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A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I

M B Martin1, T F Franke, G E Stoica

  • 1Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA.

Endocrinology
|December 7, 2000
PubMed

Insights

The serine/threonine protein kinase, Akt, mediates cross-talk between growth factor receptors and estrogen receptor-alpha (ER-alpha). Akt activation by EGF and IGF-I influences ER-alpha expression and activity.

Area of Science:

  • Cellular Biology
  • Molecular Endocrinology
  • Signal Transduction

Background:

  • Cross-talk between growth factor signaling pathways and nuclear receptors is crucial for cellular regulation.
  • Epidermal growth factor (EGF) and insulin-related growth factor I (IGF-I) signaling pathways are known to influence estrogen receptor-alpha (ER-alpha) activity.
  • The role of serine/threonine protein kinase, Akt, in mediating this cross-talk requires further elucidation.

Purpose of the Study:

  • To investigate the involvement of Akt in the cross-talk between EGF/IGF-I receptors and ER-alpha.
  • To determine the downstream effects of Akt activation on ER-alpha expression and activity.
  • To identify specific mechanisms by which Akt modulates ER-alpha function.

Main Methods:

  • Treatment of MCF-7 cells with EGF or IGF-I and assessment of Akt phosphorylation and activity.
  • Use of phosphatidylinositol 3-kinase and p70S6K inhibitors to study Akt activation.
  • Stable transfection of cells with dominant-negative or constitutively active Akt mutants.
  • Coexpression studies in COS-1 cells with ER-alpha and Akt mutants.
  • Analysis of ER-alpha, progesterone receptor, and pS2 expression at protein and mRNA levels.
  • Site-directed mutagenesis of ER-alpha to identify key residues involved in Akt-mediated activation.

Main Results:

  • EGF and IGF-I treatment rapidly activated Akt in MCF-7 cells.
  • Akt activation was dependent on phosphatidylinositol 3-kinase but not p70S6K.
  • Dominant-negative Akt blocked EGF/IGF-I effects on ER-alpha, while constitutively active Akt mimicked them.
  • Constitutively active Akt decreased ER-alpha levels and increased progesterone receptor and pS2 levels.
  • Akt enhanced ER-alpha activity via the amino-terminal activation function-1 (AF-1), involving serines S104, S106, S118, and S167.

Conclusions:

  • Akt plays a critical role in mediating the cross-talk between EGF/IGF-I receptors and ER-alpha.
  • Akt activation by growth factors leads to modulation of ER-alpha expression and transcriptional activity.
  • Specific serine residues in ER-alpha are essential for Akt-mediated functional regulation.

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