Activation of Akt by Advanced Glycation End Products (AGEs): Involvement of IGF-1 Receptor and Caveolin-1
Journal
PLoS ONE
Journal Volume
8
Journal Issue
3
Date Issued
2013
Author(s)
Yang, Su-Jung
Chen, Chen-Yu
Wen, Hui-Chin
Chen, Ching-Yu
Chang, Shi-Chuan
Liao, Jyh-Fei
Chang, Chung-Ho
Abstract
Diabetes is characterized by chronic hyperglycemia, which in turn facilitates the formation of advanced glycation end products (AGEs). AGEs activate signaling proteins such as Src, Akt and ERK1/2. However, the mechanisms by which AGEs activate these kinases remain unclear. We examined the effect of AGEs on Akt activation in 3T3-L1 preadipocytes. Addition of AGEs to 3T3-L1 cells activated Akt in a dose- and time-dependent manner. The AGEs-stimulated Akt activation was blocked by a PI3-kinase inhibitor LY 294002, Src inhibitor PP2, an antioxidant NAC, superoxide scavenger Tiron, or nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase inhibitor DPI, suggesting the involvement of Src and NAD(P)H oxidase in the activation of PI3-kinase-Akt pathway by AGEs. AGEs-stimulated Src tyrosine phosphorylation was inhibited by NAC, suggesting that Src is downstream of NAD(P)H oxidase. The AGEs-stimulated Akt activity was sensitive to Insulin-like growth factor 1 receptor (IGF-1R) kinase inhibitor AG1024. Furthermore, AGEs induced phosphorylation of IGF-1 receptorβsubunit (IGF-1Rβ) on Tyr1135/1136, which was sensitive to PP2, indicating that AGEs stimulate Akt activity by transactivating IGF-1 receptor. In addition, the AGEs-stimulated Akt activation was attenuated by β-methylcyclodextrin that abolishes the structure of caveolae, and by lowering caveolin-1 (Cav-1) levels with siRNAs. Furthermore, addition of AGEs enhanced the interaction of phospho-Cav-1 with IGF-1Rβ and transfection of 3T3-L1 cells with Cav-1 Y14F mutants inhibited the activation of Akt by AGEs. These results suggest that AGEs activate NAD(P)H oxidase and Src which in turn phosphorylates IGF-1 receptor and Cav-1 leading to activation of IGF-1 receptor and the downstream Akt in 3T3-L1 cells. AGEs treatment promoted the differentiation of 3T3-L1 preadipocytes and addition of AG1024, LY 294002 or Akt inhibitor attenuated the promoting effect of AGEs on adipogenesis, suggesting that IGF-1 receptor, PI3-Kinase and Akt are involved in the facilitation of adipogenesis by AGEs. ? 2013 Yang et al.
SDGs
Other Subjects
2 morpholino 8 phenylchromone; 3 bromo 5 tert butyl 4 hydroxybenzylidenemalononitrile; 4 amino 7 tert butyl 5 (4 chlorophenyl)pyrazolo[3,4 d]pyrimidine; advanced glycation end product; beta methylcyclodextrin; caveolin 1; enzyme inhibitor; mutant protein; nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase inhibitor DPI; oxidoreductase; phosphatidylinositol 3 kinase; protein kinase B; protein tyrosine kinase; reactive oxygen metabolite; reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase; small interfering RNA; somatomedin C receptor; tiron; unclassified drug; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 3 bromo 5 tert butyl 4 hydroxybenzylidenemalononitrile; advanced glycation end product; antioxidant; caveolin 1; chromone derivative; glycerol 3 phosphate dehydrogenase; morpholine derivative; protein kinase B; protein tyrosine kinase; reduced nicotinamide adenine dinucleotide phosphate oxidase; small interfering RNA; somatomedin C receptor; tyrphostin; adipogenesis; animal cell; animal tissue; article; caveola; cell differentiation; concentration response; controlled study; dose response; enzyme activation; enzyme activity; enzyme inhibition; genetic transfection; membrane structure; mouse; nonhuman; proadipocyte; protein phosphorylation; protein protein interaction; transactivation; 3T3 cell line; adipocyte; animal; antagonists and inhibitors; cytology; metabolism; phosphorylation; signal transduction; transcription initiation; 3T3 Cells; Adipocytes; Animals; Antioxidants; Caveolin 1; Chromones; Enzyme Activation; Glycerolphosphate Dehydrogenase; Glycosylation End Products, Advanced; Mice; Morpholines; NADPH Oxidase; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; RNA, Small Interfering; Signal Transduction; src-Family Kinases; Transcriptional Activation; Tyrphostins
Type
journal article