Drosophila Tankyrase Regulates Axin Through Cell Membrane Recruitment and Proteolysis. Zhenghan Wang, Ofelia Tacchelly Benites, Eungi Yang, Geoffrey Noble, Megan Johnson, Michael Randall, Yashi Ahmed. Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH.

   Aberrant activation of the Wnt signal transduction pathway triggers the development of colorectal carcinoma. Recently identified small molecule inhibitors of the poly-ADP-ribose (pADPr) polymerase Tankyrase attenuate Wnt signaling in cultured colon carcinoma cells by stabilizing the negative regulatory component Axin, and thereby provide a promising new therapeutic strategy. However, functional redundancy in vertebrate Tankyrase genes has impeded efforts to identify the in vivo contexts in which Tankyrase regulates Axin and Wnt signaling. Here, using a Drosophila model, we provide the first in vivo evidence that Tankyrase and the pADPr-directed E3 ubiquitin ligase RNF146/Iduna function together to promote Axin proteolysis in all epithelial cells throughout development. By preventing supraphysiologic increases in Axin, Tankyrase and RNF146 promote Wnt signaling in multiple developmental contexts. Newly developed Axin antisera reveal that in contrast with the prevailing model, endogenous Axin is enriched at the cell membrane both in the presence and in the absence of Wnt stimulation, and unexpectedly, that Tankyrase mediates not only the turnover of Axin, but also its recruitment to the cell membrane. Thus through dual roles in the cell membrane recruitment and proteolysis of Axin, Tankyrase prevents supraphysiologic Axin levels in all epithelial cells, and thereby also promotes signaling in cells responding to Wnt exposure.