IGF-1 mediated phosphorylation of specific IRS-1 serines in Ames dwarf fibroblasts is associated with longevity.

John Papaconstantinou,Ching-Chyuan Hsieh

doi:10.18632/oncotarget.6112

John Papaconstantinou, Ching-Chyuan Hsieh

Open Access

https://doi.org/10.18632/oncotarget.6112

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Abstract

Insulin/IGF-1 signaling involves phosphorylation/dephosphorylation of serine/threonine or tyrosine residues of the insulin receptor substrate (IRS) proteins and is associated with hormonal control of longevity determination of certain long-lived mice. The stimulation of serine phosphorylations by IGF-1 suggests there is insulin/IGF-1 crosstalk that involves the phosphorylation of the same serine residues. By this mechanism, insulin and IGF-1 mediated phosphorylation of specific IRS-1 serines could play a role in longevity determination.We used fibroblasts from WT and Ames dwarf mice to examine whether: (a) IGF-1 stimulates phosphorylation of IRS-1 serines targeted by insulin; (b) the levels of serine phosphorylation differ in WT vs. Ames fibroblasts; and (c) aging affects the levels of these serine phosphorylations which are altered in the Ames dwarf mutant. We have shown that IRS-1 is a substrate for IGF-1 induced phosphorylation of Ser307, Ser612, Ser636/639, and Ser1101; that the levels of phosphorylation of these serines are significantly lower in Ames vs. WT cells; that IGF-1 mediated phosphorylation of these serines increases with age in WT cells. We propose that insulin/IGF-1 cross talk and level of phosphorylation of specific IRS-1 serines may promote the Ames dwarf longevity phenotype.

Highlights

The extended lifespan of the Ames and Snell dwarf mice is attributed to the attenuation of the insulin/IGF-1 signaling pathways [1, 2]
We used fibroblasts from WT and Ames dwarf mice to examine whether: (a) IGF-1 stimulates phosphorylation of insulin receptor substrate (IRS)-1 serines targeted by insulin; (b) the levels of serine phosphorylation differ in WT vs. Ames fibroblasts; and (c) aging affects the levels of these serine phosphorylations which are altered in the Ames dwarf mutant
In these studies we examined whether IGF-1 stimulates the phosphorylation of IRS-1 Ser307, Ser612, Ser636/639 and Ser1101 residues that are known to be phosphorylated in response to insulin treatment, whether these IGF-1 stimulated phosphorylations in Ames fibroblasts are consistent with decreased insulin/IGF-1 pathway activity associated with longevity

Summary

Introduction

The extended lifespan of the Ames and Snell dwarf mice is attributed to the attenuation of the insulin/IGF-1 signaling pathways [1, 2]. In these mice GH deficiency reduces production and circulating levels of insulin and IGF-1 [1, 3]. Decreased mRNA and protein pool levels of the hepatic IGF-1 axis in Ames mice suggest that the regulation of genes targeted by the insulin/IGF-1-signaling pathway may contribute to physiological conditions supporting longevity [7]. In the Ames mouse, IGF-1 regulates the insulin signaling pathway suggesting the involvement of insulin/IGF-1 crosstalk interactions

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