Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 319 (5868): 1402-1405

Copyright © 2008 by the American Association for the Advancement of Science

Hepatic Glucose Sensing via the CREB Coactivator CRTC2

Renaud Dentin,1 Susan Hedrick,1 Jianxin Xie,2 John Yates, III,3 Marc Montminy1*

Abstract: Chronic hyperglycemia contributes to the development of diabetes-associated complications. Increases in the concentration of circulating glucose activate the hexosamine biosynthetic pathway (HBP) and promote the O-glycosylation of proteins by O-glycosyl transferase (OGT). We show that OGT triggered hepatic gluconeogenesis through the O-glycosylation of the transducer of regulated cyclic adenosine monophosphate response element–binding protein (CREB) 2 (TORC2 or CRTC2). CRTC2 was O-glycosylated at sites that normally sequester CRTC2 in the cytoplasm through a phosphorylation-dependent mechanism. Decreasing amounts of O-glycosylated CRTC2 by expression of the deglycosylating enzyme O-GlcNAcase blocked effects of glucose on gluconeogenesis, demonstrating the importance of the HBP in the development of glucose intolerance.

1 The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Cell Signaling Technology, 3 Trask Lane, Danvers, MA 01923, USA.
3 The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

* To whom correspondence should be addressed. E-mail: montminy{at}salk.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Glucotoxicity Induces Glucose-6-Phosphatase Catalytic Unit Expression by Acting on the Interaction of HIF-1{alpha} With CREB-Binding Protein.
A. Gautier-Stein, M. Soty, J. Chilloux, C. Zitoun, F. Rajas, and G. Mithieux (2012)
Diabetes 61, 2451-2460
   Abstract »    Full Text »    PDF »
Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism.
W. Yi, P. M. Clark, D. E. Mason, M. C. Keenan, C. Hill, W. A. Goddard III, E. C. Peters, E. M. Driggers, and L. C. Hsieh-Wilson (2012)
Science 337, 975-980
   Abstract »    Full Text »    PDF »
Metabolic labeling enables selective photocrosslinking of O-GlcNAc-modified proteins to their binding partners.
S.-H. Yu, M. Boyce, A. M. Wands, M. R. Bond, C. R. Bertozzi, and J. J. Kohler (2012)
PNAS 109, 4834-4839
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Stress Inhibits STAT3-Dependent Suppression of Hepatic Gluconeogenesis via Dephosphorylation and Deacetylation.
K. Kimura, T. Yamada, M. Matsumoto, Y. Kido, T. Hosooka, S.-i. Asahara, T. Matsuda, T. Ota, H. Watanabe, Y. Sai, et al. (2012)
Diabetes 61, 61-73
   Abstract »    Full Text »    PDF »
mTOR links incretin signaling to HIF induction in pancreatic beta cells.
S. Van de Velde, M. F. Hogan, and M. Montminy (2011)
PNAS 108, 16876-16882
   Abstract »    Full Text »    PDF »
O-linked {beta}-N-acetylglucosamine supports p38 MAPK activation by high glucose in glomerular mesangial cells.
H. Goldberg, C. Whiteside, and I. G. Fantus (2011)
Am J Physiol Endocrinol Metab 301, E713-E726
   Abstract »    Full Text »    PDF »
Evidence Coupling Increased Hexosamine Biosynthesis Pathway Activity to Membrane Cholesterol Toxicity and Cortical Filamentous Actin Derangement Contributing to Cellular Insulin Resistance.
P. Bhonagiri, G. R. Pattar, K. M. Habegger, A. M. McCarthy, L. Tackett, and J. S. Elmendorf (2011)
Endocrinology 152, 3373-3384
   Abstract »    Full Text »    PDF »
Pleiotropic and Age-dependent Effects of Decreased Protein Modification by O-Linked N-Acetylglucosamine on Pancreatic {beta}-Cell Function and Vascularization.
