PMID- 33872697
OWN - NLM
STAT- MEDLINE
DCOM- 20220331
LR  - 20230505
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Print)
IS  - 0898-6568 (Linking)
VI  - 84
DP  - 2021 Aug
TI  - Glucagon transiently stimulates mTORC1 by activation of an EPAC/Rap1 signaling 
      axis.
PG  - 110010
LID - S0898-6568(21)00098-X [pii]
LID - 10.1016/j.cellsig.2021.110010 [doi]
AB  - Activation of the protein kinase mechanistic target of rapamycin (mTOR) in both 
      complexes 1 and 2 (mTORC1/2) in the liver is repressed during fasting and rapidly 
      stimulated in response to a meal. The effect of feeding on hepatic mTORC1/2 is 
      attributed to an increase in plasma levels of nutrients, such as amino acids, and 
      insulin. By contrast, fasting is associated with elevated plasma levels of 
      glucagon, which is conventionally viewed as having a counter-regulatory role to 
      insulin. More recently an expanded role for glucagon action in post-prandial 
      metabolism has been demonstrated. Herein we investigated the impact of insulin 
      and glucagon on mTORC1/2 activation. In H4IIE and HepG2 cultures, insulin 
      enhanced phosphorylation of the mTORC1 substrates S6K1 and 4E-BP1. Surprisingly, 
      the effect of glucagon on mTORC1 was biphasic, wherein there was an acute 
      increase in phosphorylation of S6K1 and 4E-BP1 over the first hour of exposure, 
      followed by latent suppression. The transient stimulatory effect of glucagon on 
      mTORC1 was not additive with insulin, suggesting convergent signaling. Glucagon 
      enhanced cAMP levels and mTORC1 stimulation required activation of the glucagon 
      receptor, PI3K/Akt, and exchange protein activated by cAMP (EPAC). EPAC acts as 
      the guanine nucleotide exchange factor for the small GTPase Rap1. Rap1 expression 
      enhanced S6K1 phosphorylation and glucagon addition to culture medium promoted 
      Rap1-GTP loading. Signaling through mTORC1 acts to regulate protein synthesis and 
      we found that glucagon promoted an EPAC-dependent increase in protein synthesis. 
      Overall, the findings support that glucagon elicits acute activation of mTORC1/2 
      by an EPAC-dependent increase in Rap1-GTP.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Sunilkumar, Siddharth
AU  - Sunilkumar S
AD  - Department of Cellular and Molecular Physiology, Penn State College of Medicine, 
      Hershey, PA 17033, United States of America.
FAU - Kimball, Scot R
AU  - Kimball SR
AD  - Department of Cellular and Molecular Physiology, Penn State College of Medicine, 
      Hershey, PA 17033, United States of America.
FAU - Dennis, Michael D
AU  - Dennis MD
AD  - Department of Cellular and Molecular Physiology, Penn State College of Medicine, 
      Hershey, PA 17033, United States of America. Electronic address: mdennis@psu.edu.
LA  - eng
GR  - R01 DK015658/DK/NIDDK NIH HHS/United States
GR  - R56 DK094141/DK/NIDDK NIH HHS/United States
GR  - R01 EY029702/EY/NEI NIH HHS/United States
GR  - S10 OD026980/OD/NIH HHS/United States
GR  - R01 DK013499/DK/NIDDK NIH HHS/United States
GR  - R01 DK094141/DK/NIDDK NIH HHS/United States
GR  - R13 DK126105/DK/NIDDK NIH HHS/United States
GR  - R01 GM039277/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210417
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 9007-92-5 (Glucagon)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - *Glucagon/metabolism/pharmacology
MH  - Guanine Nucleotide Exchange Factors/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - *Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Signal Transduction
PMC - PMC8169602
MID - NIHMS1696861
OTO - NOTNLM
OT  - Cyclic AMP
OT  - Diabetes
OT  - Glucagon
OT  - Insulin
OT  - Liver
OT  - Protein synthesis
COIS- Disclosures. No conflicts of interest, financial or otherwise, are declared by 
      the authors.
EDAT- 2021/04/20 06:00
MHDA- 2022/04/01 06:00
PMCR- 2022/08/01
CRDT- 2021/04/19 20:13
PHST- 2021/01/22 00:00 [received]
PHST- 2021/04/12 00:00 [revised]
PHST- 2021/04/13 00:00 [accepted]
PHST- 2021/04/20 06:00 [pubmed]
PHST- 2022/04/01 06:00 [medline]
PHST- 2021/04/19 20:13 [entrez]
PHST- 2022/08/01 00:00 [pmc-release]
AID - S0898-6568(21)00098-X [pii]
AID - 10.1016/j.cellsig.2021.110010 [doi]
PST - ppublish
SO  - Cell Signal. 2021 Aug;84:110010. doi: 10.1016/j.cellsig.2021.110010. Epub 2021 
      Apr 17.