Article

mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide

Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
The EMBO Journal (Impact Factor: 10.75). 11/2010; 29(23):3939-51. DOI: 10.1038/emboj.2010.271
Source: PubMed

ABSTRACT The mechanisms that couple translation and protein processing are poorly understood in higher eukaryotes. Although mammalian target of rapamycin (mTOR) complex 1 (mTORC1) controls translation initiation, the function of mTORC2 in protein synthesis remains to be defined. In this study, we find that mTORC2 can colocalize with actively translating ribosomes and can stably interact with rpL23a, a large ribosomal subunit protein present at the tunnel exit. Exclusively during translation of Akt, mTORC2 mediates phosphorylation of the nascent polypeptide at the turn motif (TM) site, Thr450, to avoid cotranslational Akt ubiquitination. Constitutive TM phosphorylation occurs because the TM site is accessible, whereas the hydrophobic motif (Ser473) site is concealed in the ribosomal tunnel. Thus, mTORC2 can function cotranslationally by phosphorylating residues in nascent chains that are critical to attain proper conformation. Our findings reveal that mTOR links protein production with quality control.

Download full-text

Full-text

Available from: Philippe P. Roux, Sep 05, 2014
0 Followers
 · 
131 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Messenger RNA (mRNA) translation is highly regulated in cells and plays an integral role in the overall process of gene expression. The initiation phase of translation is considered to be the most rate-limiting and is often targeted by oncogenic signaling pathways to promote global protein synthesis and the selective translation of tumor-promoting mRNAs. Translational control is a crucial component of cancer development as it allows cancer cells to adapt to the altered metabolism that is generally associated with the tumor state. The phosphoinositide 3-kinase (PI3K)/Akt and Ras/mitogen-activated protein kinase (MAPK) pathways are strongly implicated in cancer etiology, and they exert their biological effects by modulating both global and specific mRNA translation. In addition to having respective translational targets, these pathways also impinge on the mechanistic/mammalian target of rapamycin (mTOR), which acts as a critical signaling node linking nutrient sensing to the coordinated regulation of cellular metabolism. mTOR is best known as a central regulator of protein synthesis and has been implicated in an increasing number of pathological conditions, including cancer. In this article, we describe the current knowledge on the roles and regulation of mRNA translation by various oncogenic signaling pathways, as well as the relevance of these molecular mechanisms to human malignancies. This article is part of a Special Issue entitled: Translation and Cancer. Copyright © 2014. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 12/2014; 1849(7). DOI:10.1016/j.bbagrm.2014.11.006 · 5.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The inhibition of the central growth regulatory kinase TOR, which participates in two complexes, TORC1 and TORC2, has been a focus of metabolic and cancer studies for many years. Most studies have dealt with TORC1, the canonical target of rapamycin, and the role of this complex in autophagy, protein synthesis, and cell growth control. Recent work on TORC2 in budding and fission yeast species points to a conserved role of this lesser-known TOR complex in the survival of DNA damage. In budding yeast, TORC2 controls lipid biosynthesis and actin cytoskeleton through downstream AGC kinases, which are now, surprisingly, implicated in the survival of oxidative DNA damage. Preliminary data from mTORC2 modulation in cancer cells suggest that an extension to human chemotherapy is worth exploring.
    EMBO Molecular Medicine 07/2014; 6(8). DOI:10.15252/emmm.201403959 · 8.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mechanistic target of rapamcyin (mTOR) is a central player in cell growth throughout the organism. However, mTOR takes on an additional, more specialized role in the developed neuron, where it regulates the protein synthesis-dependent, plastic changes underlying learning and memory. mTOR is sequestered in two multiprotein complexes (mTORC1 and mTORC2) that have different substrate specificities, thus allowing for distinct functions at synapses. We will examine how learning activates the mTOR complexes, survey the critical effectors of this pathway in the context of synaptic plasticity, and assess whether mTOR plays an instructive or permissive role in generating molecular memory traces.
    Learning & memory (Cold Spring Harbor, N.Y.) 09/2013; 20(10):518-30. DOI:10.1101/lm.027664.112 · 4.38 Impact Factor