mTOR-mediated regulation of translation factors by amino acids.
The mammalian-target-of-rapamycin (mTOR) is a multidomain protein that is important in regulating several components of the translational machinery. mTOR signalling is stimulated by hormones (e.g., insulin) and by amino acids. Our recent data suggest that TOR signalling responds to intracellular amino acids rather than to external amino acid levels. The translational repressor eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is regulated through mTOR and undergoes phosphorylation at multiple sites, which affects its function. It contains two regulatory motifs: the C-terminal TOS motif interacts with the mTOR-binding partner, raptor, and mediates phosphorylation of specific sites in 4E-BP1. However, the N-terminal RAIP motif affects a larger range of mTOR-regulated sites. Since this motif does not bind raptor, mTOR must signal to 4E-BP1 via additional mechanisms that are independent of raptor. The kinase that phosphorylates and inhibits elongation factor 2 (eEF2 kinase) is inactivated by insulin via mTOR. Insulin decreases the ability of eEF2 kinase to bind calmodulin, its essential activator, and this effect requires mTOR signalling and a novel phosphorylation site in eEF2 kinase, Ser78. Ser78 is not phosphorylated by known components of the mTOR pathway implying the existence of novel mTOR-regulated kinases that control eEF2 kinase.
Proud
Christopher G
CG
Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. c.g.proud@dundee.ac.uk
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D018797:Cell Cycle Proteins; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D007328:Insulin; D020652:Peptide Elongation Factor 2; D010750:Phosphoproteins; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases