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Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis

Julie L Boerner1, Jacqueline S Biscardi, Corinne M Silva

  • 1Department of Microbiology, The Cancer Center, University of Virginia Health System, Charlottesville, Virginia 22908, USA.

Molecular Carcinogenesis
|September 17, 2005
PubMed

Insights

Phosphorylation of epidermal growth factor receptor (EGFR) at tyrosine 845 (pY845) is crucial for DNA synthesis. This finding highlights pY845 as a key regulator in cancer progression, potentially involving signal transducer and activator of transcription 5b (STAT5b).

Area of Science:

  • Cellular signaling pathways
  • Cancer biology
  • Molecular oncology

Background:

  • Signaling networks are critical in cancer progression.
  • Epidermal growth factor receptor (EGFR) overexpression is linked to poor prognosis.
  • EGFR is hypothesized to mediate signaling from various cell surface receptors.

Purpose of the Study:

  • To investigate the role of c-Src-dependent phosphorylation of EGFR at tyrosine 845 (Tyr 845) in DNA synthesis.
  • To determine the downstream effectors of pY845 signaling in cancer cells.
  • To elucidate the mechanism by which EGFR signaling contributes to mitogenesis.

Main Methods:

  • Utilized murine fibroblast and breast cancer models.
  • Employed dominant interfering forms of signal transducer and activator of transcription 5b (STAT5b).
  • Microinjected a peptide containing pY845 into SKBr3 breast cancer cells and murine fibroblasts.

Main Results:

  • c-Src-dependent phosphorylation of EGFR at Tyr 845 was essential for DNA synthesis induced by G protein-coupled agonists (ET, LPA) and growth hormone (GH).
  • STAT5b, a downstream effector of pY845, abrogated agonist-induced DNA synthesis in breast cancer models.
  • A pY845-containing peptide inhibited EGF-stimulated S-phase entry in both cell systems.

Conclusions:

  • Phosphorylation of EGFR at Tyr 845 (pY845) is critical for DNA synthesis induced by diverse mitogens.
  • STAT5b is a key signaling effector of pY845, but other effectors may also be involved.
  • Targeting pY845 signaling represents a potential therapeutic strategy in EGFR-driven cancers.

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