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Nucleotide P2Y1 receptor regulates EGF receptor mitogenic signaling and expression in epithelial cells

Sonja Buvinic1, Marcela Bravo-Zehnder, José Luis Boyer

  • 1Centro de Regulación Celular y Patología JV Luco, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8330033, Santiago, Chile.

Journal of Cell Science
|December 7, 2007
PubMed

Insights

Extracellular nucleotides acting via the P2Y1 receptor (P2Y(1)R) stimulate cell growth by activating epidermal growth factor receptor (EGFR). This pathway highlights P2Y(1)R

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Oncology

Background:

  • G-protein-coupled receptors (GPCRs) modulate epidermal growth factor receptor (EGFR) activity.
  • The P2Y1 receptor (P2Y(1)R), activated by extracellular nucleotides like ADP, is a ubiquitous GPCR.
  • Basal and stimulated cell proliferation are influenced by extracellular signaling molecules.

Purpose of the Study:

  • To investigate the role of P2Y1 receptor (P2Y(1)R) in transactivating EGFR.
  • To elucidate the signaling pathway linking P2Y(1)R stimulation to mitogenesis.
  • To explore the implications of P2Y(1)R-mediated EGFR activation in epithelial cell proliferation and cancer.

Main Methods:

  • Experiments were conducted in tumoral HeLa and normal FRT epithelial cells, as well as MDCK cells.
  • Cell proliferation assays were performed following P2Y(1)R stimulation.
  • Involvement of protein kinase C (PKC), Src, and metalloproteases was assessed.
  • Effects of apyrase and P2Y(1)R inhibitors were evaluated.

Main Results:

  • P2Y(1)R stimulation triggers EGFR transactivation and mitogenesis within 15-60 minutes.
  • The pathway involves PKC, Src, and cell surface metalloproteases.
  • Inhibition of extracellular nucleotides or P2Y(1)R reduced basal proliferation in HeLa and FRT cells.
  • MDCK cells ectopically expressing P2Y(1)R exhibited increased proliferation dependent on EGFR activity.

Conclusions:

  • Cell-released nucleotides act as potent mitogenic stimuli via P2Y(1)R-mediated EGFR activation.
  • P2Y(1)R plays a significant role in EGFR-dependent epithelial cell proliferation.
  • P2Y(1)R represents a potential therapeutic target for cancer treatment.

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