The A 2A adenosine receptor is prototypically coupled to stimulation of adenylyl cyclase by means of G s . However, in human endothelial cells, adenosine stimulates proliferation and mitogen-activated protein kinase (MAP kinase) by means of the A 2A receptor in a manner that is independent of cAMP. Here, we have investigated the regulation of p70S6-kinase, which relays signals from membrane-bound growth factor receptors to stimulation of translational efficiency in the G1 phase of the cell cycle. Our experiments show that adenosine analogues promote phosphorylation of p70S6 kinase in endothelial cells. The pharmacologic profile indicates that this effect is mediated by means of the A 2A receptor. We have confirmed this pharmacologic classification by using a transfected Chinese hamster ovary-(CHO) A 2A cell line (which stably expresses the human A 2A adenosine receptor); all findings that were obtained in endothelial cells were faithfully reproduced in CHO-A 2A . The signalling cascade that links the receptor to p70S6 kinase is independent of cAMP and MAP kinase activation but sensitive to rapamycin. Furthermore, the A 2Areceptor-dependent activation of p70S6 kinase stimulation relies on a phosphatidylinositol-3 kinase isoform, because it is inhibited by wortmannin and the synthetic inhibitor LY294002. Conversely, MAP kinase stimulation by the A 2A receptor was not affected by wortmannin. Taken together, our experiments show that the A 2A adenosine receptor regulates cAMP levels, MAP kinase, and p70S6 kinase in human endothelial cells by means of three independent pathways.