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Science 300 (5625): 1574-1577

Copyright © 2003 by the American Association for the Advancement of Science

TRB3: A tribbles Homolog That Inhibits Akt/PKB Activation by Insulin in Liver

Keyong Du,1* Stephan Herzig,1* Rohit N. Kulkarni,2 Marc Montminy1{dagger}

Abstract: Insulin resistance is a major hallmark in the development of type II diabetes, which is characterized by the failure of insulin to promote glucose uptake in muscle and to suppress glucose production in liver. The serine-threonine kinase Akt (PKB) is a principal target of insulin signaling that inhibits hepatic glucose output when glucose is available from food. Here we show that TRB3, a mammalian homolog of Drosophila tribbles, functions as a negative modulator of Akt. TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. Amounts of TRB3 RNA and protein were increased in livers of db/db diabetic mice compared with those in wild-type mice. Hepatic overexpression of TRB3 in amounts comparable to those in db/db mice promoted hyperglycemia and glucose intolerance. Our results suggest that, by interfering with Akt activation, TRB3 contributes to insulin resistance in individuals with susceptibility to type II diabetes.

1 Peptide Biology Laboratories, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037—1002, USA.
2 Joslin Diabetes Center, Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.

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* These authors contributed equally to this work.

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

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A Novel Regulatory Mechanism of the Bone Morphogenetic Protein (BMP) Signaling Pathway Involving the Carboxyl-Terminal Tail Domain of BMP Type II Receptor.
M. C. Chan, P. H. Nguyen, B. N. Davis, N. Ohoka, H. Hayashi, K. Du, G. Lagna, and A. Hata (2007)
Mol. Cell. Biol. 27, 5776-5789
   Abstract »    Full Text »    PDF »
Regulation of the Pro-apoptotic Scaffolding Protein POSH by Akt.
T. R. Lyons, J. Thorburn, P. W. Ryan, A. Thorburn, S. M. Anderson, and C. K. Kassenbrock (2007)
J. Biol. Chem. 282, 21987-21997
   Abstract »    Full Text »    PDF »
Survival Factor Withdrawal-induced Apoptosis of TF-1 Cells Involves a TRB2-Mcl-1 Axis-dependent Pathway.
K.-R. Lin, S.-F. Lee, C.-M. Hung, C.-L. Li, H.-F. Yang-Yen, and J. J. Y. Yen (2007)
J. Biol. Chem. 282, 21962-21972
   Abstract »    Full Text »    PDF »
Human Tribbles-1 Controls Proliferation and Chemotaxis of Smooth Muscle Cells via MAPK Signaling Pathways.
H. Y. Sung, H. Guan, A. Czibula, A. R. King, K. Eder, E. Heath, S. K. Suvarna, S. K. Dower, A. G. Wilson, S. E. Francis, et al. (2007)
J. Biol. Chem. 282, 18379-18387
   Abstract »    Full Text »    PDF »
TRB3 Inhibits the Transcriptional Activation of Stress-regulated Genes by a Negative Feedback on the ATF4 Pathway.
C. Jousse, C. Deval, A.-C. Maurin, L. Parry, Y. Cherasse, C. Chaveroux, R. Lefloch, P. Lenormand, A. Bruhat, and P. Fafournoux (2007)
J. Biol. Chem. 282, 15851-15861
   Abstract »    Full Text »    PDF »
Nuclear Forkhead Box O1 Controls and Integrates Key Signaling Pathways in Hepatocytes.
M. Naimi, N. Gautier, C. Chaussade, A. M. Valverde, D. Accili, and E. Van Obberghen (2007)
Endocrinology 148, 2424-2434
   Abstract »    Full Text »    PDF »
Genetic Deletion of Trb3, the Mammalian Drosophila tribbles Homolog, Displays Normal Hepatic Insulin Signaling and Glucose Homeostasis.
H. Okamoto, E. Latres, R. Liu, K. Thabet, A. Murphy, D. Valenzeula, G. D. Yancopoulos, T. N. Stitt, D. J. Glass, and M. W. Sleeman (2007)
Diabetes 56, 1350-1356
   Abstract »    Full Text »    PDF »
Abnormal glucose homeostasis in adult female rat offspring after intrauterine ethanol exposure.
