@article{71c12a3006004804a06948e49536a133,
title = "Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase",
abstract = "Spatiotemporal control of Wnt/β-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/β-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the β-catenin destruction complex. Although Wnt/β-catenin is a niche-restricted signaling program, tissue-specific factors that regulate TNKS1 are not known. Here, we report prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS1 inhibitor that robustly represses canonical Wnt/β-catenin signaling in human cells, zebrafish, and mice. Structural and biochemical studies reveal that PAGE4 acts as an optimal substrate decoy that potently hijacks substrate binding sites on TNKS1 to prevent AXIN1 PARylation and degradation. Consistently, transgenic expression of PAGE4 in mice phenocopies TNKS1 knockout. Physiologically, PAGE4 is selectively expressed in stromal prostate fibroblasts and functions to establish a proper Wnt/β-catenin signaling niche through suppression of autocrine signaling. Our findings reveal a non-canonical mechanism for TNKS1 inhibition that functions to establish tissue-specific control of the Wnt/β-catenin pathway.",
keywords = "Axin, PAGE4, PARylation, RNF146, TNKS, Tankyrase, Wnt, cancer-testis antigen, prostate, β-catenin",
author = "Sajjan Koirala and Jonathon Klein and Yumei Zheng and Glenn, {Nicole O.} and Travis Eisemann and {Fon Tacer}, Klementina and Miller, {Darcie J.} and Ozlem Kulak and Meifen Lu and Finkelstein, {David B.} and Geoffrey Neale and Heather Tillman and Peter Vogel and Strand, {Douglas W.} and Lawrence Lum and Brautigam, {Chad A.} and Pascal, {John M.} and Clements, {Wilson K.} and Potts, {Patrick Ryan}",
note = "Funding Information: We thank members of the Potts lab and Dr. Brenda Schulman for helpful discussions and critical reading of the manuscript. We would like to thank Dr. Michael Root (Thomas Jefferson University) for help with the analysis of the competition binding experiments.We would like to also acknowledge the St. Jude Children{\textquoteright}s Research Hospital Transgenic Core Facility (Hartmut Berns) and the Proteomics Core Facility (Vishwajeeth Pagala and Junmin Peng). This work was partially supported by Cancer Prevention and Research Institute of Texas grant RP140661 (P.R.P.) and Canadian Institutes of Health Research grant PJT374609 (J.M.P). This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) ( P30 GM124165 ). The Eiger 16M detector on the 24-ID-E beamline is funded by an NIH Office of Research Infrastructure Programs (ORIP) High-End Instrumentation (HEI) grant ( S10OD021527 ). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-AC02-06CH11357 . Funding Information: We thank members of the Potts lab and Dr. Brenda Schulman for helpful discussions and critical reading of the manuscript. We would like to thank Dr. Michael Root (Thomas Jefferson University) for help with the analysis of the competition binding experiments.We would like to also acknowledge the St. Jude Children's Research Hospital Transgenic Core Facility (Hartmut Berns) and the Proteomics Core Facility (Vishwajeeth Pagala and Junmin Peng). This work was partially supported by Cancer Prevention and Research Institute of Texas grant RP140661 (P.R.P.) and Canadian Institutes of Health Research grant PJT374609 (J.M.P). This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (P30 GM124165). The Eiger 16M detector on the 24-ID-E beamline is funded by an NIH Office of Research Infrastructure Programs (ORIP) High-End Instrumentation (HEI) grant (S10OD021527). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-AC02-06CH11357. P.R.P. and S.K. conceptualized the study, designed experiments, and developed reagents. J.K. performed mouse studies. Y.Z. D.J.M. and S.K. purified, crystallized, and solved the structure of the PAGE4-TNKS1 complex. N.O.G. and W.K.C. performed zebrafish studies. T.E. and J.M.P. performed fluorescence polarization studies. O.K. L.L. and S.K. performed reporter assays. M.L. performed histology and immunofluorescence staining. H.T. and P.V. performed the pathology analyses. D.B.F. and G.N. performed RNA-seq and microarray analysis. D.W.S. provided prostate samples. S.K. and C.A.B. performed AUC. S.K. K.F.T. and P.R.P. performed experiments and analyzed data. S.K. and P.R.P. wrote the manuscript. P.R.P. is a paid consultant for Levo Therapeutics, Inc. and Amgen, Inc. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jul,
day = "21",
doi = "10.1016/j.celrep.2020.107922",
language = "English (US)",
volume = "32",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}