PMID- 36095197
OWN - NLM
STAT- MEDLINE
DCOM- 20220914
LR  - 20231108
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 38
DP  - 2022 Sep 20
TI  - Tissue-restricted inhibition of mTOR using chemical genetics.
PG  - e2204083119
LID - 10.1073/pnas.2204083119 [doi]
LID - e2204083119
AB  - Mammalian target of rapamycin (mTOR) is a highly conserved eukaryotic protein 
      kinase that coordinates cell growth and metabolism, and plays a critical role in 
      cancer, immunity, and aging. It remains unclear how mTOR signaling in individual 
      tissues contributes to whole-organism processes because mTOR inhibitors, like the 
      natural product rapamycin, are administered systemically and target multiple 
      tissues simultaneously. We developed a chemical-genetic system, termed selecTOR, 
      that restricts the activity of a rapamycin analog to specific cell populations 
      through targeted expression of a mutant FKBP12 protein. This analog has reduced 
      affinity for its obligate binding partner FKBP12, which reduces its ability to 
      inhibit mTOR in wild-type cells and tissues. Expression of the mutant FKBP12, 
      which contains an expanded binding pocket, rescues the activity of this rapamycin 
      analog. Using this system, we show that selective mTOR inhibition can be achieved 
      in Saccharomyces cerevisiae and human cells, and we validate the utility of our 
      system in an intact metazoan model organism by identifying the tissues 
      responsible for a rapamycin-induced developmental delay in Drosophila.
FAU - Wassarman, Douglas R
AU  - Wassarman DR
AUID- ORCID: 0000-0002-6922-9378
AD  - Department of Cellular and Molecular Pharmacology, University of California, San 
      Francisco, CA 94158.
AD  - HHMI, University of California, San Francisco, CA 94158.
FAU - Bankapalli, Kondalarao
AU  - Bankapalli K
AD  - Department of Genome Sciences, University of Washington, Seattle, WA 98195.
FAU - Pallanck, Leo J
AU  - Pallanck LJ
AD  - Department of Genome Sciences, University of Washington, Seattle, WA 98195.
FAU - Shokat, Kevan M
AU  - Shokat KM
AD  - Department of Cellular and Molecular Pharmacology, University of California, San 
      Francisco, CA 94158.
AD  - HHMI, University of California, San Francisco, CA 94158.
LA  - eng
GR  - RF1 AG057330/AG/NIA NIH HHS/United States
GR  - T32 GM145460/GM/NIGMS NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R01 CA221969/CA/NCI NIH HHS/United States
GR  - F31 CA243439/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220912
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 5.2.1.- (Tacrolimus Binding Protein 1A)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Humans
MH  - Organ Specificity
MH  - Phosphorylation
MH  - *Protein Kinase Inhibitors/pharmacology
MH  - Signal Transduction
MH  - *Sirolimus/analogs & derivatives/pharmacology
MH  - *TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics
MH  - Tacrolimus Binding Protein 1A/genetics/metabolism
PMC - PMC9499525
OTO - NOTNLM
OT  - Drosophila
OT  - kinase inhibitor
OT  - mTOR
OT  - rapamycin
OT  - tissue specific
COIS- Competing interest statement: The authors declare a competing interest. K.M.S. is 
      an inventor on patents owned by University of California, San Francisco, covering 
      mTOR targeting small molecules licensed to Calithera Biosciences and Revolution 
      Medicines. K.M.S. has consulting agreements for the following companies, which 
      involve monetary and/or stock compensation: Revolution Medicines, Black Diamond 
      Therapeutics, BridGene Biosciences, Denali Therapeutics, Dice Molecules, eFFECTOR 
      Therapeutics, Erasca, Genentech/Roche, Janssen Pharmaceuticals, Kumquat 
      Biosciences, Kura Oncology, Mitokinin, Type6 Therapeutics, Venthera, Wellspring 
      Biosciences (Araxes Pharma), Turning Point, Ikena, Initial Therapeutics, and 
      BioTheryX.
EDAT- 2022/09/13 06:00
MHDA- 2022/09/15 06:00
PMCR- 2022/09/12
CRDT- 2022/09/12 15:23
PHST- 2022/09/12 15:23 [entrez]
PHST- 2022/09/13 06:00 [pubmed]
PHST- 2022/09/15 06:00 [medline]
PHST- 2022/09/12 00:00 [pmc-release]
AID - 202204083 [pii]
AID - 10.1073/pnas.2204083119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Sep 20;119(38):e2204083119. doi: 
      10.1073/pnas.2204083119. Epub 2022 Sep 12.