Dissociation of phosphatidylinositol-3 kinase activity and mitogenic inhibition in vascular smooth muscle cells.
Phosphatidylinositol-3 kinase becomes activated upon association with stimulated tyrosine kinase coupled receptors, but it is also catalytically active in platelets incubated with the G-protein coupled growth factor receptor agonist, thrombin. Furthermore, phorbol esters have been shown to be growth inhibitory when added to vascular smooth muscle cells simultaneously with thrombin. In order to clarify the role of phosphatidylinositol-3 (PI-3) kinase in thrombin-induced mitogenesis, we asked whether PI-3 kinase activity is decreased in parallel to mitogenesis in cells stimulated with phorbol-12-myristate-13-acetate (PMA) and thrombin. Although PMA inhibits thrombin-stimulated growth by 92% when the two compounds are added simultaneously, the level of PI-3 kinase activity under similar conditions is not decreased. This phenomenon is independent of protein kinase C, since there is no difference in PI-3 kinase activity when similar experiments are performed after protein kinase C is down-regulated by 24 h pre-incubation with PMA. We conclude that either (i) PI-3 kinase is not required for the mitogenic signalling of thrombin, or (ii) PMA is acting downstream of PI-3 kinase in thrombin's signalling pathway.
Weiss
R H
RH
Department of Internal Medicine, University of California, Davis 95616, USA.
Apostolidis
A
A
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate