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CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation

mTORC1 (mammalian target of rapamycin complex 1) integrates information regarding availability of nutrients and energy to coordinate protein synthesis and autophagy. Using ribonucleic acid interference screens for autophagy-regulating phosphatases in human breast cancer cells, we identify CIP2A (can...

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Autores principales: Puustinen, Pietri, Rytter, Anna, Mortensen, Monika, Kohonen, Pekka, Moreira, José M., Jäättelä, Marja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941044/
https://www.ncbi.nlm.nih.gov/pubmed/24590173
http://dx.doi.org/10.1083/jcb.201304012
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author Puustinen, Pietri
Rytter, Anna
Mortensen, Monika
Kohonen, Pekka
Moreira, José M.
Jäättelä, Marja
author_facet Puustinen, Pietri
Rytter, Anna
Mortensen, Monika
Kohonen, Pekka
Moreira, José M.
Jäättelä, Marja
author_sort Puustinen, Pietri
collection PubMed
description mTORC1 (mammalian target of rapamycin complex 1) integrates information regarding availability of nutrients and energy to coordinate protein synthesis and autophagy. Using ribonucleic acid interference screens for autophagy-regulating phosphatases in human breast cancer cells, we identify CIP2A (cancerous inhibitor of PP2A [protein phosphatase 2A]) as a key modulator of mTORC1 and autophagy. CIP2A associates with mTORC1 and acts as an allosteric inhibitor of mTORC1-associated PP2A, thereby enhancing mTORC1-dependent growth signaling and inhibiting autophagy. This regulatory circuit is reversed by ubiquitination and p62/SQSTM1-dependent autophagic degradation of CIP2A and subsequent inhibition of mTORC1 activity. Consistent with CIP2A’s reported ability to protect c-Myc against proteasome-mediated degradation, autophagic degradation of CIP2A upon mTORC1 inhibition leads to destabilization of c-Myc. These data characterize CIP2A as a distinct regulator of mTORC1 and reveals mTORC1-dependent control of CIP2A degradation as a mechanism that links mTORC1 activity with c-Myc stability to coordinate cellular metabolism, growth, and proliferation.
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spelling pubmed-39410442014-09-03 CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation Puustinen, Pietri Rytter, Anna Mortensen, Monika Kohonen, Pekka Moreira, José M. Jäättelä, Marja J Cell Biol Research Articles mTORC1 (mammalian target of rapamycin complex 1) integrates information regarding availability of nutrients and energy to coordinate protein synthesis and autophagy. Using ribonucleic acid interference screens for autophagy-regulating phosphatases in human breast cancer cells, we identify CIP2A (cancerous inhibitor of PP2A [protein phosphatase 2A]) as a key modulator of mTORC1 and autophagy. CIP2A associates with mTORC1 and acts as an allosteric inhibitor of mTORC1-associated PP2A, thereby enhancing mTORC1-dependent growth signaling and inhibiting autophagy. This regulatory circuit is reversed by ubiquitination and p62/SQSTM1-dependent autophagic degradation of CIP2A and subsequent inhibition of mTORC1 activity. Consistent with CIP2A’s reported ability to protect c-Myc against proteasome-mediated degradation, autophagic degradation of CIP2A upon mTORC1 inhibition leads to destabilization of c-Myc. These data characterize CIP2A as a distinct regulator of mTORC1 and reveals mTORC1-dependent control of CIP2A degradation as a mechanism that links mTORC1 activity with c-Myc stability to coordinate cellular metabolism, growth, and proliferation. The Rockefeller University Press 2014-03-03 /pmc/articles/PMC3941044/ /pubmed/24590173 http://dx.doi.org/10.1083/jcb.201304012 Text en © 2014 Puustinen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Puustinen, Pietri
Rytter, Anna
Mortensen, Monika
Kohonen, Pekka
Moreira, José M.
Jäättelä, Marja
CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation
title CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation
title_full CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation
title_fullStr CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation
title_full_unstemmed CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation
title_short CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation
title_sort cip2a oncoprotein controls cell growth and autophagy through mtorc1 activation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941044/
https://www.ncbi.nlm.nih.gov/pubmed/24590173
http://dx.doi.org/10.1083/jcb.201304012
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