Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2

  • Nature volume 449, pages 366369 (20 September 2007)
  • doi:10.1038/nature06128
  • Download Citation
Published online:


During feeding, increases in circulating pancreatic insulin inhibit hepatic glucose output through the activation of the Ser/Thr kinase AKT and subsequent phosphorylation of the forkhead transcription factor FOXO1 (refs 1–3). Under fasting conditions, FOXO1 increases gluconeogenic gene expression in concert with the cAMP responsive coactivator TORC2 (refs 4–8). In response to pancreatic glucagon, TORC2 is de-phosphorylated at Ser 171 and transported to the nucleus, in which it stimulates the gluconeogenic programme by binding to CREB. Here we show in mice that insulin inhibits gluconeogenic gene expression during re-feeding by promoting the phosphorylation and ubiquitin-dependent degradation of TORC2. Insulin disrupts TORC2 activity by induction of the Ser/Thr kinase SIK2, which we show here undergoes AKT2-mediated phosphorylation at Ser 358. Activated SIK2 in turn stimulated the Ser 171 phosphorylation and cytoplasmic translocation of TORC2. Phosphorylated TORC2 was degraded by the 26S proteasome during re-feeding through an association with COP1, a substrate receptor for an E3 ligase complex that promoted TORC2 ubiquitination at Lys 628. Because TORC2 protein levels and activity were increased in diabetes owing to a block in TORC2 phosphorylation, our results point to an important role for this pathway in the maintenance of glucose homeostasis.

  • Subscribe to Nature for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


  1. 1.

    et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292, 1728–1731 (2001)

  2. 2.

    , & Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J. Biol. Chem. 274, 15982–15985 (1999)

  3. 3.

    et al. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKCλ/ζ. Cell Metab. 3, 343–353 (2006)

  4. 4.

    et al. CREB regulates hepatic gluconeogenesis via the co-activator PGC-1. Nature 413, 179–183 (2001)

  5. 5.

    et al. Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature 423, 550–555 (2003)

  6. 6.

    , , , & Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc. Natl Acad. Sci. USA 100, 11285–11290 (2003)

  7. 7.

    & More TORC for the gluconeogenic engine. Bioessays 28, 231–234 (2006)

  8. 8.

    et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005)

  9. 9.

    , & Regulatable promoters for use in gene therapy applications: modification of the 5′-flanking region of the CFTR gene with multiple cAMP response elements to support basal, low-level gene expression that can be upregulated by exogenous agents that raise intracellular levels of cAMP. Hum. Gene Ther. 7, 1883–1893 (1996)

  10. 10.

    et al. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119, 61–74 (2004)

  11. 11.

    & Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor requires nuclear-cytoplasmic trafficking of the von Hippel–Lindau tumor suppressor protein. Mol. Cell. Biol. 22, 5319–5336 (2002)

  12. 12.

    , & Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination. Mol. Cell. Biol. 23, 6396–6405 (2003)

  13. 13.

    , & Nucleocytoplasmic shuttling modulates activity and ubiquitination-dependent turnover of SUMO-specific protease 2. Mol. Cell. Biol. 26, 4675–4689 (2006)

  14. 14.

    , , & Identification of a structural motif that confers specific interaction with the WD40 repeat domain of Arabidopsis COP1. EMBO J. 20, 118–127 (2001)

  15. 15.

    et al. Characterization of human constitutive photomorphogenesis protein 1, a RING finger ubiquitin ligase that interacts with Jun transcription factors and modulates their transcriptional activity. J. Biol. Chem. 278, 19682–19690 (2003)

  16. 16.

    et al. Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. Science 303, 1371–1374 (2004)

  17. 17.

    et al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429, 86–92 (2004)

  18. 18.

    et al. TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312, 1763–1766 (2006)

  19. 19.

    et al. ATM engages autodegradation of the E3 ubiquitin ligase COP1 after DNA damage. Science 313, 1122–1126 (2006)

  20. 20.

    et al. Shotgun identification of protein modifications from protein complexes and lens tissue. Proc. Natl Acad. Sci. USA 99, 7900–7905 (2002)

  21. 21.

    et al. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression. J. Biol. Chem. 279, 20314–20326 (2004)

  22. 22.

    et al. TORCs: transducers of regulated CREB activity. Mol. Cell 12, 413–423 (2003)

  23. 23.

    et al. PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3. Nature Med. 10, 530–534 (2004)

Download references


We thank R. Crystal for Ad-CRE-Luc and Ad-Rsv-Luc reporters. We also thank J. Meisenhelder for help with two-dimensional tryptic mapping and L. Vera for mouse tail vein injections. This work was supported by NIH grants. R.D. is a recipient of a post-doctoral fellowship from the Fondation pour la Recherche Médicale and is supported by the Bettencourt Schuller Foundation. Y.L. is a Hillblom Foundation Fellow. S.-H.K. was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea. M.M. is supported by the Keickhefer Foundation. This research was also supported in part by the Foundation for Medical Research, Inc.

Author information

Author notes

    • Renaud Dentin
    •  & Yi Liu

    These authors contributed equally to this work.


  1. Peptide Biology Laboratories, Salk Institute For Biological Studies, La Jolla, California 92037, USA

    • Renaud Dentin
    • , Yi Liu
    • , Susan Hedrick
    • , Thomas Vargas
    • , Jose Heredia
    •  & Marc Montminy
  2. Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, 440-746, Gyeonggi-do, Korea

    • Seung-Hoi Koo
  3. The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

    • John Yates III


  1. Search for Renaud Dentin in:

  2. Search for Yi Liu in:

  3. Search for Seung-Hoi Koo in:

  4. Search for Susan Hedrick in:

  5. Search for Thomas Vargas in:

  6. Search for Jose Heredia in:

  7. Search for John Yates in:

  8. Search for Marc Montminy in:

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Marc Montminy.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    The file contains Supplementary Figures S1-S30 with Legends.


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.