Reversible exposure of human platelet fibrinogen receptors by antiplatelet tetraspanin monoclonal antibodies via induction of a conformational change in membrane glycoprotein IIb/IIIa complex.
Antihuman platelet tetraspanin (CD9 antigen) monoclonal antibodies, HI117 and SJ9A4, can induce human platelet aggregation and secretion. As platelet aggregation is mediated by fibrinogen binding to its receptors exposed on platelet glycoprotein IIb/IIIa complex, we, therefore, investigated the induction of platelet fibrinogen receptors by HI117 and SJ9A4. It was found that HI117 and SJ9A4 induced specific fibrinogen binding to human platelets, suggesting that the two monoclonal antibodies evoked obvious exposure of fibrinogen receptors on human platelets. But in the absence of fibrinogen, the monoclonal antibody-exposed fibrinogen receptors gradually lost their capacity to bind fibrinogen and closed. Our results also showed that HI117 and SJ9A4, when activating platelets, caused a conformational change in glycoprotein IIb/IIIa complex, which must contribute to the exposure of functional fibrinogen receptors on this integrin. The effect of HI117 and SJ9A4 on glycoprotein IIb/IIIa complex seems, however, to be indirect, because the HI1117 and SJ9A4-induced fibrinogen binding was reduced by pretreatment of platelets with sphingosine, aspirin, apyrase, and/or PGI2. Taken together, we conclude that the antihuman platelet tetraspanin monoclonal antibodies, HI117 and SJ9A4, reversibly expose platelet fibrinogen receptors via inducing a conformational change in glycoprotein IIb/IlIa complex. Three signaling pathways, that is, thromboxane, secreted ADP, and cAMP pathways may be involved in this process, while protein kinase C activation seems to be the final common step of the three pathways.
Wu
H
H
Laboratory of Thrombosis and Hemostasis, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin. hzwu@public.tpt.tj.cn
Peng
L
L
Li
J
J
Wu
W
W
Hou
Q
Q
Liu
H
H
Wang
M
M
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology*; D001665:Binding Sites; D001792:Blood Platelets / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008562:Membrane Glycoproteins; D010974:Platelet Aggregation / Q000187:drug effects / Q000276:immunology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D060245:Tetraspanin 29
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C554869:CD9 protein, human; D008562:Membrane Glycoproteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D060245:Tetraspanin 29