title: mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry.
abstract: Variants in the IMP2 (insulin-like growth factor 2 [IGF2] mRNA-binding protein 2) gene are implicated in susceptibility to type 2 diabetes. We describe the ability of mammalian target of rapamycin (mTOR) to regulate the cap-independent translation of IGF2 mRNA through phosphorylation of IMP2, an oncofetal RNA-binding protein. IMP2 is doubly phosphorylated in a rapamycin-inhibitable, amino acid-dependent manner in cells and by mTOR in vitro. Double phosphorylation promotes IMP2 binding to the IGF2 leader 3 mRNA 5' untranslated region, and the translational initiation of this mRNA through eIF-4E- and 5' cap-independent internal ribosomal entry. Unexpectedly, the interaction of IMP2 with mTOR complex 1 occurs through mTOR itself rather than through raptor. Whereas depletion of mTOR strongly inhibits IMP2 phosphorylation in cells, comparable depletion of raptor has no effect; moreover, the ability of mTOR to phosphorylate IMP2 in vitro is unaffected by the elimination of raptor. Dual phosphorylation of IMP2 at the mTOR sites is evident in the mouse embryo, likely coupling nutrient sufficiency to IGF2 expression and fetal growth. Doubly phosphorylated IMP2 is also widely expressed in adult tissues, including islets of Langerhans.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Dai
authors.forename: Joseph
authors.initials: J
authors.lastname: Rapley
authors.forename: Matthew
authors.initials: M
authors.lastname: Angel
authors.forename: M Fatih
authors.initials: MF
authors.lastname: Yanik
authors.forename: Michael D
authors.initials: MD
authors.lastname: Blower
authors.forename: Joseph
authors.initials: J
authors.lastname: Avruch
mesh_terms: D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000076223:Regulatory-Associated Protein of mTOR; D012270:Ribosomes / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D020121:5' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents; C035170:IGF2 protein, human; C513121:IGF2 protein, mouse; C498779:IGF2BP2 protein, human; C559768:IGF2BP2 protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D007335:Insulin-Like Growth Factor II; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus