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Genes & Dev. 25 (11): 1159-1172

Copyright © 2011 by Cold Spring Harbor Laboratory Press.

mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry

Ning Dai1,2,3, Joseph Rapley1,2,3, Matthew Angel4, M. Fatih Yanik4, Michael D. Blower1,5,, and Joseph Avruch1,2,3,6

1 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
2 Diabetes Unit and Medical Services, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
3 Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA;
4 Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
5 Department of Genetics, Harvard Medical School, Boston, Massachusetts, 02115, USA

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.

Key Words: mTOR • IMP2 • amino acid-dependent phosphorylation • IGF2 • mRNA translation • internal ribosome entry • type 2 diabetes

Received for publication February 16, 2011. Accepted for publication April 11, 2011.

6 Corresponding author.

E-MAIL avruch{at}molbio.mgh.harvard.edu; FAX (617) 726-5649.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.2042311.

Supplemental material is available for this article.

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