Y. Soesanto, B. Luo, G. Parker, D. Jones, R. C. Cooksey, and D. A. McClain (2011)
J. Biol. Chem. 286, 26118-26126
   Abstract »    Full Text »    PDF »
Inhibition of Glyceroneogenesis by Histone Deacetylase 3 Contributes to Lipodystrophy in Mice with Adipose Tissue Inflammation.
J. Zhang, T. M. Henagan, Z. Gao, and J. Ye (2011)
Endocrinology 152, 1829-1838
   Abstract »    Full Text »    PDF »
O-GlcNAcylation Increases ChREBP Protein Content and Transcriptional Activity in the Liver.
C. Guinez, G. Filhoulaud, F. Rayah-Benhamed, S. Marmier, C. Dubuquoy, R. Dentin, M. Moldes, A.-F. Burnol, X. Yang, T. Lefebvre, et al. (2011)
Diabetes 60, 1399-1413
   Abstract »    Full Text »    PDF »
Metabolic cross-talk allows labeling of O-linked {beta}-N-acetylglucosamine-modified proteins via the N-acetylgalactosamine salvage pathway.
M. Boyce, I. S. Carrico, A. S. Ganguli, S.-H. Yu, M. J. Hangauer, S. C. Hubbard, J. J. Kohler, and C. R. Bertozzi (2011)
PNAS 108, 3141-3146
   Abstract »    Full Text »    PDF »
Drosophila Salt-inducible Kinase (SIK) Regulates Starvation Resistance through cAMP-response Element-binding Protein (CREB)-regulated Transcription Coactivator (CRTC).
S. Choi, W. Kim, and J. Chung (2011)
J. Biol. Chem. 286, 2658-2664
   Abstract »    Full Text »    PDF »
Rose hip exerts antidiabetic effects via a mechanism involving downregulation of the hepatic lipogenic program.
U. Andersson, E. Henriksson, K. Strom, J. Alenfall, O. Goransson, and C. Holm (2011)
Am J Physiol Endocrinol Metab 300, E111-E121
   Abstract »    Full Text »    PDF »
Pin1 Associates with and Induces Translocation of CRTC2 to the Cytosol, Thereby Suppressing cAMP-responsive Element Transcriptional Activity.
Y. Nakatsu, H. Sakoda, A. Kushiyama, H. Ono, M. Fujishiro, N. Horike, M. Yoneda, H. Ohno, Y. Tsuchiya, H. Kamata, et al. (2010)
J. Biol. Chem. 285, 33018-33027
   Abstract »    Full Text »    PDF »
AMPK-dependent Repression of Hepatic Gluconeogenesis via Disruption of CREB{middle dot}CRTC2 Complex by Orphan Nuclear Receptor Small Heterodimer Partner.
J.-M. Lee, W.-Y. Seo, K.-H. Song, D. Chanda, Y. D. Kim, D.-K. Kim, M.-W. Lee, D. Ryu, Y.-H. Kim, J.-R. Noh, et al. (2010)
J. Biol. Chem. 285, 32182-32191
   Abstract »    Full Text »    PDF »
O-GlcNAc Signaling in the Cardiovascular System.
G. A. Ngoh, H. T. Facundo, A. Zafir, and S. P. Jones (2010)
Circ. Res. 107, 171-185
   Abstract »    Full Text »    PDF »
Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5.
P. W Caton, N. K Nayuni, J. Kieswich, N. Q Khan, M. M Yaqoob, and R. Corder (2010)
J. Endocrinol. 205, 97-106
   Abstract »    Full Text »    PDF »
Control of Steroid 21-oic Acid Synthesis by Peroxisome Proliferator-activated Receptor {alpha} and Role of the Hypothalamic-Pituitary-Adrenal Axis.
T. Wang, Y. M. Shah, T. Matsubara, Y. Zhen, T. Tanabe, T. Nagano, S. Fotso, K. W. Krausz, T. M. Zabriskie, J. R. Idle, et al. (2010)
J. Biol. Chem. 285, 7670-7685
   Abstract »    Full Text »    PDF »
Insulin Resistance in Adolescents with Type 1 Diabetes and Its Relationship to Cardiovascular Function.
K. J. Nadeau, J. G. Regensteiner, T. A. Bauer, M. S. Brown, J. L. Dorosz, A. Hull, P. Zeitler, B. Draznin, and J. E. B. Reusch (2010)
J. Clin. Endocrinol. Metab. 95, 513-521
   Abstract »    Full Text »    PDF »
Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes.
M. Saberi, D. Bjelica, S. Schenk, T. Imamura, G. Bandyopadhyay, P. Li, V. Jadhar, C. Vargeese, W. Wang, K. Bowman, et al. (2009)
