Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.

The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and ac...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Morris E Feldman, Beth Apsel, Aino Uotila, Robbie Loewith, Zachary A Knight, Davide Ruggero, Kevan M Shokat
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/698cb7ff5fb24dd29363fef1892083c8
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:698cb7ff5fb24dd29363fef1892083c8
record_format	dspace
spelling	oai:doaj.org-article:698cb7ff5fb24dd29363fef1892083c82021-11-25T05:33:48ZActive-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.1544-91731545-788510.1371/journal.pbio.1000038https://doaj.org/article/698cb7ff5fb24dd29363fef1892083c82009-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19209957/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.Morris E FeldmanBeth ApselAino UotilaRobbie LoewithZachary A KnightDavide RuggeroKevan M ShokatPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 7, Iss 2, p e38 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Morris E Feldman Beth Apsel Aino Uotila Robbie Loewith Zachary A Knight Davide Ruggero Kevan M Shokat Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
description	The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.
format	article
author	Morris E Feldman Beth Apsel Aino Uotila Robbie Loewith Zachary A Knight Davide Ruggero Kevan M Shokat
author_facet	Morris E Feldman Beth Apsel Aino Uotila Robbie Loewith Zachary A Knight Davide Ruggero Kevan M Shokat
author_sort	Morris E Feldman
title	Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
title_short	Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
title_full	Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
title_fullStr	Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
title_full_unstemmed	Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.
title_sort	active-site inhibitors of mtor target rapamycin-resistant outputs of mtorc1 and mtorc2.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/698cb7ff5fb24dd29363fef1892083c8
work_keys_str_mv	AT morrisefeldman activesiteinhibitorsofmtortargetrapamycinresistantoutputsofmtorc1andmtorc2 AT bethapsel activesiteinhibitorsofmtortargetrapamycinresistantoutputsofmtorc1andmtorc2 AT ainouotila activesiteinhibitorsofmtortargetrapamycinresistantoutputsofmtorc1andmtorc2 AT robbieloewith activesiteinhibitorsofmtortargetrapamycinresistantoutputsofmtorc1andmtorc2 AT zacharyaknight activesiteinhibitorsofmtortargetrapamycinresistantoutputsofmtorc1andmtorc2 AT davideruggero activesiteinhibitorsofmtortargetrapamycinresistantoutputsofmtorc1andmtorc2 AT kevanmshokat activesiteinhibitorsofmtortargetrapamycinresistantoutputsofmtorc1andmtorc2
_version_	1718414582477750272

Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2.

Ejemplares similares