Glucagon represses signaling through the mammalian target of rapamycin in rat liver by activating AMP-activated protein kinase.
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.
Kimball
Scot R
SR
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. skimball@psu.edu
Siegfried
Brett A
BA
Jefferson
Leonard S
LS
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005934:Glucagon / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases
D000596:Amino Acids; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D005934:Glucagon; D011494:Protein Kinases; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C488755:Stk11 protein, rat; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D017868:Cyclic AMP-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases