.
1994,
Pubmed
Waaler,
A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice.
2012,
Pubmed
,
Xenbase
Wang,
The ADP-ribose polymerase Tankyrase regulates adult intestinal stem cell proliferation during homeostasis in Drosophila.
2016,
Pubmed
Willert,
A Drosophila Axin homolog, Daxin, inhibits Wnt signaling.
1999,
Pubmed
Xu,
Analysis of genetic mosaics in developing and adult Drosophila tissues.
1993,
Pubmed
Yang,
Wnt pathway activation by ADP-ribosylation.
2016,
Pubmed
Zeng,
The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation.
1997,
Pubmed
,
Xenbase
Zhang,
RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling.
2011,
Pubmed
