title: IGF-1 mediated phosphorylation of specific IRS-1 serines in Ames dwarf fibroblasts is associated with longevity.
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.
authors.affiliation: The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: John
authors.initials: J
authors.lastname: Papaconstantinou
authors.affiliation: The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Ching-Chyuan
authors.initials: CC
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D008136:Longevity / Q000502:physiology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D012694:Serine; D007334:Insulin-Like Growth Factor I
keywords: Ames dwarf mouse; Gerotarget; IGF-1; IRS-1 serine phosphorylation; dermal fibroblasts; longevity