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Nuclear export-independent inhibition of Foxa2 by insulin

Jessica J Howell1, Markus Stoffel

  • 1Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, Wolfgang-Pauli Strasse 16, 8093 Zurich, Switzerland.

The Journal of Biological Chemistry
|July 11, 2009
PubMed

Insights

The Forkhead box A2 (Foxa2) transcription factor

Area of Science:

  • Metabolic regulation
  • Molecular endocrinology
  • Hepatology

Background:

  • Forkhead box A2 (Foxa2) is crucial for liver glucose and lipid homeostasis.
  • Foxa2 inactivation exacerbates metabolic phenotypes in obesity and hyperinsulinemia.
  • Insulin signaling inhibits Foxa2 activity via phosphorylation and nuclear exclusion.

Purpose of the Study:

  • To elucidate the mechanism and significance of Foxa2 nuclear export.
  • To investigate the role of phosphorylation in Foxa2 inactivation by insulin.

Main Methods:

  • Demonstration of a functional nuclear export signal in Foxa2.
  • Investigation of CRM1-dependent nuclear exclusion pathway.
  • In vitro and in vivo phosphorylation assays of nuclear export-defective Foxa2.

Main Results:

  • Foxa2 possesses a functional nuclear export signal, mediating insulin-induced nuclear exclusion via CRM1.
  • Nuclear export-defective Foxa2 is phosphorylated and inactivated by insulin.
  • Phosphorylation is identified as the primary mechanism for Foxa2 inhibition by insulin signaling.

Conclusions:

  • Insulin signaling inhibits Foxa2 activity primarily through phosphorylation, not solely nuclear export.
  • Export-independent mechanisms contribute to Foxa2 inhibition under insulin signaling.
  • Foxa2 regulation is critical for maintaining metabolic homeostasis in the liver.

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