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First published online December 5, 2007
doi: 10.1242/10.1242/jcs.03490

Journal of Cell Science 120, 4289-4301 (2007)
Published by The Company of Biologists 2007
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Research Article

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

Sonja Buvinic1,2, Marcela Bravo-Zehnder1,2,3, José Luis Boyer4,5, Juan Pablo Huidobro-Toro1,2 and Alfonso González1,2,3,*

1 Centro de Regulación Celular y Patología JV Luco, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8330033, Santiago, Chile
2 Millennium Institute for Fundamental and Applied Biology (MIFAB), 7780344 Santiago, Chile
3 Departamento de Inmunología Clínica y Reumatología, Facultad Medicina, Pontificia Universidad Católica de Chile, 8330033, Santiago, Chile
4 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
5 INSPIRE Pharmaceuticals Inc., Durham, NC 27703, USA

* Author for correspondence (e-mail: agonzara{at}med.puc.cl)

Accepted 17 September 2007

Epidermal growth factor receptor (EGFR) function is transregulated by a variety of stimuli, including agonists of certain G-protein-coupled receptors (GPCRs). One of the most ubiquitous GPCRs is the P2Y1 receptor (P2RY1, hereafter referred to as P2Y1R) for extracellular nucleotides, mainly ADP. Here, we show in tumoral HeLa cells and normal FRT epithelial cells that P2Y1R broadcasts mitogenic signals by transactivating the EGFR. The pathway involves PKC, Src and cell surface metalloproteases. Stimulation of P2Y1R for as little as 15-60 minutes triggers mitogenesis, mirroring the half-life of extracellular ADP. Apyrase degradation of extracellular nucleotides and drug inhibition of P2Y1R, both reduced basal cell proliferation of HeLa and FRT cells, but not MDCK cells, which do not express P2Y1R. Thus, cell-released nucleotides constitute strong mitogenic stimuli, which act via P2Y1R. Strikingly, MDCK cells ectopically expressing P2Y1R display a highly proliferative phenotype that depends on EGFR activity associated with an increased level of EGFR, thus disclosing a novel aspect of GPCR-mediated regulation of EGFR function. These results highlight a role of P2Y1R in EGFR-dependent epithelial cell proliferation. P2Y1R could potentially mediate both trophic stimuli of basally released nucleotides and first-line mitogenic stimulation upon tissue damage. It could also contribute to carcinogenesis and serve as target for antitumor therapies.

Key words: Nucleotides, GPCR, EGFR, Transactivation, Epithelia, Proliferation






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