Am J Physiol Endocrinol Metab 297, E1137-E1146
   Abstract »    Full Text »    PDF »
The Hexosamine Biosynthesis Pathway Is Essential for Pancreatic Beta Cell Development.
G. Filhoulaud, G. Guillemain, and R. Scharfmann (2009)
J. Biol. Chem. 284, 24583-24594
   Abstract »    Full Text »    PDF »
Regulation of Calcium/Calmodulin-dependent Kinase IV by O-GlcNAc Modification.
W. B. Dias, W. D. Cheung, Z. Wang, and G. W. Hart (2009)
J. Biol. Chem. 284, 21327-21337
   Abstract »    Full Text »    PDF »
Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein.
J. Chen, H. Cha-Molstad, A. Szabo, and A. Shalev (2009)
Am J Physiol Endocrinol Metab 296, E1133-E1139
   Abstract »    Full Text »    PDF »
Hexosamine Biosynthesis Pathway Flux Contributes to Insulin Resistance via Altering Membrane Phosphatidylinositol 4,5-Bisphosphate and Cortical Filamentous Actin.
P. Bhonagiri, G. R. Pattar, E. M. Horvath, K. M. Habegger, A. M. McCarthy, and J. S. Elmendorf (2009)
Endocrinology 150, 1636-1645
   Abstract »    Full Text »    PDF »
A PGC-1{alpha}-O-GlcNAc Transferase Complex Regulates FoxO Transcription Factor Activity in Response to Glucose.
M. P. Housley, N. D. Udeshi, J. T. Rodgers, J. Shabanowitz, P. Puigserver, D. F. Hunt, and G. W. Hart (2009)
J. Biol. Chem. 284, 5148-5157
   Abstract »    Full Text »    PDF »
The coactivator CRTC1 promotes cell proliferation and transformation via AP-1.
G. Canettieri, S. Coni, M. Della Guardia, V. Nocerino, L. Antonucci, L. Di Magno, R. Screaton, I. Screpanti, G. Giannini, and A. Gulino (2009)
PNAS 106, 1445-1450
   Abstract »    Full Text »    PDF »
Elevation of Global O-GlcNAc Levels in 3T3-L1 Adipocytes by Selective Inhibition of O-GlcNAcase Does Not Induce Insulin Resistance.
M. S. Macauley, A. K. Bubb, C. Martinez-Fleites, G. J. Davies, and D. J. Vocadlo (2008)
J. Biol. Chem. 283, 34687-34695
   Abstract »    Full Text »    PDF »
New Insights into Metabolic Signaling and Cell Survival: The Role of {beta}-O-Linkage of N-Acetylglucosamine.
G. A. Ngoh and S. P. Jones (2008)
J. Pharmacol. Exp. Ther. 327, 602-609
   Abstract »    Full Text »    PDF »
Activation of TORC1 Transcriptional Coactivator through MEKK1-induced Phosphorylation.
Y.-T. Siu, Y.-P. Ching, and D.-Y. Jin (2008)
Mol. Biol. Cell 19, 4750-4761
   Abstract »    Full Text »    PDF »
Regulation of Akt signaling by O-GlcNAc in euglycemia.
Y. A. Soesanto, B. Luo, D. Jones, R. Taylor, J. S. Gabrielsen, G. Parker, and D. A. McClain (2008)
Am J Physiol Endocrinol Metab 295, E974-E980
   Abstract »    Full Text »    PDF »
A Mitotic GlcNAcylation/Phosphorylation Signaling Complex Alters the Posttranslational State of the Cytoskeletal Protein Vimentin.
C. Slawson, T. Lakshmanan, S. Knapp, and G. W. Hart (2008)
Mol. Biol. Cell 19, 4130-4140
   Abstract »    Full Text »    PDF »
Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity.
R. J. Copeland, J. W. Bullen, and G. W. Hart (2008)
Am J Physiol Endocrinol Metab 295, E17-E28
   Abstract »    Full Text »    PDF »
O-GlcNAc Regulates FoxO Activation in Response to Glucose.
M. P. Housley, J. T. Rodgers, N. D. Udeshi, T. J. Kelly, J. Shabanowitz, D. F. Hunt, P. Puigserver, and G. W. Hart (2008)
J. Biol. Chem. 283, 16283-16292
   Abstract »    Full Text »    PDF »
SIGNAL TRANSDUCTION: Sweet Conundrum.
M. J. Birnbaum (2008)
Science 319, 1348-1349
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882