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Regulation of Wnt/Wingless signaling by the ADP-ribose polymerase Tankyrase / by Zhenghan Wang

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Author	Wang, Zhenghan
Title	Regulation of Wnt/Wingless signaling by the ADP-ribose polymerase Tankyrase / by Zhenghan Wang
Date	2016
Abstract	The Wnt/β-catenin signaling pathway controls numerous biological processes from embryogenesis to adult homeostasis; aberrant Wnt signaling underlies a wide range of human diseases. 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. Recently, Tankyrase, an ADP-ribose polymerase, was discovered as a novel modulator of Wnt signaling that promotes Axin degradation in human cultured cells. Small-molecule inhibitors of Tankyrase stabilize Axin and attenuate signaling activation, thus providing a promising strategy to treat Wnt-driven cancers. However, the in vivo role of Tankyrase in Wnt signaling has been controversial. To address this controversy and further investigate Tankyrase function in a physiological setting, we established a Drosophila Tnks mutant model and made three major discoveries. First, we demonstrated that Tankyrase, together with the downstream E3 ubiquitin ligase Rnf146, maintains Axin levels below a critical in vivo threshold to ensure proper Wnt pathway activation. Second, we discovered that a membrane-associated pool of Axin is preferentially targeted by Tankyrase for degradation under basal condition. Furthermore, we found that Wnt stimulation results in rapid stabilization of ADP-ribosylated Axin at the membrane, which facilitates the interaction between Axin and the Wnt co-receptor LRP6 to activate the pathway, indicating dual functions of Axin ADP-ribosylation. Third, we identified a physiological context in which Tankyrase maintains intestinal stem cell homeostasis by regulating Wnt signaling. More importantly, our results revealed that Tankyrase is crucial for Wnt pathway activation in the regions where Wnt signaling activity is low, but it is dispensable where the activity is high. These findings indicate a tissue-specific role of Tankyrase in Wnt signaling regulation. Our work has not only addressed a previous controversy regarding Tankyrase function, but also informed our understanding of Tankyrase as a Wnt signaling regulator, which will shed light on future investigation of Wnt-driven diseases.
Description	1 online resource (viii, 134 leaves) : illustrations (some color)
Format	application/pdf
College	Geisel School of Medicine at Dartmouth -- Department of Genetics.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	Made available by the author under a Creative Commons Attribution-NonCommercial License.; Made available by the Trustees of Dartmouth College under a Creative Commons Attribution-NonCommercial License. https://creativecommons.org/licenses/by-nc/4.0/
DOI	https://doi.org/10.1349/ddlp.2388

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Regulation of Wnt/Wingless signaling by the ADP-ribose polymerase Tankyrase / by Zhenghan Wang

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