mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.
In response to nutrients, energy sufficiency, hormones, and mitogenic agents, S6K1 phosphorylates several targets linked to translation. However, the molecular mechanisms whereby S6K1 is activated, encounters substrate, and contributes to translation initiation are poorly understood. We show that mTOR and S6K1 maneuver on and off the eukaryotic initiation factor 3 (eIF3) translation initiation complex in a signal-dependent, choreographed fashion. When inactive, S6K1 associates with the eIF3 complex, while the S6K1 activator mTOR/raptor does not. Cell stimulation promotes mTOR/raptor binding to the eIF3 complex and phosphorylation of S6K1 at its hydrophobic motif. Phosphorylation results in S6K1 dissociation, activation, and subsequent phosphorylation of its translational targets, including eIF4B, which is then recruited into the complex in a phosphorylation-dependent manner. Thus, the eIF3 preinitiation complex acts as a scaffold to coordinate a dynamic sequence of events in response to stimuli that promote efficient protein synthesis.
Holz
Marina K
MK
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ballif
Bryan A
BA
Gygi
Steven P
SP
Blenis
John
J
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008934:Mitogens / Q000494:pharmacology; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D010442:Peptide Chain Initiation, Translational; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012314:RNA Cap Analogs / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D039621:Eukaryotic Initiation Factor-3; D039642:Eukaryotic Initiation Factors; D006728:Hormones; D007328:Insulin; D008934:Mitogens; D046912:Multiprotein Complexes; D010703:Phorbol Esters; D021122:Protein Subunits; D011506:Proteins; D012314:RNA Cap Analogs; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; C031799:eIF-4B; C017516:7-methylguanosine triphosphate; D011494:Protein Kinases; C546842:MTOR protein, human; C069329:RPS6KA1 protein, human; D019893:Ribosomal Protein S6 Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus