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Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation

We previously established a mechanism of negative regulation of transforming growth factor β signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the deribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosyla...

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Autores principales: Watanabe, Yukihide, Papoutsoglou, Panagiotis, Maturi, Varun, Tsubakihara, Yutaro, Hottiger, Michael O., Heldin, Carl-Henrik, Moustakas, Aristidis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933475/
https://www.ncbi.nlm.nih.gov/pubmed/27129221
http://dx.doi.org/10.1074/jbc.M116.729699
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author Watanabe, Yukihide
Papoutsoglou, Panagiotis
Maturi, Varun
Tsubakihara, Yutaro
Hottiger, Michael O.
Heldin, Carl-Henrik
Moustakas, Aristidis
author_facet Watanabe, Yukihide
Papoutsoglou, Panagiotis
Maturi, Varun
Tsubakihara, Yutaro
Hottiger, Michael O.
Heldin, Carl-Henrik
Moustakas, Aristidis
author_sort Watanabe, Yukihide
collection PubMed
description We previously established a mechanism of negative regulation of transforming growth factor β signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the deribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosylation of Smad3 and Smad4, two central signaling proteins of the pathway. Here we demonstrate that the bone morphogenetic protein (BMP) pathway can also be regulated by the opposing actions of PARP1 and PARG. PARG positively contributes to BMP signaling and forms physical complexes with Smad5 and Smad4. The positive role PARG plays during BMP signaling can be neutralized by PARP1, as demonstrated by experiments where PARG and PARP1 are simultaneously silenced. In contrast to PARG, ectopic expression of PARP1 suppresses BMP signaling, whereas silencing of endogenous PARP1 enhances signaling and BMP-induced differentiation. The two major Smad proteins of the BMP pathway, Smad1 and Smad5, interact with PARP1 and can be ADP-ribosylated in vitro, whereas PARG causes deribosylation. The overall outcome of this mode of regulation of BMP signal transduction provides a fine-tuning mechanism based on the two major enzymes that control cellular ADP-ribosylation.
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spelling pubmed-49334752016-07-08 Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation Watanabe, Yukihide Papoutsoglou, Panagiotis Maturi, Varun Tsubakihara, Yutaro Hottiger, Michael O. Heldin, Carl-Henrik Moustakas, Aristidis J Biol Chem Gene Regulation We previously established a mechanism of negative regulation of transforming growth factor β signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the deribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosylation of Smad3 and Smad4, two central signaling proteins of the pathway. Here we demonstrate that the bone morphogenetic protein (BMP) pathway can also be regulated by the opposing actions of PARP1 and PARG. PARG positively contributes to BMP signaling and forms physical complexes with Smad5 and Smad4. The positive role PARG plays during BMP signaling can be neutralized by PARP1, as demonstrated by experiments where PARG and PARP1 are simultaneously silenced. In contrast to PARG, ectopic expression of PARP1 suppresses BMP signaling, whereas silencing of endogenous PARP1 enhances signaling and BMP-induced differentiation. The two major Smad proteins of the BMP pathway, Smad1 and Smad5, interact with PARP1 and can be ADP-ribosylated in vitro, whereas PARG causes deribosylation. The overall outcome of this mode of regulation of BMP signal transduction provides a fine-tuning mechanism based on the two major enzymes that control cellular ADP-ribosylation. American Society for Biochemistry and Molecular Biology 2016-06-10 2016-04-21 /pmc/articles/PMC4933475/ /pubmed/27129221 http://dx.doi.org/10.1074/jbc.M116.729699 Text en © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) .
spellingShingle Gene Regulation
Watanabe, Yukihide
Papoutsoglou, Panagiotis
Maturi, Varun
Tsubakihara, Yutaro
Hottiger, Michael O.
Heldin, Carl-Henrik
Moustakas, Aristidis
Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
title Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
title_full Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
title_fullStr Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
title_full_unstemmed Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
title_short Regulation of Bone Morphogenetic Protein Signaling by ADP-ribosylation
title_sort regulation of bone morphogenetic protein signaling by adp-ribosylation
topic Gene Regulation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933475/
https://www.ncbi.nlm.nih.gov/pubmed/27129221
http://dx.doi.org/10.1074/jbc.M116.729699
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