title: CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation.
abstract: 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.
authors.affiliation: Cell Death and Metabolism, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Pietri
authors.initials: P
authors.lastname: Puustinen
authors.forename: Anna
authors.initials: A
authors.lastname: Rytter
authors.forename: Monika
authors.initials: M
authors.lastname: Mortensen
authors.forename: Pekka
authors.initials: P
authors.lastname: Kohonen
authors.forename: José M
authors.initials: JM
authors.lastname: Moreira
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
mesh_terms: D001324:Autoantigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001343:Autophagy / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D046912:Multiprotein Complexes / Q000502:physiology*; D054648:Protein Phosphatase 2 / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C525688:PPP2R3A protein, human; D054648:Protein Phosphatase 2