PMID- 17517883
OWN - NLM
STAT- MEDLINE
DCOM- 20070913
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 28
DP  - 2007 Jul 13
TI  - The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of 
      mammalian target of rapamycin complex 1.
PG  - 20329-39
AB  - The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a 
      raptor-binding protein that is phosphorylated directly by mammalian target of 
      rapamycin (mTOR) complex 1 (mTORC1) but not mTORC2 in vitro, predominantly at 
      PRAS40 (Ser(183)). The binding of S6K1 and 4E-BP1 to raptor requires a TOR 
      signaling (TOS) motif, which contains an essential Phe followed by four 
      alternating acidic and small hydrophobic amino acids. PRAS40 binding to raptor 
      was severely inhibited by mutation of PRAS40 (Phe(129) to Ala). Immediately 
      carboxyl-terminal to Phe(129) are two small hydrophobic amino acid followed by 
      two acidic residues. PRAS40 binding to raptor was also abolished by mutation of 
      the major mTORC1 phosphorylation site, Ser(183), to Asp. PRAS40 (Ser(183)) was 
      phosphorylated in intact cells; this phosphorylation was inhibited by rapamycin, 
      by 2-deoxyglucose, and by overexpression of the tuberous sclerosis complex 
      heterodimer. PRAS40 (Ser(183)) phosphorylation was also inhibited reversibly by 
      withdrawal of all or of only the branched chain amino acids; this inhibition was 
      reversed by overexpression of the Rheb GTPase. Overexpressed PRAS40 suppressed 
      the phosphorylation of S6K1 and 4E-BP1 at their rapamycin-sensitive 
      phosphorylation sites, and reciprocally, overexpression of S6K1 or 4E-BP1 
      suppressed phosphorylation of PRAS40 (Ser(183)) and its binding to raptor. RNA 
      interference-induced depletion of PRAS40 enhanced the amino acid-stimulated 
      phosphorylation of both S6K1 and 4E-BP1. These results establish PRAS40 as a 
      physiological mTORC1 substrate that contains a variant TOS motif. Moreover, they 
      indicate that the ability of raptor to bind endogenous substrates is limiting for 
      the activity of mTORC1 in vivo and is therefore a potential locus of regulation.
FAU - Oshiro, Noriko
AU  - Oshiro N
AD  - Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
FAU - Takahashi, Rinako
AU  - Takahashi R
FAU - Yoshino, Ken-ichi
AU  - Yoshino K
FAU - Tanimura, Keiko
AU  - Tanimura K
FAU - Nakashima, Akio
AU  - Nakashima A
FAU - Eguchi, Satoshi
AU  - Eguchi S
FAU - Miyamoto, Takafumi
AU  - Miyamoto T
FAU - Hara, Kenta
AU  - Hara K
FAU - Takehana, Kenji
AU  - Takehana K
FAU - Avruch, Joseph
AU  - Avruch J
FAU - Kikkawa, Ushio
AU  - Kikkawa U
FAU - Yonezawa, Kazuyoshi
AU  - Yonezawa K
LA  - eng
GR  - P30 DK040561/DK/NIDDK NIH HHS/United States
GR  - DK 17776/DK/NIDDK NIH HHS/United States
GR  - P30 DK040561-12/DK/NIDDK NIH HHS/United States
GR  - CA 73818/CA/NCI NIH HHS/United States
GR  - R01 CA073818/CA/NCI NIH HHS/United States
GR  - R37 DK017776/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20070521
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (AKT1S1 protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (EIF4EBP2 protein, human)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neuropeptides)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (RHEB protein, human)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Amino Acid Substitution
MH  - Eukaryotic Initiation Factors/genetics/metabolism
MH  - Gene Expression
MH  - HeLa Cells
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Monomeric GTP-Binding Proteins/genetics/metabolism
MH  - Multiprotein Complexes
MH  - Mutation, Missense
MH  - Neuropeptides/genetics/metabolism
MH  - Phosphoproteins/genetics/*metabolism
MH  - Phosphorylation
MH  - Protein Binding/physiology
MH  - Protein Processing, Post-Translational/*physiology
MH  - Proteins/genetics/*metabolism
MH  - RNA Interference
MH  - Ras Homolog Enriched in Brain Protein
MH  - Regulatory-Associated Protein of mTOR
MH  - Ribosomal Protein S6 Kinases/genetics/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/genetics/*metabolism
PMC - PMC3199301
MID - NIHMS330724
EDAT- 2007/05/23 09:00
MHDA- 2007/09/14 09:00
PMCR- 2011/10/21
CRDT- 2007/05/23 09:00
PHST- 2007/05/23 09:00 [pubmed]
PHST- 2007/09/14 09:00 [medline]
PHST- 2007/05/23 09:00 [entrez]
PHST- 2011/10/21 00:00 [pmc-release]
AID - S0021-9258(19)78026-0 [pii]
AID - 10.1074/jbc.M702636200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Jul 13;282(28):20329-39. doi: 10.1074/jbc.M702636200. Epub 2007 
      May 21.