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Research article

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
Biochemical Journal May 15, 2011, 436 (1) 169-179; DOI: 10.1042/BJ20102103
Laura R. Pearce
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Eeva M. Sommer
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Kei Sakamoto
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Stephan Wullschleger
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Dario R. Alessi
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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  • For correspondence: d.r.alessi@dundee.ac.uk
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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 SEC13 protein 8) and complex 2 (mTORC2) consisting of mTOR, Rictor (rapamycin-insensitive companion of mTOR), Sin1 (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, PKCα (protein kinase Cα) 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 PKCα 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 1) 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.

  • 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)

Abbreviations: ENaC, epithelial sodium channel; FoxO, forkhead box O; GST, glutathione transferase; HEK, human embryonic kidney; IGF1, insulin-like growth factor 1; MEF, mouse embryonic fibroblast; mLST8, mammalian lethal with SEC13 protein 8; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; NDRG1, N-Myc down-regulated gene 1; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PRAS40, proline-rich Akt substrate of 40 kDa; Raptor, regulatory associated protein of mTOR; Rictor, rapamycin-insensitive companion of mTOR; S6K, S6 kinase; SGK, serum- and glucocorticoid-induced protein kinase; Sin1, stress-activated protein kinase-interacting protein 1

  • © The Authors Journal compilation © 2011 Biochemical Society
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May 2011

Volume: 436 Issue: 1

Biochemical Journal: 436 (1)
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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
Biochemical Journal May 2011, 436 (1) 169-179; DOI: 10.1042/BJ20102103
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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
Biochemical Journal May 2011, 436 (1) 169-179; DOI: 10.1042/BJ20102103

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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)

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