title: Akt-dependent activation of mTORC1 complex involves phosphorylation of mTOR (mammalian target of rapamycin) by IκB kinase α (IKKα).
abstract: The serine/threonine protein kinase Akt promotes cell survival, growth, and proliferation through phosphorylation of different downstream substrates. A key effector of Akt is the mammalian target of rapamycin (mTOR). Akt is known to stimulate mTORC1 activity through phosphorylation of tuberous sclerosis complex 2 (TSC2) and PRAS40, both negative regulators of mTOR activity. We previously reported that IκB kinase α (IKKα), a component of the kinase complex that leads to NF-κB activation, plays an important role in promoting mTORC1 activity downstream of activated Akt. Here, we demonstrate IKKα-dependent regulation of mTORC1 using multiple PTEN null cancer cell lines and an animal model with deletion of IKKα. Importantly, IKKα is shown to phosphorylate mTOR at serine 1415 in a manner dependent on Akt to promote mTORC1 activity. These results demonstrate that IKKα is an effector of Akt in promoting mTORC1 activity.
authors.affiliation: From the Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Han C
authors.initials: HC
authors.lastname: Dan
authors.affiliation: From the Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Aaron
authors.initials: A
authors.lastname: Ebbs
authors.affiliation: Institute for Genetics University of Cologne, Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Mouse Cancer Genetics Program, NCI, National Institutes of Health, Frederick, Maryland 21702, and.
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
authors.affiliation: From the Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Basseres
authors.affiliation: From the Lineberger Comprehensive Cancer Center University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, abaldwin@med.unc.edu.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000076223:Regulatory-Associated Protein of mTOR; D012694:Serine / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D012694:Serine; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase
keywords: Akt; Cell Proliferation; IKK; Mammalian Target of Rapamycin (mTOR); Phosphatase and Tensin Homolog (PTEN); Phosphorylation; Raptor