PMID- 20457610
OWN - NLM
STAT- MEDLINE
DCOM- 20100824
LR  - 20221214
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 26
DP  - 2010 Jun 25
TI  - Regulation of mTORC1 by the Rab and Arf GTPases.
PG  - 19705-9
LID - 10.1074/jbc.C110.102483 [doi]
AB  - The mammalian target of rapamycin (mTOR) is a key cell growth regulator, which 
      forms two distinct functional complexes (mTORC1 and mTORC2). mTORC1, which is 
      directly inhibited by rapamycin, promotes cell growth by stimulating protein 
      synthesis and inhibiting autophagy. mTORC1 is regulated by a wide range of extra- 
      and intracellular signals, including growth factors, nutrients, and energy 
      levels. Precise regulation of mTORC1 is important for normal cellular physiology 
      and development, and dysregulation of mTORC1 contributes to hypertrophy and 
      tumorigenesis. In this study, we screened Drosophila small GTPases for their 
      function in TORC1 regulation and found that TORC1 activity is regulated by 
      members of the Rab and Arf family GTPases, which are key regulators of 
      intracellular vesicle trafficking. In mammalian cells, uncontrolled activation of 
      Rab5 and Arf1 strongly inhibit mTORC1 activity. Interestingly, the effect of Rab5 
      and Arf1 on mTORC1 is specific to amino acid stimulation, whereas glucose-induced 
      mTORC1 activation is not blocked by Rab5 or Arf1. Similarly, active Rab5 
      selectively inhibits mTORC1 activation by Rag GTPases, which are involved in 
      amino acid signaling, but does not inhibit the effect of Rheb, which directly 
      binds and activates mTORC1. Our data demonstrate a key role of Rab and Arf family 
      small GTPases and intracellular trafficking in mTORC1 activation, particularly in 
      response to amino acids.
FAU - Li, Li
AU  - Li L
AD  - Department of Pharmacology and Moores Cancer Center, University of California San 
      Diego, La Jolla, California 92093, USA.
FAU - Kim, Eunjung
AU  - Kim E
FAU - Yuan, Haixin
AU  - Yuan H
FAU - Inoki, Ken
AU  - Inoki K
FAU - Goraksha-Hicks, Pankuri
AU  - Goraksha-Hicks P
FAU - Schiesher, Rachel L
AU  - Schiesher RL
FAU - Neufeld, Thomas P
AU  - Neufeld TP
FAU - Guan, Kun-Liang
AU  - Guan KL
LA  - eng
GR  - R01 DK124709/DK/NIDDK NIH HHS/United States
GR  - GM51586/GM/NIGMS NIH HHS/United States
GR  - R01 GM051586/GM/NIGMS NIH HHS/United States
GR  - GM62694/GM/NIGMS NIH HHS/United States
GR  - R01 GM062509/GM/NIGMS NIH HHS/United States
GR  - R01 GM062694/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20100510
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amino Acids)
RN  - 0 (CRTC1 protein, human)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
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 (ADP-Ribosylation Factor 1)
RN  - EC 3.6.5.2 (rab5 GTP-Binding Proteins)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - ADP-Ribosylation Factor 1/genetics/*metabolism
MH  - Amino Acids/pharmacology
MH  - Animals
MH  - COS Cells
MH  - Cell Line
MH  - Chlorocebus aethiops
MH  - Glucose/pharmacology
MH  - HeLa Cells
MH  - Humans
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes
MH  - Mutation
MH  - Phosphorylation/drug effects
MH  - Protein Binding
MH  - Proteins
MH  - RNA Interference
MH  - Ribosomal Protein S6 Kinases/genetics/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/genetics/*metabolism
MH  - Transfection
MH  - rab5 GTP-Binding Proteins/genetics/*metabolism
PMC - PMC2888380
EDAT- 2010/05/12 06:00
MHDA- 2010/08/25 06:00
PMCR- 2011/06/25
CRDT- 2010/05/12 06:00
PHST- 2010/05/12 06:00 [entrez]
PHST- 2010/05/12 06:00 [pubmed]
PHST- 2010/08/25 06:00 [medline]
PHST- 2011/06/25 00:00 [pmc-release]
AID - S0021-9258(18)49644-5 [pii]
AID - C110.102483 [pii]
AID - 10.1074/jbc.C110.102483 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Jun 25;285(26):19705-9. doi: 10.1074/jbc.C110.102483. Epub 2010 
      May 10.