The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.

The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in polycystic kidney disease (PKD). Emerging evidence suggests that phospholipase D (PLD) and its product phosphatidic acid (PA) regulate mTOR activity. In this study, we assessed in vitro the regulatory function of P...

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Autores principales:	Yang Liu, Andres Käch, Urs Ziegler, Albert C M Ong, Darren P Wallace, Alexandre Arcaro, Andreas L Serra
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a546f237ed6a4c50ac5fabc86144f933
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spelling	oai:doaj.org-article:a546f237ed6a4c50ac5fabc86144f9332021-11-18T08:58:21ZThe role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.1932-620310.1371/journal.pone.0073173https://doaj.org/article/a546f237ed6a4c50ac5fabc86144f9332013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24009738/?tool=EBIhttps://doaj.org/toc/1932-6203The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in polycystic kidney disease (PKD). Emerging evidence suggests that phospholipase D (PLD) and its product phosphatidic acid (PA) regulate mTOR activity. In this study, we assessed in vitro the regulatory function of PLD and PA on the mTOR signaling pathway in PKD. We found that the basal level of PLD activity was elevated in PKD cells. Targeting PLD by small molecule inhibitors reduced cell proliferation and blocked mTOR signaling, whereas exogenous PA stimulated mTOR signaling and abolished the inhibitory effect of PLD on PKD cell proliferation. We also show that blocking PLD activity enhanced the sensitivity of PKD cells to rapamycin and that combining PLD inhibitors and rapamycin synergistically inhibited PKD cell proliferation. Furthermore, we demonstrate that targeting mTOR did not induce autophagy, whereas targeting PLD induced autophagosome formation. Taken together, our findings suggest that deregulated mTOR pathway activation is mediated partly by increased PLD signaling in PKD cells. Targeting PLD isoforms with pharmacological inhibitors may represent a new therapeutic strategy in PKD.Yang LiuAndres KächUrs ZieglerAlbert C M OngDarren P WallaceAlexandre ArcaroAndreas L SerraPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e73173 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yang Liu Andres Käch Urs Ziegler Albert C M Ong Darren P Wallace Alexandre Arcaro Andreas L Serra The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.
description	The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in polycystic kidney disease (PKD). Emerging evidence suggests that phospholipase D (PLD) and its product phosphatidic acid (PA) regulate mTOR activity. In this study, we assessed in vitro the regulatory function of PLD and PA on the mTOR signaling pathway in PKD. We found that the basal level of PLD activity was elevated in PKD cells. Targeting PLD by small molecule inhibitors reduced cell proliferation and blocked mTOR signaling, whereas exogenous PA stimulated mTOR signaling and abolished the inhibitory effect of PLD on PKD cell proliferation. We also show that blocking PLD activity enhanced the sensitivity of PKD cells to rapamycin and that combining PLD inhibitors and rapamycin synergistically inhibited PKD cell proliferation. Furthermore, we demonstrate that targeting mTOR did not induce autophagy, whereas targeting PLD induced autophagosome formation. Taken together, our findings suggest that deregulated mTOR pathway activation is mediated partly by increased PLD signaling in PKD cells. Targeting PLD isoforms with pharmacological inhibitors may represent a new therapeutic strategy in PKD.
format	article
author	Yang Liu Andres Käch Urs Ziegler Albert C M Ong Darren P Wallace Alexandre Arcaro Andreas L Serra
author_facet	Yang Liu Andres Käch Urs Ziegler Albert C M Ong Darren P Wallace Alexandre Arcaro Andreas L Serra
author_sort	Yang Liu
title	The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.
title_short	The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.
title_full	The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.
title_fullStr	The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.
title_full_unstemmed	The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.
title_sort	role of phospholipase d in modulating the mtor signaling pathway in polycystic kidney disease.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/a546f237ed6a4c50ac5fabc86144f933
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The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.

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