PMID- 24990947
OWN - NLM
STAT- MEDLINE
DCOM- 20150128
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 289
IP  - 36
DP  - 2014 Sep 5
TI  - Akt-dependent activation of mTORC1 complex involves phosphorylation of mTOR 
      (mammalian target of rapamycin) by IkappaB kinase alpha (IKKalpha).
PG  - 25227-40
LID - 10.1074/jbc.M114.554881 [doi]
AB  - 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 IkappaB kinase alpha (IKKalpha), a component of the kinase complex that leads 
      to NF-kappaB activation, plays an important role in promoting mTORC1 activity 
      downstream of activated Akt. Here, we demonstrate IKKalpha-dependent regulation of 
      mTORC1 using multiple PTEN null cancer cell lines and an animal model with 
      deletion of IKKalpha. Importantly, IKKalpha is shown to phosphorylate mTOR at serine 1415 
      in a manner dependent on Akt to promote mTORC1 activity. These results 
      demonstrate that IKKalpha is an effector of Akt in promoting mTORC1 activity.
CI  - (c) 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Dan, Han C
AU  - Dan HC
AD  - 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.
FAU - Ebbs, Aaron
AU  - Ebbs A
AD  - From the Lineberger Comprehensive Cancer Center University of North Carolina 
      School of Medicine, Chapel Hill, North Carolina 27599.
FAU - Pasparakis, Manolis
AU  - Pasparakis M
AD  - Institute for Genetics University of Cologne, Cologne, Germany.
FAU - Van Dyke, Terry
AU  - Van Dyke T
AD  - Mouse Cancer Genetics Program, NCI, National Institutes of Health, Frederick, 
      Maryland 21702, and.
FAU - Basseres, Daniela S
AU  - Basseres DS
AD  - From the Lineberger Comprehensive Cancer Center University of North Carolina 
      School of Medicine, Chapel Hill, North Carolina 27599.
FAU - Baldwin, Albert S
AU  - Baldwin AS
AD  - From the Lineberger Comprehensive Cancer Center University of North Carolina 
      School of Medicine, Chapel Hill, North Carolina 27599, abaldwin@med.unc.edu.
LA  - eng
GR  - R37 AI035098/AI/NIAID NIH HHS/United States
GR  - R01 CA075080/CA/NCI NIH HHS/United States
GR  - R00 CA149178/CA/NCI NIH HHS/United States
GR  - CA75080/CA/NCI NIH HHS/United States
GR  - K99CA149178/CA/NCI NIH HHS/United States
GR  - K99 CA149178/CA/NCI NIH HHS/United States
GR  - R01 AI035098/AI/NIAID NIH HHS/United States
GR  - CA73756/CA/NCI NIH HHS/United States
GR  - R01 CA073756/CA/NCI NIH HHS/United States
GR  - AI35098/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140702
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Enzyme Activation
MH  - Female
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - I-kappa B Kinase/genetics/*metabolism
MH  - Immunoblotting
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice, Knockout
MH  - Multiprotein Complexes/genetics/*metabolism
MH  - Mutation
MH  - Phosphorylation
MH  - Protein Binding
MH  - Proto-Oncogene Proteins c-akt/genetics/*metabolism
MH  - RNA Interference
MH  - Regulatory-Associated Protein of mTOR
MH  - Serine/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/metabolism
PMC - PMC4155685
OTO - NOTNLM
OT  - Akt
OT  - Cell Proliferation
OT  - IKK
OT  - Mammalian Target of Rapamycin (mTOR)
OT  - Phosphatase and Tensin Homolog (PTEN)
OT  - Phosphorylation
OT  - Raptor
EDAT- 2014/07/06 06:00
MHDA- 2015/01/30 06:00
PMCR- 2015/09/05
CRDT- 2014/07/04 06:00
PHST- 2014/07/04 06:00 [entrez]
PHST- 2014/07/06 06:00 [pubmed]
PHST- 2015/01/30 06:00 [medline]
PHST- 2015/09/05 00:00 [pmc-release]
AID - S0021-9258(20)31672-0 [pii]
AID - M114.554881 [pii]
AID - 10.1074/jbc.M114.554881 [doi]
PST - ppublish
SO  - J Biol Chem. 2014 Sep 5;289(36):25227-40. doi: 10.1074/jbc.M114.554881. Epub 2014 
      Jul 2.