X.-H. Yao and B. L. Gregoire Nyomba (2007)
Am J Physiol Regulatory Integrative Comp Physiol 292, R1926-R1933
   Abstract »    Full Text »    PDF »
Large-scale phosphorylation analysis of mouse liver.
J. Villen, S. A. Beausoleil, S. A. Gerber, and S. P. Gygi (2007)
PNAS 104, 1488-1493
   Abstract »    Full Text »    PDF »
Glucose, dexamethasone, and the unfolded protein response regulate TRB3 mRNA expression in 3T3-L1 adipocytes and L6 myotubes.
S. Z. Yacoub Wasef, K. A. Robinson, M. N. Berkaw, and M. G. Buse (2006)
Am J Physiol Endocrinol Metab 291, E1274-E1280
   Abstract »    Full Text »    PDF »
Skeletal Muscle-Selective Knockout of LKB1 Increases Insulin Sensitivity, Improves Glucose Homeostasis, and Decreases TRB3.
H.-J. Koh, D. E. Arnolds, N. Fujii, T. T. Tran, M. J. Rogers, N. Jessen, Y. Li, C. W. Liew, R. C. Ho, M. F. Hirshman, et al. (2006)
Mol. Cell. Biol. 26, 8217-8227
   Abstract »    Full Text »    PDF »
Effect of TRB3 on Insulin and Nutrient-stimulated Hepatic p70 S6 Kinase Activity.
R. Matsushima, N. Harada, N. J. G. Webster, Y. M. Tsutsumi, and Y. Nakaya (2006)
J. Biol. Chem. 281, 29719-29729
   Abstract »    Full Text »    PDF »
PGC-1{alpha} and PGC-1beta have both similar and distinct effects on myofiber switching toward an oxidative phenotype.
O. H. Mortensen, L. Frandsen, P. Schjerling, E. Nishimura, and N. Grunnet (2006)
Am J Physiol Endocrinol Metab 291, E807-E816
   Abstract »    Full Text »    PDF »
TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism..
L. Qi, J. E. Heredia, J. Y. Altarejos, R. Screaton, N. Goebel, S. Niessen, I. X. MacLeod, C. W. Liew, R. N. Kulkarni, J. Bain, et al. (2006)
Science 312, 1763-1766
   Abstract »    Full Text »    PDF »
Minireview: Ribonucleic Acid Interference for the Identification of New Targets for the Treatment of Metabolic Diseases.
C. M. Rondinone (2006)
Endocrinology 147, 2650-2656
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Peroxisome Proliferator-Activated Receptor {alpha} Activation Decreases Metastatic Potential of Melanoma Cells In vitro via Down-Regulation of Akt..
M. Grabacka, P. M. Plonka, K. Urbanska, and K. Reiss (2006)
Clin. Cancer Res. 12, 3028-3036
   Abstract »    Full Text »    PDF »
Insulin Resistance and Atherosclerosis.
J. Nigro, N. Osman, A. M. Dart, and P. J. Little (2006)
Endocr. Rev. 27, 242-259
   Abstract »    Full Text »    PDF »
Chronic Ethanol Intake Impairs Insulin Signaling in Rats by Disrupting Akt Association with the Cell Membrane: ROLE OF TRB3 IN INHIBITION OF Akt/PROTEIN KINASE B ACTIVATION.
L. He, F. A. Simmen, H. M. Mehendale, M. J. J. Ronis, and T. M. Badger (2006)
J. Biol. Chem. 281, 11126-11134
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Histone Acetylation-independent Effect of Histone Deacetylase Inhibitors on Akt through the Reshuffling of Protein Phosphatase 1 Complexes.
C.-S. Chen, S.-C. Weng, P.-H. Tseng, H.-P. Lin, and C.-S. Chen (2005)
J. Biol. Chem. 280, 38879-38887
   Abstract »    Full Text »    PDF »
Peroxisome proliferator-activated receptor {alpha} is required for feedback regulation of highly unsaturated fatty acid synthesis.
Y. Li, T. Y. Nara, and M. T. Nakamura (2005)
J. Lipid Res. 46, 2432-2440
   Abstract »    Full Text »    PDF »
KiSS-1/G Protein-Coupled Receptor 54 Metastasis Suppressor Pathway Increases Myocyte-Enriched Calcineurin Interacting Protein 1 Expression and Chronically Inhibits Calcineurin Activity.
N. Stathatos, I. Bourdeau, A. V. Espinosa, M. Saji, V. V. Vasko, K. D. Burman, C. A. Stratakis, and M. D. Ringel (2005)
J. Clin. Endocrinol. Metab. 90, 5432-5440
   Abstract »    Full Text »    PDF »

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