Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney

Laura R. Pearce, Eeva M. Sommer, Kei Sakamoto, Stephan Wullschleger, Dario R. Alessi

    Research output: Contribution to journalArticle

    102 Citations (Scopus)

    Abstract

    The mTOR (mammalian target of rapamycin) protein kinase is an important regulator of cell growth and is a key target for therapeutic intervention in cancer. Two complexes of mTOR have been identified: complex 1 (mTORC1), consisting of mTOR, Raptor (regulatory associated protein of mTOR) and mLST8 (mammalian lethal with SEC 13 protein 8) and complex 2 (mTORC2) consisting of mTOR, Rictor (rapamycin-insensitive companion of mTOR), Sin I (stress-activated protein kinase-interacting protein 1), mLST8 and Protor-1 or Protor-2. Both complexes phosphorylate the hydrophobic motifs of AGC kinase family members: mTORC1 phosphorylates S6K (S6 kinase), whereas mTORC2 regulates phosphorylation of Akt, PKC alpha (protein kinase C alpha) and SGK1 (serum- and glucocorticoid-induced protein kinase 1). To investigate the roles of the Protor isoforms, we generated single as well as double Protor-1- and Protor-2-knockout mice and studied how activation of known mTORC2 substrates was affected. We observed that loss of Protor-1 and/or Protor-2 did not affect the expression of the other mTORC2 components, nor their ability to assemble into an active complex. Moreover, Protor knockout mice display no defects in the phosphorylation of Akt and PKC alpha at their hydrophobic or turn motifs. Strikingly, we observed that Protor-1 knockout mice displayed markedly reduced hydrophobic motif phosphorylation of SGK1 and its physiological substrate NDRG1 (N-Myc downregulated gene I) in the kidney. Taken together, these results suggest that Protor-1 may play a role in enabling mTORC2 to efficiently activate SGK1, at least in the kidney.

    Original languageEnglish
    Pages (from-to)169-179
    Number of pages11
    JournalBiochemical Journal
    Volume436
    Early online date18 Mar 2011
    DOIs
    Publication statusPublished - 15 May 2011

    Keywords

    • Mammalian target of rapamycin (mTOR)
    • Mammalian target of rapamycin complex 2 (mTORC2)
    • N-Myc down-regulated gene 1 (NDRG1)
    • Phosphoinositide 3-kinase (PI3K)
    • Protor/PRR5
    • Serum- and glucocorticoid-induced protein kinase 1 (SGK1)

    Cite this

    Pearce, Laura R. ; Sommer, Eeva M. ; Sakamoto, Kei ; Wullschleger, Stephan ; Alessi, Dario R. / Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. In: Biochemical Journal. 2011 ; Vol. 436. pp. 169-179.
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    abstract = "The mTOR (mammalian target of rapamycin) protein kinase is an important regulator of cell growth and is a key target for therapeutic intervention in cancer. Two complexes of mTOR have been identified: complex 1 (mTORC1), consisting of mTOR, Raptor (regulatory associated protein of mTOR) and mLST8 (mammalian lethal with SEC 13 protein 8) and complex 2 (mTORC2) consisting of mTOR, Rictor (rapamycin-insensitive companion of mTOR), Sin I (stress-activated protein kinase-interacting protein 1), mLST8 and Protor-1 or Protor-2. Both complexes phosphorylate the hydrophobic motifs of AGC kinase family members: mTORC1 phosphorylates S6K (S6 kinase), whereas mTORC2 regulates phosphorylation of Akt, PKC alpha (protein kinase C alpha) and SGK1 (serum- and glucocorticoid-induced protein kinase 1). To investigate the roles of the Protor isoforms, we generated single as well as double Protor-1- and Protor-2-knockout mice and studied how activation of known mTORC2 substrates was affected. We observed that loss of Protor-1 and/or Protor-2 did not affect the expression of the other mTORC2 components, nor their ability to assemble into an active complex. Moreover, Protor knockout mice display no defects in the phosphorylation of Akt and PKC alpha at their hydrophobic or turn motifs. Strikingly, we observed that Protor-1 knockout mice displayed markedly reduced hydrophobic motif phosphorylation of SGK1 and its physiological substrate NDRG1 (N-Myc downregulated gene I) in the kidney. Taken together, these results suggest that Protor-1 may play a role in enabling mTORC2 to efficiently activate SGK1, at least in the kidney.",
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    Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. / Pearce, Laura R.; Sommer, Eeva M.; Sakamoto, Kei; Wullschleger, Stephan; Alessi, Dario R.

    In: Biochemical Journal, Vol. 436, 15.05.2011, p. 169-179.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney

    AU - Pearce, Laura R.

    AU - Sommer, Eeva M.

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    AU - Wullschleger, Stephan

    AU - Alessi, Dario R.

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    KW - Mammalian target of rapamycin complex 2 (mTORC2)

    KW - N-Myc down-regulated gene 1 (NDRG1)

    KW - Phosphoinositide 3-kinase (PI3K)

    KW - Protor/PRR5

    KW - Serum- and glucocorticoid-induced protein kinase 1 (SGK1)

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