PMID- 31530866
OWN - NLM
STAT- MEDLINE
DCOM- 20201030
LR  - 20211204
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Sep 17
TI  - TBK1 Limits mTORC1 by Promoting Phosphorylation of Raptor Ser877.
PG  - 13470
LID - 10.1038/s41598-019-49707-8 [doi]
LID - 13470
AB  - While best known for its role in the innate immune system, the TANK-binding 
      kinase 1 (TBK1) is now known to play a role in modulating cellular growth and 
      autophagy. One of the major ways that TBK1 accomplishes this task is by 
      modulating the mechanistic Target of Rapamycin (mTOR), a master regulator that 
      when activated promotes cell growth and inhibits autophagy. However, whether TBK1 
      promotes or inhibits mTOR activity is highly cell type and context dependent. To 
      further understand the mechanism whereby TBK1 regulates mTOR, we tested the 
      hypothesis that TBK1 phosphorylates a key component of the mTOR complex 1 
      (mTORC1), Raptor. Using kinase assays coupled with mass spectrometry, we mapped 
      the position of the TBK1 dependent phosphorylation sites on Raptor in vitro. 
      Among the sites identified in vitro, we found that TBK1 promotes Raptor Ser877 
      phosphorylation in cells both basally and in response to pathogen-associated 
      molecules known to induce TBK1 activity. The levels of Raptor Ser877 
      phosphorylation were inversely correlated with the levels of mTOR activity. 
      Expression of a mutant Raptor that could not be phosphorylated at Ser877 led to 
      an increase in mTORC1 activity. We conclude that TBK1 limits mTORC1 activity by 
      promoting Raptor Ser877 phosphorylation.
FAU - Antonia, Ricardo J
AU  - Antonia RJ
AUID- ORCID: 0000-0003-2864-8098
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC, USA.
AD  - The Helen Diller Family Comprehensive Cancer Center, The University of California 
      San Francisco, San Francisco, California, USA.
FAU - Castillo, Johnny
AU  - Castillo J
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC, USA.
FAU - Herring, Laura E
AU  - Herring LE
AUID- ORCID: 0000-0003-4496-7312
AD  - UNC Proteomics Core Facility, Department of Pharmacology, University of North 
      Carolina at Chapel Hill, Chapel Hill, USA.
FAU - Serafin, D Stephen
AU  - Serafin DS
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC, USA.
AD  - Department of Cell Biology and Physiology, University of North Carolina at Chapel 
      Hill, Chapel Hill, USA.
FAU - Liu, Pengda
AU  - Liu P
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC, USA.
AD  - Department of Biochemistry and Biophysics, University of North Carolina at Chapel 
      Hill, Chapel Hill, USA.
FAU - Graves, Lee M
AU  - Graves LM
AD  - UNC Proteomics Core Facility, Department of Pharmacology, University of North 
      Carolina at Chapel Hill, Chapel Hill, USA.
FAU - Baldwin, Albert S
AU  - Baldwin AS
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel 
      Hill, Chapel Hill, NC, USA. albert_baldwin@med.unc.edu.
FAU - Hagan, Robert S
AU  - Hagan RS
AUID- ORCID: 0000-0002-1504-0086
AD  - Division of Pulmonary Diseases and Critical Care Medicine, Department of 
      Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA. 
      robhagan@email.unc.edu.
AD  - Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, 
      NC, 27599, USA. robhagan@email.unc.edu.
LA  - eng
GR  - K08 HL143271/HL/NHLBI NIH HHS/United States
GR  - R35 CA197684/CA/NCI NIH HHS/United States
GR  - T32 CA071341/CA/NCI NIH HHS/United States
GR  - P30 CA016086/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 - 20190917
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TBK1 protein, human)
SB  - IM
MH  - Amino Acid Sequence
MH  - Cell Line
MH  - Enzyme Activation
MH  - Humans
MH  - Immunity, Innate
MH  - Mass Spectrometry
MH  - Mechanistic Target of Rapamycin Complex 1/chemistry/*metabolism
MH  - Models, Molecular
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Serine-Threonine Kinases/chemistry/*metabolism
MH  - Regulatory-Associated Protein of mTOR/chemistry/*metabolism
MH  - Serine/*metabolism
MH  - Signal Transduction
MH  - Structure-Activity Relationship
PMC - PMC6748941
COIS- The authors declare no competing interests.
EDAT- 2019/09/19 06:00
MHDA- 2020/10/31 06:00
PMCR- 2019/09/17
CRDT- 2019/09/19 06:00
PHST- 2018/09/04 00:00 [received]
PHST- 2019/08/29 00:00 [accepted]
PHST- 2019/09/19 06:00 [entrez]
PHST- 2019/09/19 06:00 [pubmed]
PHST- 2020/10/31 06:00 [medline]
PHST- 2019/09/17 00:00 [pmc-release]
AID - 10.1038/s41598-019-49707-8 [pii]
AID - 49707 [pii]
AID - 10.1038/s41598-019-49707-8 [doi]
PST - epublish
SO  - Sci Rep. 2019 Sep 17;9(1):13470. doi: 10.1038/s41598-019-49707-8.