|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 278, Issue 18, 15641-15651, May 2, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From INSERM U145, IFR50, Faculté de Médecine,
06107 Nice Cedex 2, France
Impaired glucose tolerance precedes type 2 diabetes and is characterized by hyperinsulinemia, which develops to
balance peripheral insulin resistance. To gain insight into the
deleterious effects of hyperinsulinemia on skeletal muscle, we studied
the consequences of prolonged insulin treatment of L6 myoblasts on
insulin-dependent signaling pathways. A 24-h long insulin
treatment desensitized the phosphoinositide 3-kinase
(PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second
stimulation with insulin or insulin-like growth factor-1 and led to
decreased insulin-induced glucose uptake. Desensitization was
correlated to a reduction in insulin receptor substrate (IRS)-1 and
IRS-2 protein levels, which was reversed by the PI3K inhibitor
LY294002. Co-treatment of cells with insulin and LY294002, while
reducing total IRS-1 phosphorylation, increased its phosphotyrosine
content, enhancing IRS-1/PI3K association. PDK1, mTOR, and MAPK
inhibitors did not block insulin-induced reduction of IRS-1, suggesting
that the PI3K serine-kinase activity causes IRS-1 serine
phosphorylation and its commitment to proteasomal degradation.
Contrarily, insulin-induced IRS-2 down-regulation occurred via a
PI3K/mTOR pathway. Suppression of IRS-1/2 down-regulation by LY294002
rescued the responsiveness of PKB and MAPK toward acute insulin
stimulation. Conversely, adenoviral-driven expression of constitutively
active PI3K induced an insulin-independent reduction in IRS-1/2 protein
levels. IRS-2 appears to be the chief molecule responsible for MAPK and
PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA
interference severely impaired activation of both kinases. In summary,
(i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating
it while a PI3K/mTOR pathway controls insulin-induced reduction of
IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking
the insulin receptor to activation of PKB and MAPK, (iii) the mechanism
of IRS-1/2 down-regulation is different in L6 cells compared with
3T3-L1 adipocytes. In conclusion, the reduction in IRS proteins via
different PI3K-mediated mechanisms contributes to the development of an
insulin-resistant state in L6 myoblasts.
Phosphoinositide 3-Kinase-mediated Reduction of Insulin Receptor
Substrate-1/2 Protein Expression via Different Mechanisms
Contributes to the Insulin-induced Desensitization of Its Signaling
Pathways in L6 Muscle Cells*
,
*
This work was supported in part by INSERM, Université
de Nice-Sophia-Antipolis, la Région PACA, European Community
Grant QLGI-CT-1999-00674, EuroDiabetesGene, and QLK3-CT-2000-01038, and
Aventis Pharma, Frankfurt, Germany, contract 99206.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by an INSERM "Poste Vert" postdoctoral fellowship
and in part by the Fondation pour la Recherche Médicale.
§
Supported by European Community Grant QLGI-CT-1999-00674.
¶
Supported by INSERM "Poste Vert" postdoctoral fellowships.
To whom correspondence should be addressed. E-mail:
vanobbeg@unice.fr.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  G. E. Lim, G. J. Huang, N. Flora, D. LeRoith, C. J. Rhodes, and P. L. Brubaker Insulin Regulates Glucagon-Like Peptide-1 Secretion from the Enteroendocrine L Cell Endocrinology, February 1, 2009; 150(2): 580 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Demozay, J.-C. Mas, S. Rocchi, and E. Van Obberghen FALDH Reverses the Deleterious Action of Oxidative Stress Induced by Lipid Peroxidation Product 4-Hydroxynonenal on Insulin Signaling in 3T3-L1 Adipocytes Diabetes, May 1, 2008; 57(5): 1216 - 1226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zhong, X. Liu, K. Schafer-Hales, A. I. Marcus, F. R. Khuri, S.-Y. Sun, and W. Zhou 2-Deoxyglucose induces Akt phosphorylation via a mechanism independent of LKB1/AMP-activated protein kinase signaling activation or glycolysis inhibition Mol. Cancer Ther., April 1, 2008; 7(4): 809 - 817. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Koketsu, H. Sakoda, M. Fujishiro, A. Kushiyama, Y. Fukushima, H. Ono, M. Anai, T. Kikuchi, T. Fukuda, H. Kamata, et al. Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice Am J Physiol Endocrinol Metab, April 1, 2008; 294(4): E719 - E725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Li, X. Yin, E. J. Zmuda, C. C. Wolford, X. Dong, M. F. White, and T. Hai The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic {beta}-Cell Apoptosis Diabetes, March 1, 2008; 57(3): 635 - 644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Cleasby, T. A. Reinten, G. J. Cooney, D. E. James, and E. W. Kraegen Functional Studies of Akt Isoform Specificity in Skeletal Muscle in Vivo; Maintained Insulin Sensitivity Despite Reduced Insulin Receptor Substrate-1 Expression Mol. Endocrinol., January 1, 2007; 21(1): 215 - 228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. McCarthy, K. O. Spisak, J. T. Brozinick, and J. S. Elmendorf Loss of cortical actin filaments in insulin-resistant skeletal muscle cells impairs GLUT4 vesicle trafficking and glucose transport Am J Physiol Cell Physiol, November 1, 2006; 291(5): C860 - C868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. F. Raab-Graham, P. C. G. Haddick, Y. N. Jan, and L. Y. Jan Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites. Science, October 6, 2006; 314(5796): 144 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nawaratne, A. Gray, C. H. Jorgensen, C. P. Downes, K. Siddle, and J. K. Sethi Regulation of Insulin Receptor Substrate 1 Pleckstrin Homology Domain by Protein Kinase C: Role of Serine 24 Phosphorylation Mol. Endocrinol., August 1, 2006; 20(8): 1838 - 1852. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tzatsos and K. V. Kandror Nutrients Suppress Phosphatidylinositol 3-Kinase/Akt Signaling via Raptor-Dependent mTOR-Mediated Insulin Receptor Substrate 1 Phosphorylation Mol. Cell. Biol., January 1, 2006; 26(1): 63 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Talukdar, W. Szeszel-Fedorowicz, and L. M. Salati Arachidonic Acid Inhibits the Insulin Induction of Glucose-6-phosphate Dehydrogenase via p38 MAP Kinase J. Biol. Chem., December 9, 2005; 280(49): 40660 - 40667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Kim, C. M. van Golen, and E. L. Feldman Insulin-Like Growth Factor I Induces Preferential Degradation of Insulin Receptor Substrate-2 through the Phosphatidylinositol 3-Kinase Pathway in Human Neuroblastoma Cells Endocrinology, December 1, 2005; 146(12): 5350 - 5357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Renstrom, J. Buren, and J. W. Eriksson Insulin Receptor Substrates-1 and -2 Are Both Depleted but via Different Mechanisms after Down-Regulation of Glucose Transport in Rat Adipocytes Endocrinology, July 1, 2005; 146(7): 3044 - 3051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Sloniger, V. Saengsirisuwan, C. J. Diehl, B. B. Dokken, N. Lailerd, A. M. Lemieux, J. S. Kim, and E. J. Henriksen Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1074 - E1081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Huang, A. C. P. Thirone, X. Huang, and A. Klip Differential Contribution of Insulin Receptor Substrates 1 Versus 2 to Insulin Signaling and Glucose Uptake in L6 Myotubes J. Biol. Chem., May 13, 2005; 280(19): 19426 - 19435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Brachmann, K. Ueki, J. A. Engelman, R. C. Kahn, and L. C. Cantley Phosphoinositide 3-Kinase Catalytic Subunit Deletion and Regulatory Subunit Deletion Have Opposite Effects on Insulin Sensitivity in Mice Mol. Cell. Biol., March 1, 2005; 25(5): 1596 - 1607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Tian Another Role for the Celebrity: Akt and Insulin Resistance Circ. Res., February 4, 2005; 96(2): 139 - 140. [Full Text] [PDF]
|
|
|
|
|
|
I. Briaud, L. M. Dickson, M. K. Lingohr, J. F. McCuaig, J. C. Lawrence, and C. J. Rhodes Insulin Receptor Substrate-2 Proteasomal Degradation Mediated by a Mammalian Target of Rapamycin (mTOR)-induced Negative Feedback Down-regulates Protein Kinase B-mediated Signaling Pathway in {beta}-Cells J. Biol. Chem., January 21, 2005; 280(3): 2282 - 2293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Werner, J. Lee, L. Hansen, M. Yuan, and S. E. Shoelson Insulin Resistance Due to Phosphorylation of Insulin Receptor Substrate-1 at Serine 302 J. Biol. Chem., August 20, 2004; 279(34): 35298 - 35305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Harrington, G. M. Findlay, A. Gray, T. Tolkacheva, S. Wigfield, H. Rebholz, J. Barnett, N. R. Leslie, S. Cheng, P. R. Shepherd, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins J. Cell Biol., July 19, 2004; 166(2): 213 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Hartman, J. C. O'Connor, J. P. Godbout, K. D. Minor, V. R. Mazzocco, and G. G. Freund Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus J. Biol. Chem., July 2, 2004; 279(27): 28045 - 28050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Demozay, S. Rocchi, J.-C. Mas, S. Grillo, L. Pirola, C. Chavey, and E. Van Obberghen Fatty Aldehyde Dehydrogenase: POTENTIAL ROLE IN OXIDATIVE STRESS PROTECTION AND REGULATION OF ITS GENE EXPRESSION BY INSULIN J. Biol. Chem., February 20, 2004; 279(8): 6261 - 6270. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |