Suppression of AMPK activation via S485 phosphorylation by IGF-I during
hyperglycemia is mediated by AKT activation in vascular smooth muscle cells.
Authors Ning J, Xi G, Clemmons DR
Submitted By Richard McIndoe on 2/22/2012
Status Published
Journal Endocrinology
Year 2011
Date Published 8/1/2011
Volume : Pages 152 : 3143 - 3154
PubMed Reference 21673100
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 AMPKa (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.