CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation
| Autor: | Monika Mortensen, Marja Jäättelä, José M.A. Moreira, Anna Rytter, Pekka Kohonen, Pietri Puustinen |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Phosphatase
mTORC1 Mechanistic Target of Rapamycin Complex 1 Autoantigens Article Proto-Oncogene Proteins c-myc Ubiquitin Cell Line Tumor Autophagy Humans Protein Phosphatase 2 RNA Small Interfering Research Articles Cell Proliferation biology Cell growth TOR Serine-Threonine Kinases Intracellular Signaling Peptides and Proteins Ubiquitination Computational Biology Membrane Proteins Cell Biology Protein phosphatase 2 Cell biology Multiprotein Complexes biology.protein RNA Interference Signal transduction biological phenomena cell phenomena and immunity Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | As part of a regulatory loop linking cell metabolism, growth, and proliferation, CIP2A promotes mTORC1-mediated cell growth and autophagy inhibition but is itself down-regulated by autophagy. 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. |
| Databáze: | OpenAIRE |
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