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Sci. Signal., 7 December 2010
Vol. 3, Issue 151, p. ec369
[DOI: 10.1126/scisignal.3151ec369]


Cell Biology mTORC2 Akt-ing at the Ribosome

Annalisa M. VanHook

Science Signaling, AAAS, Washington, DC 20005, USA

Signaling through the mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) controls various cellular growth, metabolic, and survival processes. mTORC1 stimulates translational initiation by phosphorylating key translation initiation factors and ribosomal regulators; mTORC2 phosphorylates several targets, including the hydrophobic motif (HM) and turn motif (TM) of the AGC family kinase Akt. Phosphorylation of the TM is constitutive, but the mechanism is unclear, because the turn motif is inaccessible in native Akt. Oh et al. report that mTORC2 associated with active ribosomes (polysomes) to phosphorylate the Akt TM during translation. TM-phosphorylated Akt was associated with the polysome-containing fraction of HeLa cell extracts, and HM-phosphorylated Akt was identified primarily in cytosolic fractions, consistent with the TM being phosphorylated during translation and the HM afterward. The kinetics of TM phosphorylation when Akt was translated in vitro was consistent with cotranslational phosphorylation, and halting translation with neomycin and RNase prevented TM phosphorylation. The TM site is located near the C-terminal tail of the Akt transcript, and shortening the tail prevented TM phosphorylation, presumably because the phosphorylation site remained inside the ribosome tunnel through which nascent peptides are extruded during the final stages of translation. Inhibiting mTOR, the kinase component of both mTORCs, with Torin1 prevented TM phosphorylation, but the mTORC1-specific inhibitor rapamycin did not, indicating that mTOR activity within the mTORC2 context was responsible for TM phosphorylation. mTORC2 did not interact with the translation initiation complex in fibroblast extracts, but mTOR and the mTORC2 component rictor associated with the ribosomal protein rpL23a, which is located at the exit of the ribosome tunnel. These results shed light on the mechanism by which mTORC2 phosphorylates two motifs that differ in sequence and in accessibility and demonstrate that mTOR-containing complexes affect translation both at the point of initiation (mTORC1) and during elongation (mTORC2).

W. J. Oh, C.-c. Wu, S. J. Kim, V. Facchinetti, L.-A. Julien, M. Finlan, P. P. Roux, B. Su, E. Jacinto, mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J. 29, 3939–3951 (2010). [PubMed]

Citation: A. M. VanHook, mTORC2 Akt-ing at the Ribosome. Sci. Signal. 3, ec369 (2010).

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