PMID- 17277771
OWN - NLM
STAT- MEDLINE
DCOM- 20070424
LR  - 20220309
IS  - 1465-7392 (Print)
IS  - 1465-7392 (Linking)
VI  - 9
IP  - 3
DP  - 2007 Mar
TI  - Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40.
PG  - 316-23
AB  - Insulin stimulates protein synthesis and cell growth by activation of the protein 
      kinases Akt (also known as protein kinase B, PKB) and mammalian target of 
      rapamycin (mTOR). It was reported that Akt activates mTOR by phosphorylation and 
      inhibition of tuberous sclerosis complex 2 (TSC2). However, in recent studies the 
      physiological requirement of Akt phosphorylation of TSC2 for mTOR activation has 
      been questioned. Here, we identify PRAS40 (proline-rich Akt/PKB substrate 40 kDa) 
      as a novel mTOR binding partner that mediates Akt signals to mTOR. PRAS40 binds 
      the mTOR kinase domain and its interaction with mTOR is induced under conditions 
      that inhibit mTOR signalling, such as nutrient or serum deprivation or 
      mitochondrial metabolic inhibition. Binding of PRAS40 inhibits mTOR activity and 
      suppresses constitutive activation of mTOR in cells lacking TSC2. PRAS40 
      silencing inactivates insulin-receptor substrate-1 (IRS-1) and Akt, and uncouples 
      the response of mTOR to Akt signals. Furthermore, PRAS40 phosphorylation by Akt 
      and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin 
      to stimulate mTOR. These findings identify PRAS40 as an important regulator of 
      insulin sensitivity of the Akt-mTOR pathway and a potential target for the 
      treatment of cancers, insulin resistance and hamartoma syndromes.
FAU - Vander Haar, Emilie
AU  - Vander Haar E
AD  - Department of Biochemistry, Molecular Biology and Biophysics, University of 
      Minnesota, 6-155 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
FAU - Lee, Seong-Il
AU  - Lee SI
FAU - Bandhakavi, Sricharan
AU  - Bandhakavi S
FAU - Griffin, Timothy J
AU  - Griffin TJ
FAU - Kim, Do-Hyung
AU  - Kim DH
LA  - eng
GR  - DK072004/DK/NIDDK 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 - 20070204
PL  - England
TA  - Nat Cell Biol
JT  - Nature cell biology
JID - 100890575
RN  - 0 (14-3-3 Proteins)
RN  - 0 (AKT1S1 protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Insulin)
RN  - 0 (MAPKAP1 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (RNA, Antisense)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 0 (proline-rich Akt substrate, 40 kDa protein, mouse)
RN  - 11118-72-2 (antimycin)
RN  - 642-15-9 (Antimycin A)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1)
SB  - IM
MH  - 14-3-3 Proteins/genetics/metabolism
MH  - 3T3 Cells
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Antimycin A/analogs & derivatives/pharmacology
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Deoxyglucose/pharmacology
MH  - Humans
MH  - Immunoprecipitation
MH  - Insulin/pharmacology/*physiology
MH  - Mice
MH  - Models, Biological
MH  - Phosphoproteins/genetics/*metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Binding/drug effects
MH  - Protein Kinases/*metabolism
MH  - Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - RNA, Antisense/genetics
MH  - Regulatory-Associated Protein of mTOR
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases
MH  - Tandem Mass Spectrometry
MH  - Transfection
EDAT- 2007/02/06 09:00
MHDA- 2007/04/25 09:00
CRDT- 2007/02/06 09:00
PHST- 2006/11/13 00:00 [received]
PHST- 2007/01/10 00:00 [accepted]
PHST- 2007/02/06 09:00 [pubmed]
PHST- 2007/04/25 09:00 [medline]
PHST- 2007/02/06 09:00 [entrez]
AID - ncb1547 [pii]
AID - 10.1038/ncb1547 [doi]
PST - ppublish
SO  - Nat Cell Biol. 2007 Mar;9(3):316-23. doi: 10.1038/ncb1547. Epub 2007 Feb 4.