PMID- 15494402
OWN - NLM
STAT- MEDLINE
DCOM- 20050314
LR  - 20230815
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 279
IP  - 52
DP  - 2004 Dec 24
TI  - Glucagon represses signaling through the mammalian target of rapamycin in rat 
      liver by activating AMP-activated protein kinase.
PG  - 54103-9
AB  - The opposing actions of glucagon and insulin on glucose metabolism within the 
      liver are essential mechanisms for maintaining plasma glucose concentrations 
      within narrow limits. Less well studied are the counterregulatory actions of 
      glucagon on protein metabolism. In the present study, the effect of glucagon on 
      amino acid-induced signaling through the mammalian target of rapamycin (mTOR), an 
      important controller of the mRNA binding step in translation initiation, was 
      examined using the perfused rat liver as an experimental model. The results show 
      that amino acids enhance signaling through mTOR resulting in phosphorylation of 
      eukaryotic initiation factor 4E-binding protein (4E-BP)1, the 70-kDa ribosomal 
      protein (rp)S6 kinase, S6K1, and rpS6. In contrast, glucagon repressed both basal 
      and amino acid-induced signaling through mTOR, as assessed by changes in the 
      phosphorylation of 4E-BP1 and S6K1. The repression was associated with the 
      activation of protein kinase A and enhanced phosphorylation of LKB1 and the 
      AMP-activated protein kinase (AMPK). Surprisingly, the phosphorylation of two 
      S6K1 substrates, rpS6 and eukaryotic initiation factor 4B, was not repressed but 
      instead was increased by glucagon treatment, regardless of the amino acid 
      concentration. The latter finding could be explained by the glucagon-induced 
      phosphorylation of the ERK1 and the 90-kDa rpS6 kinase p90(rsk). Thus, glucagon 
      represses phosphorylation of 4E-BP1 and S6K1 through the activation of a protein 
      kinase A-LKB-AMPK-mTOR signaling pathway, while simultaneously enhancing 
      phosphorylation of other downstream effectors of mTOR through the activation of 
      the extracellular signal-regulated protein kinase 1-p90(rsk) signaling pathway. 
      Amino acids also enhance AMPK phosphorylation, although to a lesser extent than 
      glucagon and amino acids combined.
FAU - Kimball, Scot R
AU  - Kimball SR
AD  - Department of Cellular and Molecular Physiology, The Pennsylvania State 
      University College of Medicine, Hershey, Pennsylvania 17033, USA. 
      skimball@psu.edu
FAU - Siegfried, Brett A
AU  - Siegfried BA
FAU - Jefferson, Leonard S
AU  - Jefferson LS
LA  - eng
GR  - DK-13499/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20041019
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amino Acids)
RN  - 0 (Carrier Proteins)
RN  - 0 (Eif4ebp1 protein, rat)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Phosphoproteins)
RN  - 9007-92-5 (Glucagon)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (Stk11 protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - AMP-Activated Protein Kinases
MH  - Amino Acids/pharmacology
MH  - Animals
MH  - Carrier Proteins/metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - Enzyme Activation/drug effects
MH  - Glucagon/*pharmacology
MH  - Intracellular Signaling Peptides and Proteins
MH  - Liver/*drug effects/enzymology/metabolism
MH  - Male
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Multienzyme Complexes/*metabolism
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/*drug effects/physiology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Ribosomal Protein S6 Kinases, 90-kDa/metabolism
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases
EDAT- 2004/10/21 09:00
MHDA- 2005/03/15 09:00
CRDT- 2004/10/21 09:00
PHST- 2004/10/21 09:00 [pubmed]
PHST- 2005/03/15 09:00 [medline]
PHST- 2004/10/21 09:00 [entrez]
AID - S0021-9258(19)63167-4 [pii]
AID - 10.1074/jbc.M410755200 [doi]
PST - ppublish
SO  - J Biol Chem. 2004 Dec 24;279(52):54103-9. doi: 10.1074/jbc.M410755200. Epub 2004 
      Oct 19.