Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A

• Published in: Blood Vol. 106; no. 3; pp. 913 - 921
• Main Authors: Kashiwagi, Hirokazu, Shiraga, Masamichi, Kato, Hisashi, Kamae, Tsuyoshi, Yamamoto, Naoko, Tadokoro, Seiji, Kurata, Yoshiyuki, Tomiyama, Yoshiaki, Kanakura, Yuzuru
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.08.2005; The Americain Society of Hematology
• Subjects: Actin Depolymerizing Factors; Actins - metabolism; Antigens, CD - analysis; Biological and medical sciences; Blood coagulation. Blood cells; Blood Platelets - metabolism; Blood Platelets - physiology; Cells, Cultured; Collagen - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Microfilament Proteins - metabolism; Molecular and cellular biology; P-Selectin - analysis; Platelet; Platelet Activation - drug effects; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Platelet Membrane Glycoproteins - analysis; rac GTP-Binding Proteins - metabolism; rac GTP-Binding Proteins - physiology; Recombinant Fusion Proteins - pharmacology; Semaphorin-3A - chemistry; Semaphorin-3A - pharmacology; Semaphorin-3A - physiology; Tetraspanin 30; Thrombin - pharmacology; Human; Endothelial cell; Glycoprotein IIbIIIa; Regulation(control); Platelet; Integrin; Actin; Hemostasis; Platelet function; Secretory protein; Semaphorin 3A; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-10-4092

Semaphorin 3A (Sema3560) is a secreted disulfide-bound homodimeric molecule that induces growth cone collapse and repulsion of axon growth in the nervous system. Recently, it has been demonstrated that Sema3A is produced by endothelial cells and inhibits integrin function in an autocrine fashion. In this study, we investigated the effects of Sema3A on platelet function by using 2 distinct human Sema3A chimera proteins. We detected expression of functional Sema3A receptors in platelets and dose-dependent and saturable binding of Sema3A to platelets. Sema3A dose-dependently inhibited activation of integrin αIIbβ3byall agonists examined including adenosine diphosphate (ADP), thrombin, convulxin, phorbol 12-myristate 13-acetate, and A23187. Sema3A inhibited not only platelet aggregation induced by thrombin or collagen but also platelet adhesion and spreading on immobilized fibrinogen. Moreover, Sema3A impaired αIIbβ3-independent spreading on glass coverslips and aggregation-independent granular secretion. Sema3A inhibited agonist-induced elevation of filamentous action (F-actin) contents, phosphorylation of cofilin, and Rac1 activation. In contrast, Sema3A did not affect the levels of cyclic nucleotides or agonist-induced increase of intracellular Ca2+ concentrations. Thus, the extensive inhibition of platelet function by Sema3A appears to be mediated, at least in part, through impairment of agonist-induced Rac1-dependent actin rearrangement.