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Transactivation of the EGF receptor mediates IGF-1-stimulated shc phosphorylation and ERK1/2 activation in COS-7

F L Roudabush1, K L Pierce, S Maudsley

  • 1Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. Luttrell@receptor-biol.duke.edu

The Journal of Biological Chemistry
|May 16, 2000
PubMed

Insights

Insulin-like growth factor 1 receptor (IGF-1R) activation triggers epidermal growth factor receptor (EGFR) transactivation, leading to Shc protein phosphorylation and ERK cascade activation. This cross-talk mechanism is crucial for IGF-1

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Receptor tyrosine kinases

Background:

  • Insulin-like growth factor 1 receptor (IGF-1R) signaling pathways regulate cell proliferation and survival.
  • Cross-talk between IGF-1R and epidermal growth factor receptor (EGFR) is implicated in cellular responses.
  • Understanding these interactions is key to deciphering complex cellular signaling networks.

Purpose of the Study:

  • To investigate the role of cross-talk between IGF-1R and EGFR in mediating cellular responses to IGF-1.
  • To elucidate the specific molecular mechanisms underlying IGF-1-induced signaling pathway activation.
  • To determine how IGF-1R activation influences EGFR activity and downstream signaling.

Main Methods:

  • Stimulation of COS-7 cells with IGF-1.
  • Immunoprecipitation assays to detect protein-protein interactions (EGFR-Shc complexes).
  • Western blotting to assess tyrosine phosphorylation of key signaling proteins (IGF-1R, EGFR, IRS-1, Shc, ERK1/2, Akt).
  • Pharmacological inhibition of EGFR kinase (Tyrphostin AG1478), HB-EGF activity ([Glu(52)]Diphtheria toxin), and metalloproteases (1,10-phenanthroline).

Main Results:

  • IGF-1 stimulation induced tyrosine phosphorylation of IGF-1R, EGFR, IRS-1, and Shc.
  • IGF-1R activation led to the assembly of EGFR-Shc complexes.
  • EGFR kinase inhibition significantly reduced IGF-1-stimulated phosphorylation of Shc and ERK1/2, but not IGF-1R, IRS-1, or Akt.
  • IGF-1-mediated ERK activation was dependent on matrix metalloprotease-released heparin-binding EGF (HB-EGF).
  • Distinct mechanisms mediate IGF-1 stimulation of the IRS-1/PI3K/Akt and EGFR/Shc/ERK1/2 pathways.

Conclusions:

  • IGF-1R activation initiates distinct signaling pathways: IRS-1/PI3K/Akt and EGFR/Shc/ERK1/2.
  • "Transactivation" of EGFR by IGF-1R is the primary mechanism for Shc phosphorylation and ERK cascade activation.
  • This cross-talk involves an autocrine loop mediated by HB-EGF release.
  • The findings clarify the differential signaling mechanisms initiated by IGF-1 through its receptor.

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