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XB-ART-53130
Genetics. May 1, 2016; 203 (1): 269-81.

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 .


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.

PubMed ID: 26975665
PMC ID: PMC4858779
Article link: Genetics.
Grant support: R01 GM103926 NIGMS NIH HHS , R01 GM103926 NIGMS NIH HHS , R01 CA105038 NCI NIH HHS , R01 GM081635 NIGMS NIH HHS , P40 OD018537 NIH HHS , P30 CA023108 NCI NIH HHS



References:
Ahmed, 2002, Pubmed[+]


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