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Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation

Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that function in pathways critical to cancer cell growth. Tankyrase-mediated PARylation marks protein targets for proteasomal degradation. Here, we generate human knockout cell lines to examine cell function and interrogate the proteome. We show tha...

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Autores principales: Bhardwaj, Amit, Yang, Yanling, Ueberheide, Beatrix, Smith, Susan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738441/
https://www.ncbi.nlm.nih.gov/pubmed/29263426
http://dx.doi.org/10.1038/s41467-017-02363-w
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author Bhardwaj, Amit
Yang, Yanling
Ueberheide, Beatrix
Smith, Susan
author_facet Bhardwaj, Amit
Yang, Yanling
Ueberheide, Beatrix
Smith, Susan
author_sort Bhardwaj, Amit
collection PubMed
description Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that function in pathways critical to cancer cell growth. Tankyrase-mediated PARylation marks protein targets for proteasomal degradation. Here, we generate human knockout cell lines to examine cell function and interrogate the proteome. We show that either tankyrase 1 or 2 is sufficient to maintain telomere length, but both are required to resolve telomere cohesion and maintain mitotic spindle integrity. Quantitative analysis of the proteome of tankyrase double knockout cells using isobaric tandem mass tags reveals targets of degradation, including antagonists of the Wnt/β-catenin signaling pathway (NKD1, NKD2, and HectD1) and three (Notch 1, 2, and 3) of the four Notch receptors. We show that tankyrases are required for Notch2 to exit the plasma membrane and enter the nucleus to activate transcription. Considering that Notch signaling is commonly activated in cancer, tankyrase inhibitors may have therapeutic potential in targeting this pathway.
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spelling pubmed-57384412017-12-22 Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation Bhardwaj, Amit Yang, Yanling Ueberheide, Beatrix Smith, Susan Nat Commun Article Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that function in pathways critical to cancer cell growth. Tankyrase-mediated PARylation marks protein targets for proteasomal degradation. Here, we generate human knockout cell lines to examine cell function and interrogate the proteome. We show that either tankyrase 1 or 2 is sufficient to maintain telomere length, but both are required to resolve telomere cohesion and maintain mitotic spindle integrity. Quantitative analysis of the proteome of tankyrase double knockout cells using isobaric tandem mass tags reveals targets of degradation, including antagonists of the Wnt/β-catenin signaling pathway (NKD1, NKD2, and HectD1) and three (Notch 1, 2, and 3) of the four Notch receptors. We show that tankyrases are required for Notch2 to exit the plasma membrane and enter the nucleus to activate transcription. Considering that Notch signaling is commonly activated in cancer, tankyrase inhibitors may have therapeutic potential in targeting this pathway. Nature Publishing Group UK 2017-12-20 /pmc/articles/PMC5738441/ /pubmed/29263426 http://dx.doi.org/10.1038/s41467-017-02363-w Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Bhardwaj, Amit
Yang, Yanling
Ueberheide, Beatrix
Smith, Susan
Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation
title Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation
title_full Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation
title_fullStr Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation
title_full_unstemmed Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation
title_short Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation
title_sort whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738441/
https://www.ncbi.nlm.nih.gov/pubmed/29263426
http://dx.doi.org/10.1038/s41467-017-02363-w
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