C-SH2 point mutation converts p85\u03b2 regulatory subunit of phosphoinositide 3-kinase to an anti-aging gene

Yoshio Kano,Shigeki Inoue,Hirotoshi Motoda,Junichi Akiyama,Kenji Kawamura,Yutaka Gomita,Tomohisa Furuta,Akihiko Kawaura,Fukumi Hiragami,Yoshihisa Koike

doi:10.1038/s41598-019-48157-6

Abstract

Insulin interacts with the insulin receptor, and the activated receptor promotes activity of the phosphoinositide-3 kinase (PI3K) enzyme. A decrease in insulin or insulin-like growth factor 1 (IGF-1) signaling increases the lifespan in mammalian species. We found that a point mutation in the C-SH2 domain of the p85β regulatory subunit of PI3K results in a prolonged lifespan. In p85β mutant cells, nerve growth factor (NGF) activates the longevity protein FOXO, and the mutant p85β gene produces strong resistance to oxidative stress, which contributes to aging. The p85β gene mutation causes increased serum insulin and low blood glucose in p85β mutant transgenic mice. Our results indicate that the p85β mutant allele alters the activity of downstream targets of PI3K by NGF and platelet-derived growth factor (PDGF) but not by insulin. We report that a point mutation in the C-SH2 domain of p85β transforms p85β into a novel anti-aging gene by abnormally regulating PI3K.

Highlights

Phosphoinositide 3-kinase (PI3K) activity is induced by growth factors such as platelet- derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), nerve growth factor (NGF), and insulin
Serum-starved PC12m3 cells[13] and PC12m321 cells were treated with NGF, EGF, FGF, insulin, and IGF-1
An increase in Akt phosphorylation was detected in PC12m3 cells and PC12m321 cells after stimulation for 30 min with NGF, EGF, FGF, insulin, and IGF-1, but the responses to NGF, EGF, and FGF were weak or absent in PC12m321 cells

Summary

Introduction

Phosphoinositide 3-kinase (PI3K) activity is induced by growth factors such as platelet- derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), nerve growth factor (NGF), and insulin. High Akt activity was observed in PC12m3 cells in both the presence of insulin and the presence of NGF, and the reason for this difference was not apparent. In the case of insulin, PI3K is activated by the binding of PI3K to insulin receptor-bound IRS1, whereas in the case of NGF, PI3K binds directly to the NGF receptor and activates PI3K These findings suggest that PI3K may be mutated in PC12m321 cells and cannot correctly bind to the NGF receptors. The p85α and p85β regulatory subunits both function in several types of cells This suggests that the mutation may be present in either p85α or p85β in PC12m321 cells, leading to the inability of PI3K to bind correctly to the NGF receptor. The mutation corresponds to the binding pocket for the NGF receptor (TrkA) in the C-SH2 domain of the p85β regulatory subunit gene of class I PI3K, resulting in replacement of a lysine with an arginine. A serine/threonine protein kinase, is a key downstream mediator of PI3K signaling[12] and negatively regulates FOXO

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Conclusion