Glycoprotein Ib-mediated platelet activation. A signalling pathway triggered by thrombin.
Platelet activation by thrombin plays a major role in the development of haemostasis and thrombosis. Thrombin activates human platelets by cleaving the N-terminal region of G-protein-coupled protease-activated receptors (PARs). On the other hand, the platelet membrane glycoprotein GPIb acts as a thrombin-binding site and promotes platelet activation by low thrombin concentrations. We present here new evidence in favour of a thrombin receptor function for GPIb. We have selected conditions in which thrombin-GPIb interactions were enhanced by thrombin immobilization. Activation was studied independently of PAR cleavage by using active-site-blocked thrombin. We show that immobilized, proteolytically inactive thrombin induces platelet adhesion and spreading, dense granule secretion and integrin alphaIIbbeta3-dependent platelet-platelet interactions. The pathway must be dependent on GPIb because it is deficient in platelets from a patient with Bernard Soulier syndrome and inhibited by a monoclonal antibody to GPIb (SZ2) or by an excess of glycocalicin. Secreted ADP plays a major role in GPIb-dependent thrombin-induced platelet activation which is, in addition, regulated by cAMP concentration. Thrombin-induced GPIb-dependent platelet activation leads to tyrosyl phosphorylation of several proteins. Inhibition of platelet-platelet interactions and protein tyrosine phosphorylations by inhibitors of phosphatidylinositol 3-kinases and protein kinase C implies that activation of the latter are important steps of the GPIb-coupled signalling pathway triggered by thrombin.
Adam
Frédéric
F
INSERM E0348, Faculté Xavier Bichat, Paris, France.
Guillin
Marie-Claude
MC
Jandrot-Perrus
Martine
M
D000244:Adenosine Diphosphate / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001606:Bernard-Soulier Syndrome / Q000378:metabolism; D001792:Blood Platelets / Q000502:physiology* / Q000648:ultrastructure; D000242:Cyclic AMP / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D018179:Receptors, Thrombin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D018179:Receptors, Thrombin; C023592:glycocalicin; D014443:Tyrosine; D000244:Adenosine Diphosphate; D000242:Cyclic AMP; D011493:Protein Kinase C; D013917:Thrombin; D000077191:Wortmannin