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Insulin-like growth factor-I induces the phosphorylation and nuclear exclusion of forkhead transcription factors in

T S Schwab1, B B Madison, A R Grauman

  • 1Department of Neurology, University of Michigan, 4414 Kresge III, 200 Zina Pitcher Place, Ann Arbor, MI 48109, USA.

Apoptosis : an International Journal on Programmed Cell Death
|September 1, 2005
PubMed

Insights

Insulin-like growth factor-I (IGF-I) promotes neuroblastoma cell survival by phosphorylating forkhead proteins FKHR and FKHRL1. This process, dependent on PI3-K signaling, regulates their cytoplasmic localization, preventing apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Akt-mediated phosphorylation of forkhead transcription factors is a known mechanism for growth factor-stimulated cell survival.
  • The role of this pathway in neuroblastoma cell survival, particularly concerning insulin-like growth factor-I (IGF-I), requires further investigation.

Purpose of the Study:

  • To investigate the association between IGF-I survival activity in SH-SY5Y human neuroblastoma cells and the phosphorylation and localization of forkhead proteins.
  • To elucidate the specific signaling pathways involved in IGF-I-mediated regulation of forkhead transcription factors.

Main Methods:

  • Utilized SH-SY5Y human neuroblastoma cells.
  • Stimulated cells with IGF-I and employed PI3-K inhibitor LY294002 and Crm1 inhibitor Leptomycin B.
  • Assessed phosphorylation of FKHR, FKHRL1, Akt, and Erks using Western blotting.
  • Tracked localization of GFP-FKHR fusion protein via microscopy.

Main Results:

  • IGF-I induced phosphorylation of FKHR (at Ser 253), FKHRL1 (at Ser 256), Akt (at Ser 473), and Erks.
  • PI3-K inhibition blocked IGF-I-stimulated phosphorylation of FKHR, FKHRL1, and Akt, but not Erks.
  • IGF-I promoted nuclear export of GFP-FKHR during serum withdrawal-induced apoptosis rescue.
  • Leptomycin B inhibited FKHRL1 phosphorylation and GFP-FKHR nuclear export in the presence of IGF-I.

Conclusions:

  • IGF-I promotes survival of neuroblastoma cells by phosphorylating FKHR and FKHRL1 through a PI3-K-dependent pathway.
  • This phosphorylation event is linked to the cytoplasmic localization of these transcription factors, preventing their nuclear import and subsequent apoptosis.
  • The findings highlight a critical signaling axis for neuroblastoma cell survival regulated by IGF-I.

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