Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase.

Cell Reports
Sajjan KoiralaPatrick Ryan Potts

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.

References

Nov 20, 1998·Science·S SmithT de Lange
Nov 1, 2000·Cell·M Bienz, H Clevers
Dec 5, 2000·The Prostate·D R ChesireW B Isaacs
Mar 6, 2004·Cancer Metastasis Reviews·Marian L Waterman
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Oct 12, 2004·Annual Review of Cell and Developmental Biology·Catriona Y Logan, Roel Nusse
Dec 23, 2004·Proceedings of the National Academy of Sciences of the United States of America·Andrea BalboPeter Schuck
Apr 15, 2005·Nature·Tannishtha Reya, Hans Clevers
Jul 22, 2005·Nature Reviews. Cancer·Andrew J G SimpsonLloyd J Old
Mar 25, 2006·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Shigeki SekineMatthias Hebrok
Apr 28, 2006·BMC Genomics·Asa J OudesAlvin Y Liu
Jun 3, 2006·Developmental Cell·Samira BenhamoucheSabine Colnot
Oct 25, 2006·The Biochemical Journal·Tsung-Yin J YehNai-Wen Chi
May 25, 2007·BMC Genomics·Brian J StevensonC Victor Jongeneel
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Sep 18, 2009·Nature·Shih-Min A HuangFeng Cong
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jul 30, 2011·PloS One·Marinella G CallowMike Costa
Feb 3, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xinhai WanNora M Navone
Feb 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Seamus MorroneWenqing Xu
Jun 12, 2012·Cell·Hans Clevers, Roel Nusse
Jun 20, 2012·Nature Reviews. Urology·Robert M Kypta, Jonathan Waxman
Sep 11, 2012·Seminars in Cell & Developmental Biology·Rachel Sennett, Michael Rendl
Nov 22, 2012·Cold Spring Harbor Perspectives in Biology·Jennifer L Stamos, William I Weis

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