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Physiological Role of Akt in Insulin-Stimulated Translocation of GLUT4 in Transfected Rat Adipose Cells

Hypertension-Endocrine Branch National Heart, Lung, and Blood Institute (L.-N.C., H.C., Y.L., M.J.Q.) and Diabetes Branch National Institute of Diabetes and Digestive and Kidney Diseases (L.Z., M.A.M., S.I.T.) National Institutes of Health Bethesda, Maryland 20892

Stimulation of glucose transport is among the most important metabolic actions of insulin. Studies in adipose cells have demonstrated that insulin stimulates its receptor to phosphorylate tyrosine residues in IRS-1, leading to activation of phosphatidylinositol 3-kinase, which plays a necessary role in mediating the translocation of the insulin-responsive glucose transporter GLUT4 to the cell surface. Akt is a serine-threonine kinase recently identified as a direct downstream target of phosphatidylinositol 3-kinase. A previous study in 3T3-L1 cells showed that overexpression of a constitutively active mutant of Akt is sufficient to recruit GLUT4 to the cell surface. Since effects of overexpression of signaling molecules in tissue culture models do not always reflect physiological function, we have overexpressed a dominant inhibitory mutant of Akt in rat adipose cells to investigate the effects of inhibiting endogenous Akt in a physiologically relevant insulin target cell. Cells were transfected with either wild type (Akt-WT), constitutively active (Akt-myr), or dominant inhibitory (Akt-K179A) forms of Akt, and effects of overexpression of these constructs on insulin-stimulated translocation of a cotransfected epitope-tagged GLUT4 were studied. Overexpression of Akt-WT resulted in significant translocation of GLUT4 to the cell surface even in the absence of insulin. Interestingly, overexpression of Akt-myr resulted in an even larger effect that was independent of insulin. More importantly, overexpression of Akt-K179A (kinase-inactive mutant) significantly inhibited insulin-stimulated translocation of GLUT4. Taken together, our data suggest that Akt is not only capable of stimulating the translocation of GLUT4 but that endogenous Akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue.

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				H. Tong, W. Chen, R. E. London, E. Murphy, and C. Steenbergen Preconditioning Enhanced Glucose Uptake Is Mediated by p38 MAP Kinase Not by Phosphatidylinositol 3-Kinase J. Biol. Chem., April 14, 2000; 275(16): 11981 - 11986. [Abstract] [Full Text] [PDF]

				G. Zeng, F. H. Nystrom, L. V. Ravichandran, L.-N. Cong, M. Kirby, H. Mostowski, and M. J. Quon Roles for Insulin Receptor, PI3-Kinase, and Akt in Insulin-Signaling Pathways Related to Production of Nitric Oxide in Human Vascular Endothelial Cells Circulation, April 4, 2000; 101(13): 1539 - 1545. [Abstract] [Full Text] [PDF]

				K. D. Sims, D. J. Straff, and M. B. Robinson Platelet-derived Growth Factor Rapidly Increases Activity and Cell Surface Expression of the EAAC1 Subtype of Glutamate Transporter through Activation of Phosphatidylinositol 3-Kinase J. Biol. Chem., February 18, 2000; 275(7): 5228 - 5237. [Abstract] [Full Text] [PDF]

				A. A. Troussard, C. Tan, T. N. Yoganathan, and S. Dedhar Cell-Extracellular Matrix Interactions Stimulate the AP-1 Transcription Factor in an Integrin-Linked Kinase- and Glycogen Synthase Kinase 3-Dependent Manner Mol. Cell. Biol., November 1, 1999; 19(11): 7420 - 7427. [Abstract] [Full Text] [PDF]

				M. M. Hill, S. F. Clark, D. F. Tucker, M. J. Birnbaum, D. E. James, and S. L. Macaulay A Role for Protein Kinase Bbeta /Akt2 in Insulin-Stimulated GLUT4 Translocation in Adipocytes Mol. Cell. Biol., November 1, 1999; 19(11): 7771 - 7781. [Abstract] [Full Text] [PDF]

				G. Bandyopadhyay, M. L. Standaert, M. P. Sajan, L. M. Karnitz, L. Cong, M. J. Quon, and R. V. Farese Dependence of Insulin-Stimulated Glucose Transporter 4 Translocation on 3-Phosphoinositide-Dependent Protein Kinase-1 and Its Target Threonine-410 in the Activation Loop of Protein Kinase C-{zeta} Mol. Endocrinol., October 1, 1999; 13(10): 1766 - 1772. [Abstract] [Full Text]

				P. G. P. Foran, L. M. Fletcher, P. B. Oatey, N. Mohammed, J. O. Dolly, and J. M. Tavare Protein Kinase B Stimulates the Translocation of GLUT4 but Not GLUT1 or Transferrin Receptors in 3T3-L1 Adipocytes by a Pathway Involving SNAP-23, Synaptobrevin-2, and/or Cellubrevin J. Biol. Chem., October 1, 1999; 274(40): 28087 - 28095. [Abstract] [Full Text] [PDF]

				K. Paz, Y.-F. Liu, H. Shorer, R. Hemi, D. LeRoith, M. Quan, H. Kanety, R. Seger, and Y. Zick Phosphorylation of Insulin Receptor Substrate-1 (IRS-1) by Protein Kinase B Positively Regulates IRS-1 Function J. Biol. Chem., October 1, 1999; 274(40): 28816 - 28822. [Abstract] [Full Text] [PDF]

