Study summary · research use only
Insulin-like growth factor-1 (IGF-1) receptor-insulin receptor substrate complexes in the uterus. Altered signaling response to estradiol in the IGF-1(m/m) mouse
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this mouse study, the abstract examined estradiol signaling through insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor substrate (IRS)-1 in the uterus, including IGF-1(m/m) mice severely deficient in IGF-1. The abstract reports tyrosine-phosphorylated IGF-1R and IRS-1 were found in uteri of estradiol-treated mice, with IRS-1 immunoprecipitates containing p85 and phosphatidylinositol (PI) 3-kinase activity, and estradiol stimulating IRS-1 and PI 3-kinase binding to IGF-1R. In IGF-1(m/m) mice these formations were very weak. IRS-2 was also tyrosine-phosphorylated and bound more IGF-1R and p85 after estradiol, but uterine IRS-2 markedly decreased 12-24 h after estradiol. The authors interpret estradiol activation of uterine IGF-1R kinase as enhancing p85 binding to IRS-1 and IRS-2, with differing roles for these docking proteins.
Abstract
Some of the actions of estradiol occur through stimulation of growth factor pathways in target organs. Tyrosine-phosphorylated (Tyr(P)) insulin-like growth factor-1 receptor (IGF-1R) and the insulin receptor substrate (IRS)-1 are found in the uterus of mice treated with estradiol. Immunoprecipitates of uterine Tyr(P) IRS-1 contained both p85, the regulatory subunit of phosphatidylinositol (PI) 3-kinase, and PI 3-kinase catalytic activity. Estradiol also stimulated binding of IRS-1 and PI 3-kinase to the IGF-1R. Depletion of IRS-1 from uterine extracts reduced PI 3-kinase associated with the receptor, which suggests that binding of the enzyme to IGF-1R occurs primarily in a complex that also contains IRS-1. Following treatment with estradiol, formation of Tyr(P) IGF-1R, Tyr(P) IRS-1, and the p85.IRS-1 complex was very weak in the uterus of IGF-1(m/m) mice, which are severely deficient in IGF-1. This indicated that most, if not all, of the estradiol-stimulated Tyr phosphorylation of uterine IRS-1 originates from ligand activation of IGF-1R kinase. IRS-2 was also Tyr-phosphorylated in the normal uterus and bound more IGF-1R and p85 in response to estradiol; however, a marked decrease in levels of uterine IRS-2 occurred 12-24 h after treatment with estradiol. Since IRS-2 was present in IGF-1R precipitates and a recombinant form of IGF-1 (long R3 IGF-1) stimulated formation of Tyr(P) IRS-2, hormonal activation of this docking protein probably occurs through the IGF-1R. In summary, our findings show that estrogen activation of uterine IGF-1R kinase results in enhanced binding of p85 (PI 3-kinase) to IRS-1 and IRS-2. The formation of one or both of these complexes may be important for the potent mitogenic action of this steroid. That estradiol stimulated a decrease of IRS-2, but not of IRS-1, suggests that these docking proteins have different roles in hormone-induced signaling in the uterus.
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