Format

Send to

Choose Destination
Genetics. 2016 May;203(1):269-81. doi: 10.1534/genetics.115.183244. Epub 2016 Mar 14.

Wnt/Wingless Pathway Activation Is Promoted by a Critical Threshold of Axin Maintained by the Tumor Suppressor APC and the ADP-Ribose Polymerase Tankyrase.

Author information

1
Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755.
2
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
3
The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom.
4
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.
5
Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755 yfa@dartmouth.edu.

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.

KEYWORDS:

APC; Axin; Tankyrase; Wingless

PMID:
26975665
PMCID:
PMC4858779
DOI:
10.1534/genetics.115.183244
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center