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Activation of P2Y2 receptor induces c‐FOS protein through a pathway involving mitogen‐activated protein kinases and phosphoinositide 3‐kinases in HeLa cells
Author(s) -
Muscella Antonella,
Elia Maria Giovanna,
Greco Simona,
Storelli Carlo,
Marsigliante Santo
Publication year - 2003
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10242
Subject(s) - wortmannin , kinase , ly294002 , microbiology and biotechnology , mapk/erk pathway , protein kinase c , phosphorylation , signal transduction , biology , protein kinase a , phosphoinositide 3 kinase , protein kinase b , phosphatidylinositol
The effects of P2Y2 purinoceptor activation on c‐Fos expression and the signaling pathways evoked by extracellular ATP/UTP in HeLa cells were investigated. We found that P2Y2 activation induced c‐Fos protein and phosphorylated the extracellular signal‐regulated kinases 1 and 2 (ERK1/2). The P2Y2‐stimulated c‐Fos induction was partly blocked (a) by U73122, a phospholipase C inhibitor, (b) by Gö6976, a conventional PKC inhibitor, (c) by PD098059, a mitogen‐activated protein kinase kinase inhibitor, and, moreover, (d) by the inhibitors of phosphoinositide 3‐kinases (PI3K), LY294002 and wortmannin. When Gö6976 and PD098059, or Gö6976 and wortmannin, were combined there was a totally inhibition of P2Y2‐induced c‐Fos increase. Either U73122 or Gö6976 did not inhibit ERK1/2 phosphorylation induced by ATP/UTP, while it was inhibited by LY294002 (or wortmannin) and by staurosporine. Additionally, wortmannin inhibited the cytosol‐to‐membrane translocation of PKC‐ε induced by ATP/UTP. These data indicated that agonist‐induced PI3K and downstream PKC‐ε activation mediated the effect of ATP/UTP on ERK1/2 activation. To test the biological consequences of ERK1/2 activation, the effect of P2Y2 on cell functions were examined. P2Y2 stimulation increased cell proliferation and this effect was attenuated by PD098059 in a dose‐dependent manner, thereby indicating that the ERK pathway mediates mitogenic signaling by P2Y2. In conclusion, the activation of conventional PKCs through P2Y2 receptor acts in concert with ERK and PI3K/PKC‐ε pathways to induce c‐Fos protein and HeLa cell proliferation. © 2003 Wiley‐Liss, Inc.