Nuclear export of FoxO1 is associated with ERK signaling in β-cells lacking insulin receptors

Teresa Mezza, Andrea Giaccari, Jun Shirakawa, Rachael Martinez, Jiang Hu, Rohit N. Kulkarni

Risultato della ricerca: Contributo in rivistaArticolo in rivista

11 Citazioni (Scopus)

Abstract

The insulin/insulin-like growth factor (IGF) signaling pathway plays a critical role in the regulation of islet cell biology. However, the signaling pathway(s) utilized by insulin to directly modulate β-cells is unclear. To interrogate whether insulin exerts endocrine effects in regulating proteins in the insulin/IGF-1 signaling cascade in vivo in physiological states via the insulin receptor, we designed two experimental approaches: 1) glucose gavage and 2) hyperinsulinemic intravenous infusion, for studies in either β-cell specific insulin receptor knock-out (βIRKO) or control mice. Immunostaining of sections of pancreas (collected immediately after glucose gavage or insulin infusion) from controls showed significant increases in pAKT+, p-p70S6K+, and pERK+ β-cells and a significant decrease in % nuclear FoxO1+ β-cells compared with corresponding vehicle-treated groups. In contrast, in βIRKOs, we observed no significant changes in pAKT+ or p-p70S6K+ β-cells in either experiment; however, pERK+ β-cells were significantly increased, and an attenuated decrease in % nuclear FoxO1+ β cells was evident in response to glucose gavage or insulin infusion. Treatment of control and βIRKO β-cell lines with glucose or insulin showed significantly decreased % nuclear FoxO1+ β-cells suggesting direct effects. Furthermore, blocking MAPK signaling had virtually no effect on FoxO1 nuclear export in controls, in contrast to attenuated export in βIRKO β-cells. These data suggest insulin acts on β-cells in an endocrine manner in the normal situation; and that in β-cells lacking insulin receptors, insulin and glucose minimally activate the Akt pathway, while ERK phosphorylation and FoxO1 nuclear export occur independently of insulin signaling.
Lingua originaleEnglish
pagine (da-a)21485-21495
Numero di pagine11
RivistaTHE JOURNAL OF BIOLOGICAL CHEMISTRY
Volume291
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Biochemistry
  • Cell Biology
  • FOXO
  • Molecular Biology
  • beta cell (β-cell)
  • insulin
  • insulin receptor
  • signal transduction

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