				A. Thorell, M. F. Hirshman, J. Nygren, L. Jorfeldt, J. F. P. Wojtaszewski, S. D. Dufresne, E. S. Horton, O. Ljungqvist, and L. J. Goodyear Exercise and insulin cause GLUT-4 translocation in human skeletal muscle Am J Physiol Endocrinol Metab, October 1, 1999; 277(4): E733 - E741. [Abstract] [Full Text] [PDF]

				M. J. Brady, P. M. Kartha, A. A. Aysola, and A. R. Saltiel The Role of Glucose Metabolites in the Activation and Translocation of Glycogen Synthase by Insulin in 3T3-L1 Adipocytes J. Biol. Chem., September 24, 1999; 274(39): 27497 - 27504. [Abstract] [Full Text] [PDF]

				S. A. Summers, E. L. Whiteman, H. Cho, L. Lipfert, and M. J. Birnbaum Differentiation-dependent Suppression of Platelet-derived Growth Factor Signaling in Cultured Adipocytes J. Biol. Chem., August 20, 1999; 274(34): 23858 - 23867. [Abstract] [Full Text] [PDF]

				J. Gu, M. Tamura, R. Pankov, E. H.J. Danen, T. Takino, K. Matsumoto, and K. M. Yamada Shc and Fak Differentially Regulate Cell Motility and Directionality Modulated by Pten J. Cell Biol., July 26, 1999; 146(2): 389 - 404. [Abstract] [Full Text] [PDF]

				D. Chen, R. V. Fucini, A. L. Olson, B. A. Hemmings, and J. E. Pessin Osmotic Shock Inhibits Insulin Signaling by Maintaining Akt/Protein Kinase B in an Inactive Dephosphorylated State Mol. Cell. Biol., July 1, 1999; 19(7): 4684 - 4694. [Abstract] [Full Text] [PDF]

				N. Filippa, C. L. Sable, C. Filloux, B. Hemmings, and E. Van Obberghen Mechanism of Protein Kinase B Activation by Cyclic AMP-Dependent Protein Kinase Mol. Cell. Biol., July 1, 1999; 19(7): 4989 - 5000. [Abstract] [Full Text] [PDF]

				Q. Wang, R. Somwar, P. J. Bilan, Z. Liu, J. Jin, J. R. Woodgett, and A. Klip Protein Kinase B/Akt Participates in GLUT4 Translocation by Insulin in L6 Myoblasts Mol. Cell. Biol., June 1, 1999; 19(6): 4008 - 4018. [Abstract] [Full Text] [PDF]

				M. L. Standaert, G. Bandyopadhyay, M. P. Sajan, L. Cong, M. J. Quon, and R. V. Farese Okadaic Acid Activates Atypical Protein Kinase C (zeta /lambda ) in Rat and 3T3/L1 Adipocytes. AN APPARENT REQUIREMENT FOR ACTIVATION OF GLUT4 TRANSLOCATION AND GLUCOSE TRANSPORT J. Biol. Chem., May 14, 1999; 274(20): 14074 - 14078. [Abstract] [Full Text] [PDF]

				A. Tirosh, R. Potashnik, N. Bashan, and A. Rudich Oxidative Stress Disrupts Insulin-induced Cellular Redistribution of Insulin Receptor Substrate-1 and Phosphatidylinositol 3-Kinase in 3T3-L1 Adipocytes. A PUTATIVE CELLULAR MECHANISM FOR IMPAIRED PROTEIN KINASE B ACTIVATION AND GLUT4 TRANSLOCATION J. Biol. Chem., April 9, 1999; 274(15): 10595 - 10602. [Abstract] [Full Text] [PDF]

				J. E. Pessin, D. C. Thurmond, J. S. Elmendorf, K. J. Coker, and S. Okada Molecular Basis of Insulin-stimulated GLUT4 Vesicle Trafficking. LOCATION! LOCATION! LOCATION! J. Biol. Chem., January 29, 1999; 274(5): 2593 - 2596. [Full Text] [PDF]

				M. P. Czech and S. Corvera Signaling Mechanisms That Regulate Glucose Transport J. Biol. Chem., January 22, 1999; 274(4): 1865 - 1868. [Full Text] [PDF]

				T. A. Kupriyanova and K. V. Kandror Akt-2 Binds to Glut4-containing Vesicles and Phosphorylates Their Component Proteins in Response to Insulin J. Biol. Chem., January 15, 1999; 274(3): 1458 - 1464. [Abstract] [Full Text] [PDF]

				J. F. Markuns, R. Napoli, M. F. Hirshman, A. M. Davalli, B. Cheatham, and L. J. Goodyear Effects of Streptozocin-Induced Diabetes and Islet Cell Transplantation on Insulin Signaling in Rat Skeletal Muscle Endocrinology, January 1, 1999; 140(1): 106 - 111. [Abstract] [Full Text]

				J. Turinsky and A. Damrau-Abney Akt kinases and 2-deoxyglucose uptake in rat skeletal muscles in vivo: study with insulin and exercise Am J Physiol Regulatory Integrative Comp Physiol, January 1, 1999; 276(1): R277 - R282. [Abstract] [Full Text] [PDF]

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				J. Liao, A. Barthel, K. Nakatani, and R. A. Roth Activation of Protein Kinase B/Akt Is Sufficient to Repress the Glucocorticoid and cAMP Induction of Phosphoenolpyruvate Carboxykinase Gene J. Biol. Chem., October 16, 1998; 273(42): 27320 - 27324. [Abstract] [Full Text] [PDF]