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10.1534/genetics.115.183244

http://scihub22266oqcxt.onion/10.1534/genetics.115.183244
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suck abstract from ncbi


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pmid26975665      Genetics 2016 ; 203 (1): 269-81
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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 #MMPMID26975665
  • Wang Z; Tacchelly-Benites O; Yang E; Thorne CA; Nojima H; Lee E; Ahmed Y
  • Genetics 2016[May]; 203 (1): 269-81 PMID26975665show ga
  • Wnt/?-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 ?-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.
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