PMID- 36735494
OWN - NLM
STAT- MEDLINE
DCOM- 20230315
LR  - 20230523
IS  - 1939-4586 (Electronic)
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 34
IP  - 4
DP  - 2023 Apr 1
TI  - Arf5-mediated regulation of mTORC1 at the plasma membrane.
PG  - ar23
LID - 10.1091/mbc.E22-07-0302 [doi]
LID - ar23
AB  - The mechanistic target of rapamycin (mTOR) kinase regulates a major signaling 
      pathway in eukaryotic cells. In addition to regulation of mTORC1 at lysosomes, 
      mTORC1 is also localized at other locations. However, little is known about the 
      recruitment and activation of mTORC1 at nonlysosomal sites. To identify 
      regulators of mTORC1 recruitment to nonlysosomal compartments, novel interacting 
      partners with the mTORC1 subunit, Raptor, were identified using 
      immunoprecipitation and mass spectrometry. We show that one of the interacting 
      partners, Arf5, is a novel regulator of mTORC1 signaling at plasma membrane 
      ruffles. Arf5-GFP localizes with endogenous mTOR at PI3,4P2-enriched membrane 
      ruffles together with the GTPase required for mTORC1 activation, Rheb. Knockdown 
      of Arf5 reduced the recruitment of mTOR to membrane ruffles. The activation of 
      mTORC1 at membrane ruffles was directly demonstrated using a plasma 
      membrane-targeted mTORC1 biosensor, and Arf5 was shown to enhance the 
      phosphorylation of the mTORC1 biosensor substrate. In addition, endogenous Arf5 
      was shown to be required for rapid activation of mTORC1-mediated S6 
      phosphorylation following nutrient starvation and refeeding. Our findings reveal 
      a novel Arf5-dependent pathway for recruitment and activation of mTORC1 at plasma 
      membrane ruffles, a process relevant for spatial and temporal regulation of 
      mTORC1 by receptor and nutrient stimuli.
FAU - Makhoul, Christian
AU  - Makhoul C
AD  - Department of Biochemistry and Pharmacology and Bio21 Molecular Science and 
      Biotechnology Institute and.
FAU - Houghton, Fiona J
AU  - Houghton FJ
AD  - Department of Biochemistry and Pharmacology and Bio21 Molecular Science and 
      Biotechnology Institute and.
FAU - Hinde, Elizabeth
AU  - Hinde E
AD  - Department of Biochemistry and Pharmacology and Bio21 Molecular Science and 
      Biotechnology Institute and.
AD  - School of Physics, The University of Melbourne, Melbourne, Victoria 3010, 
      Australia.
FAU - Gleeson, Paul A
AU  - Gleeson PA
AD  - Department of Biochemistry and Pharmacology and Bio21 Molecular Science and 
      Biotechnology Institute and.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230203
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neuropeptides)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (ADP-Ribosylation Factors)
SB  - IM
MH  - Cell Membrane/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - *Multiprotein Complexes/metabolism
MH  - *Neuropeptides/metabolism
MH  - Ras Homolog Enriched in Brain Protein/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - ADP-Ribosylation Factors/metabolism
PMC - PMC10092653
EDAT- 2023/02/04 06:00
MHDA- 2023/03/10 06:00
PMCR- 2023/05/22
CRDT- 2023/02/03 12:33
PHST- 2023/02/04 06:00 [pubmed]
PHST- 2023/03/10 06:00 [medline]
PHST- 2023/02/03 12:33 [entrez]
PHST- 2023/05/22 00:00 [pmc-release]
AID - E22-07-0302 [pii]
AID - 10.1091/mbc.E22-07-0302 [doi]
PST - ppublish
SO  - Mol Biol Cell. 2023 Apr 1;34(4):ar23. doi: 10.1091/mbc.E22-07-0302. Epub 2023 Feb 
      3.