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Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling

The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding...

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Autores principales: Mariotti, Laura, Templeton, Catherine M., Ranes, Michael, Paracuellos, Patricia, Cronin, Nora, Beuron, Fabienne, Morris, Edward, Guettler, Sebastian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980433/
https://www.ncbi.nlm.nih.gov/pubmed/27494558
http://dx.doi.org/10.1016/j.molcel.2016.06.019
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author Mariotti, Laura
Templeton, Catherine M.
Ranes, Michael
Paracuellos, Patricia
Cronin, Nora
Beuron, Fabienne
Morris, Edward
Guettler, Sebastian
author_facet Mariotti, Laura
Templeton, Catherine M.
Ranes, Michael
Paracuellos, Patricia
Cronin, Nora
Beuron, Fabienne
Morris, Edward
Guettler, Sebastian
author_sort Mariotti, Laura
collection PubMed
description The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling.
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spelling pubmed-49804332016-08-19 Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling Mariotti, Laura Templeton, Catherine M. Ranes, Michael Paracuellos, Patricia Cronin, Nora Beuron, Fabienne Morris, Edward Guettler, Sebastian Mol Cell Article The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling. Cell Press 2016-08-04 /pmc/articles/PMC4980433/ /pubmed/27494558 http://dx.doi.org/10.1016/j.molcel.2016.06.019 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mariotti, Laura
Templeton, Catherine M.
Ranes, Michael
Paracuellos, Patricia
Cronin, Nora
Beuron, Fabienne
Morris, Edward
Guettler, Sebastian
Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling
title Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling
title_full Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling
title_fullStr Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling
title_full_unstemmed Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling
title_short Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling
title_sort tankyrase requires sam domain-dependent polymerization to support wnt-β-catenin signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980433/
https://www.ncbi.nlm.nih.gov/pubmed/27494558
http://dx.doi.org/10.1016/j.molcel.2016.06.019
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