The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity.
The eukaryotic translation initiation factor 4B (eIF4B) plays a critical role in recruiting the 40S ribosomal subunit to the mRNA. In response to insulin, eIF4B is phosphorylated on Ser422 by S6K in a rapamycin-sensitive manner. Here we demonstrate that the p90 ribosomal protein S6 kinase (RSK) phosphorylates eIF4B on the same residue. The relative contribution of the RSK and S6K modules to the phosphorylation of eIF4B is growth factor-dependent, and the two phosphorylation events exhibit very different kinetics. The S6K and RSK proteins are members of the AGC protein kinase family, and require PDK1 phosphorylation for activation. Consistent with this requirement, phosphorylation of eIF4B Ser422 is abrogated in PDK1 null embryonic stem cells. Phosphorylation of eIF4B on Ser422 by RSK and S6K is physiologically significant, as it increases the interaction of eIF4B with the eukaryotic translation initiation factor 3.
Shahbazian
David
D
Department of Biochemistry, McGill Cancer Centre, McGill University, Montreal, Quebec, Canada.
Roux
Philippe P
PP
Mieulet
Virginie
V
Cohen
Michael S
MS
Raught
Brian
B
Taunton
Jack
J
Hershey
John W B
JW
Blenis
John
J
Pende
Mario
M
Sonenberg
Nahum
N
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000737:chemistry / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000737:chemistry / Q000172:deficiency; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D064413:3-Phosphoinositide-Dependent Protein Kinases; D039621:Eukaryotic Initiation Factor-3; D039642:Eukaryotic Initiation Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D010768:Phosphoserine; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C031799:eIF-4B; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; C069329:RPS6KA1 protein, human; C512964:Rps6ka1 protein, mouse; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3