PT  - JOURNAL ARTICLE
AU  - Buvinic, Sonja
AU  - Bravo-Zehnder, Marcela
AU  - Boyer, José Luis
AU  - Huidobro-Toro, Juan Pablo
AU  - González, Alfonso
TI  - Nucleotide P2Y<sub>1</sub> receptor regulates EGF receptor mitogenic signaling and expression in epithelial cells
AID  - 10.1242/jcs.03490
DP  - 2007 Dec 15
TA  - Journal of Cell Science
PG  - 4289--4301
VI  - 120
IP  - 24
4099  - http://jcs.biologists.org/content/120/24/4289.short
4100  - http://jcs.biologists.org/content/120/24/4289.full
SO  - J. Cell Sci.2007 Dec 15; 120
AB  - 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.