Thrombopoietin increases platelet sensitivity to alpha-thrombin via activation of the ERK2-cPLA2 pathway.
Thrombopoietin (TPO) regulates stem cell proliferation and maturation of megakaryocytes by activating the c-Mp1-receptor, a member of the hematopoietic cytokine family. As human platelets possess c-Mp1-receptors and supraphysiological concentrations of TPO trigger platelet aggregation and secretion, we searched for the signalling pathways through which the c-Mp1-receptor might activate platelets. A physiological concentration of TPO (20 ng/mL) did not trigger platelet functions, but increased their sensitivity to alpha-thrombin resulting in a 4-fold faster dense granule secretion. The effect of TPO was abolished by indomethacin and caused by synergism with signal generation by alpha-thrombin at the level of the cytosolic phospholipase A2 (cPLA2) pathway resulting in more arachidonate release, cPLA2 phosphorylation and thromboxane A2 formation. A similar synergism was seen at the level of extracellular signal-regulated kinase 2 (ERK2 or p42-MAPK). These data suggest, that TPO increases the sensitivity of platelets to alpha-thrombin by enhancing cPLA2 activation via the ERK2-cPLA2 pathway.
van Willigen
G
G
Department of Haematology, University Hospital Utrecht, The Netherlands. G.vanWilligen@lab.azu.nl
Gorter
G
G
Akkerman
J W
JW
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002417:Cattle; D003594:Cytoplasmic Granules / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D054513:Group IV Phospholipases A2; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008301:Maleimides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010741:Phospholipases A / Q000502:physiology*; D054467:Phospholipases A2; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013917:Thrombin / Q000819:agonists*; D013926:Thrombopoietin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
D002227:Carbazoles; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D011725:Pyridines; C081021:Go 6976; D012710:Serum Albumin, Bovine; D012701:Serotonin; D013928:Thromboxane A2; D013926:Thrombopoietin; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2; D013917:Thrombin; C070515:bisindolylmaleimide I; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C064758:Ro 31-8220; D007213:Indomethacin