Suppression of AMPK Activation via S485 Phosphorylation by IGF-I during Hyperglycemia Is Mediated by AKT Activation in Vascular Smooth Muscle Cells
Open Access
- 14 June 2011
- journal article
- other
- Published by The Endocrine Society in Endocrinology
- Vol. 152 (8), 3143-3154
- https://doi.org/10.1210/en.2011-0155
Abstract
As a metabolic sensor, the serine/threonine protein kinase AMP-activated protein kinase (AMPK) promotes the adaptation of cells to signals arising from nutrients, hormones, and growth factors. The ability of IGF-I to stimulate protein synthesis is suppressed by AMPK, therefore, these studies were undertaken to determine whether IGF-I modulates AMPK activity. IGF-I dose-dependently suppressed phosphorylation of AMPK T172, and it stimulated AMPK S485 phosphorylation in vascular smooth muscle cells (VSMC). To determine whether stimulation of AMPK S485 phosphorylation was mediating this response, VSMC were transduced with a mutant AMPKα (AMPK S485A). Expression of this altered form inhibited the ability of IGF-I to suppress AMPK T172 activation, which resulted in inhibition of IGF-I-stimulated phosphorylation of P70S6 kinase. In contrast, expression of an AMPK S485D mutant resulted in constitutive suppression of AMPK activity and was associated with increased IGF-I-stimulated P70S6K phosphorylation and protein synthesis. The addition of a specific AKT inhibitor or expression of an AKT1 short hairpin RNA inhibited AMPK S485 phosphorylation, and it attenuated the IGF-I-induced decrease in AMPK T172 phosphorylation. Exposure to high glucose concentrations suppressed AMPK activity and stimulated S485 phosphorylation, and IGF-I stimulated a further increase in S485 phosphorylation and AMPK T172 suppression. We conclude that AMPK S485 phosphorylation negatively regulates AMPK activity by modulating the T172 phosphorylation response to high glucose and IGF-I. IGF-I stimulates S485 phosphorylation through AKT1. The results suggest that AMPK plays an inhibitory role in modulating IGF-I-stimulated protein synthesis and that IGF-I must down-regulate AMPK activity to induce an optimal anabolic response.This publication has 45 references indexed in Scilit:
- Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK PathwaysMolecular and Cellular Biology, 2011
- Regulation of G1 Cell Cycle Progression: Distinguishing the Restriction Point from a Nutrient-Sensing Cell Growth Checkpoint(s)Genes & Cancer, 2010
- AMP-Activated Protein Kinase Inhibits IGF-I Signaling and Protein Synthesis in Vascular Smooth Muscle Cells via Stimulation of Insulin Receptor Substrate 1 S794 and Tuberous Sclerosis 2 S1345 PhosphorylationMolecular Endocrinology, 2010
- p53 Regulation of the IGF-1/AKT/mTOR Pathways and the Endosomal CompartmentCold Spring Harbor Perspectives in Biology, 2009
- Activation of NAD(P)H:Quinone Oxidoreductase 1 Prevents Arterial Restenosis by Suppressing Vascular Smooth Muscle Cell ProliferationCirculation Research, 2009
- Berberine inhibits platelet-derived growth factor-induced growth and migration partly through an AMPK-dependent pathway in vascular smooth muscle cellsEuropean Journal of Pharmacology, 2008
- Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle CellsPublished by Elsevier BV ,2008
- AMPK activation inhibits the expression of HIF-1α induced by insulin and IGF-1Biochemical and Biophysical Research Communications, 2006
- AMP-Activated Protein Kinase Induces a p53-Dependent Metabolic CheckpointMolecular Cell, 2005
- Insulin-like Growth Factor-I Extends in VitroReplicative Life Span of Skeletal Muscle Satellite Cells by Enhancing G1/S Cell Cycle Progression via the Activation of Phosphatidylinositol 3′-Kinase/Akt Signaling PathwayPublished by Elsevier BV ,2000