The Wnt signal transduction pathway directs essential steps in embryonic development. Inappropriate activation of Wnt signaling triggers the development of several cancers, including the vast majority of colorectal cancers. Thus, understanding the basic mechanisms that underlie Wnt pathway activation will facilitate the design of innovative strategies for the treatment of a large number of diseases. A major goal of our research is to elucidate the regulation of two distinct multiprotein complexes - termed the ?beta-catenin destruction complex? and the ?signalosome?- that are fundamental for the control of Wnt signaling in the ?off? and ?on? states, respectively. Axin, a concentration-limiting scaffold protein, plays important roles in the assembly of both complexes. How these distinct roles of Axin are coordinated remains a mystery. Regulators of Axin, including the ADP-ribose polymerase Tankyrase (Tnks) have recently emerged as promising therapeutic targets. In the current model, the sole role of Tnks is to target Axin for proteasomal degradation, and thereby to control steady state Axin levels in the unstimulated state. However, we have found, unexpectedly, that ADP- ribosylation of Axin by Tnks also promotes Axin's critical role in activation of the pathway following Wnt stimulation. Our findings force major revision of the prevailing model for Tnks function in Wnt signaling and may underlie the effectiveness of small molecule Tnks inhibitors, which are among the most promising anti- Wnt pathway agents under development. Thus, in contrast with the prevailing model, we hypothesize that Tnks plays key roles in controlling Axin activity both in the destruction complex (in the unstimulated state) and in the signalosome (following Wnt stimulation). We propose to test this hypothesis by analyzing differences in the state of Axin ADP-ribosylation under basal and Wnt-stimulated conditions. We will determine how Axin ADP- ribosylation regulates the composition and activity of the ?-catenin destruction complex and signalosome. We will address the physiological roles of ADP-ribosylation on Axin activity in the unstimulated and Wnt-stimulated states in vivo. These studies are driven by an ongoing collaboration between two scientists who have a shared interest in Wnt signaling: Yashi Ahmed, an experienced Drosophila geneticist and cell biologist, and Ethan Lee, an expert in using in vivo approaches in Xenopus and in vitro pathway reconstitution. We will combine our innovative genetic, cell biological, and biochemical approaches in vertebrate and invertebrate models to provide insight into the regulation of Wnt signaling. The proposed research has significance for the development of new therapeutic strategies for Wnt-driven diseases.

Public Health Relevance

PUBLICHEALTHRELEVANCE:TheWntsignaltransductionpathwayisessentialforcellproliferatonandcell differentiationduringanimaldevelopmentandisfrequentlyderegulatedinhumancongenitaldisordersand cancers.AttenuationofWntsignalingunderliesnumerousbirthdefectsarisingfromimproperdevelopmentof theskeleton,heart,nervoussystem,retina,limbs,reproductiveorgans,andskin.Inappropriateactivationof Wntsignaltransductionisfoundinseveralcancers,includingthevastmajorityofcolorectalcancers.Thegoals ofthisproposalaretoelucidatetheregulationofAxin,acoreWntpathwaycomponent,byTankyrase(Tnks), anADP-ribosepolymerasethatprovidesapromisingtherapeutictarget.Wewillachievethesegoalsby dissectingtheeffectsofTnksonAxinactivityusinggenetic,cellbiological,andbiochemicalapproaches. KnowledgegainedfromthesestudieswillinformourunderstandingoftwoessentialstepsinWntsignalingand mayprovidenovelentrypointsfortargetingWnt-drivendiseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Melillo, Amanda A
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Dartmouth College
Other Basic Sciences
Schools of Medicine
United States
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Tian, Ai; Benchabane, Hassina; Ahmed, Yashi (2018) Wingless/Wnt Signaling in Intestinal Development, Homeostasis, Regeneration and Tumorigenesis: A Drosophila Perspective. J Dev Biol 6:
Tacchelly-Benites, Ofelia; Wang, Zhenghan; Yang, Eungi et al. (2018) Axin phosphorylation in both Wnt-off and Wnt-on states requires the tumor suppressor APC. PLoS Genet 14:e1007178