TORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide. EMBO J 29, 3939-51

Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
The EMBO Journal (Impact Factor: 10.43). 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.

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Available from: Philippe P. Roux, Sep 05, 2014
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    • "mTORC2 phosphorylates several AGC kinases , including Akt, PKC and SGK1, and thereby regulates cell survival and cytoskeletal organization [53] [54] [55] [56]. mTORC2 was also reported to associate with the ribosome in response to growth factors [57], where it phosphorylates residues in nascent polypeptide chains that contribute to proper protein folding [58]. mTORC1 and mTORC2 contain shared protein partners, including mTOR, mLST8 (mammalian lethal with Sec13 protein 8) and Deptor (DEP-domain-containing mTOR-interacting protein) [52]. "
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    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 · 6.33 Impact Factor
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    • "Mammalian TORC2 is required for the phosphorylation of Akt and cPKC at the turn motif (TM) site [12, 16]. Mammalian TORC2 interacts with actively translating ribosomes and phosphorylates the TM site of newly synthesized Akt and cPKC polypeptides during translation [17], which promotes the proper folding of newly synthesized Akt or cPKC polypeptides. However, the stability of Akt proteins may be rescued by association with the chaperone protein HSP90 when Akt is lacking TM phosphorylation [16]. "
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    ABSTRACT: Constitutive activation of Akt is believed to be an oncogenic signal in multiple myeloma and is associated with poor patient prognosis and resistance to available treatment. The stability of Akt proteins is regulated by phosphorylating the highly conserved turn motif (TM) of these proteins and the chaperone protein HSP90. In this study we investigate the antitumor effects of inhibiting mTORC2 plus HSP90 in myeloma cell lines. We show that chronic exposure of cells to rapamycin can inhibit mTORC2 pathway, and AKT will be destabilized by administration of the HSP90 inhibitor 17-allylamino-geldanamycin (17-AAG). Finally, we show that the rapamycin synergizes with 17-AAG and inhibits myeloma cells growth and promotes cell death to a greater extent than either drug alone. Our studies provide a clinical rationale of use mTOR inhibitors and chaperone protein inhibitors in combination regimens for the treatment of human blood cancers.
    BioMed Research International 08/2014; 2014:190629. DOI:10.1155/2014/190629 · 2.71 Impact Factor
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    • "Furthermore , this complex is activated by plasma membrane stress, which stems from cell surface expansion during growth, or from chemical or mechanical stress on the plasma membrane (Berchtold et al, 2012). Finally, one study suggested that contacts between ScTORC2 and ribosomes activate the kinase, a mechanism possibly conserved in human cells (Oh et al, 2010; Zinzalla et al, 2011). In S. pombe, disruption of SpTORC2 is non-lethal but results in a delayed entrance into mitosis and generates slightly elongated cells (Weisman & Choder, 2001; Ikeda et al, 2008; Ikai et al, 2011). "
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    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 · 8.67 Impact Factor
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