QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

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

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buvinic, S. Articles by González, A. Search for Related Content PubMed PubMed Citation Articles by Buvinic, S. Articles by González, A. Social Bookmarking                         What's this?

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

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				I. Grimm, N. Messemer, M. Stanke, C. Gachet, and H. Zimmermann Coordinate pathways for nucleotide and EGF signaling in cultured adult neural progenitor cells J. Cell Sci., July 15, 2009; 122(14): 2524 - 2533. [Abstract] [Full Text] [PDF]

				A. W. Boots, M. Hristova, D. I. Kasahara, G. R. M. M. Haenen, A. Bast, and A. van der Vliet ATP-mediated Activation of the NADPH Oxidase DUOX1 Mediates Airway Epithelial Responses to Bacterial Stimuli J. Biol. Chem., June 26, 2009; 284(26): 17858 - 17867. [Abstract] [Full Text] [PDF]

				A. Norambuena, M. I. Poblete, M. V. Donoso, C. S. Espinoza, A. Gonzalez, and J. P. Huidobro-Toro P2Y1 Receptor Activation Elicits Its Partition out of Membrane Rafts and Its Rapid Internalization from Human Blood Vessels: Implications for Receptor Signaling Mol. Pharmacol., December 1, 2008; 74(6): 1666 - 1677. [Abstract] [Full Text] [PDF]