PMID- 37511253
OWN - NLM
STAT- MEDLINE
DCOM- 20230818
LR  - 20230818
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 14
DP  - 2023 Jul 15
TI  - Regulation of mTOR Signaling: Emerging Role of Cyclic Nucleotide-Dependent 
      Protein Kinases and Implications for Cardiometabolic Disease.
LID - 10.3390/ijms241411497 [doi]
LID - 11497
AB  - The mechanistic target of rapamycin (mTOR) kinase is a central regulator of cell 
      growth and metabolism. It is the catalytic subunit of two distinct large protein 
      complexes, mTOR complex 1 (mTORC1) and mTORC2. mTOR activity is subjected to 
      tight regulation in response to external nutrition and growth factor stimulation. 
      As an important mechanism of signaling transduction, the 'second messenger' 
      cyclic nucleotides including cAMP and cGMP and their associated cyclic 
      nucleotide-dependent kinases, including protein kinase A (PKA) and protein kinase 
      G (PKG), play essential roles in mediating the intracellular action of a variety 
      of hormones and neurotransmitters. They have also emerged as important regulators 
      of mTOR signaling in various physiological and disease conditions. However, the 
      mechanism by which cAMP and cGMP regulate mTOR activity is not completely 
      understood. In this review, we will summarize the earlier work establishing the 
      ability of cAMP to dampen mTORC1 activation in response to insulin and growth 
      factors and then discuss our recent findings demonstrating the regulation of mTOR 
      signaling by the PKA- and PKG-dependent signaling pathways. This signaling 
      framework represents a new non-canonical regulation of mTOR activity that is 
      independent of AKT and could be a novel mechanism underpinning the action of a 
      variety of G protein-coupled receptors that are linked to the mTOR signaling 
      network. We will further review the implications of these signaling events in the 
      context of cardiometabolic disease, such as obesity, non-alcoholic fatty liver 
      disease, and cardiac remodeling. The metabolic and cardiac phenotypes of mouse 
      models with targeted deletion of Raptor and Rictor, the two essential components 
      for mTORC1 and mTORC2, will be summarized and discussed.
FAU - Shi, Fubiao
AU  - Shi F
AD  - Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt 
      University Medical Center, Nashville, TN 37232, USA.
FAU - Collins, Sheila
AU  - Collins S
AUID- ORCID: 0000-0001-6812-8551
AD  - Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt 
      University Medical Center, Nashville, TN 37232, USA.
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 
      Nashville, TN 37232, USA.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20230715
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Nucleotides, Cyclic)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Cardiovascular Diseases
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/metabolism
MH  - *Multiprotein Complexes/metabolism
MH  - Nucleotides, Cyclic/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rapamycin-Insensitive Companion of mTOR Protein/metabolism
MH  - *Sirolimus
MH  - *TOR Serine-Threonine Kinases/metabolism
PMC - PMC10380887
OTO - NOTNLM
OT  - PKA
OT  - PKG
OT  - Raptor
OT  - Rictor
OT  - cAMP
OT  - cGMP
OT  - cardiac hypertrophy
OT  - fatty liver disease
OT  - mTOR
OT  - obesity
COIS- The authors declare no conflict of interest.
EDAT- 2023/07/29 11:53
MHDA- 2023/07/31 06:43
PMCR- 2023/07/15
CRDT- 2023/07/29 01:23
PHST- 2023/06/16 00:00 [received]
PHST- 2023/07/07 00:00 [revised]
PHST- 2023/07/13 00:00 [accepted]
PHST- 2023/07/31 06:43 [medline]
PHST- 2023/07/29 11:53 [pubmed]
PHST- 2023/07/29 01:23 [entrez]
PHST- 2023/07/15 00:00 [pmc-release]
AID - ijms241411497 [pii]
AID - ijms-24-11497 [pii]
AID - 10.3390/ijms241411497 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Jul 15;24(14):11497. doi: 10.3390/ijms241411497.