title: Fucoidan is a novel platelet agonist for the C-type lectin-like receptor 2 (CLEC-2).
abstract: Fucoidan, a sulfated polysaccharide from Fucus vesiculosus, decreases bleeding time and clotting time in hemophilia, possibly through inhibition of tissue factor pathway inhibitor. However, its effect on platelets and the receptor by which fucoidan induces cellular processes has not been elucidated. In this study, we demonstrate that fucoidan induces platelet activation in a concentration-dependent manner. Fucoidan-induced platelet activation was completely abolished by the pan-Src family kinase (SFK) inhibitor, PP2, or when Syk is inhibited. PP2 abolished phosphorylations of Syk and Phospholipase C-γ2. Fucoidan-induced platelet activation had a lag phase, which is reminiscent of platelet activation by collagen and CLEC-2 receptor agonists. Platelet activation by fucoidan was only slightly inhibited in FcRγ-chain null mice, indicating that fucoidan was not acting primarily through GPVI receptor. On the other hand, fucoidan-induced platelet activation was inhibited in platelet-specific CLEC-2 knock-out murine platelets revealing CLEC-2 as a physiological target of fucoidan. Thus, our data show fucoidan as a novel CLEC-2 receptor agonist that activates platelets through a SFK-dependent signaling pathway. Furthermore, the efficacy of fucoidan in hemophilia raises the possibility that decreased bleeding times could be achieved through activation of platelets.
authors: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140; Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
authors: Bhanu Kanth
authors: BK
authors: Manne
authors: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140; Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
authors: Todd M
authors: TM
authors: Getz
authors: Centre for Cardiovascular Sciences, Institute for Biomedical Research, The College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors: Craig E
authors: CE
authors: Hughes
authors: Centre for Cardiovascular Sciences, Institute for Biomedical Research, The College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors: Osama
authors: O
authors: Alshehri
authors: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140; Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
authors: Carol
authors: C
authors: Dangelmaier
authors: Cardiovascular Research Institute, University of Delaware, Newark, Delaware 19716.
authors: Ulhas P
authors: UP
authors: Naik
authors: Centre for Cardiovascular Sciences, Institute for Biomedical Research, The College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors: Steve P
authors: SP
authors: Watson
authors: Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140; Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140; Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140. Electronic address: spk@temple.edu.
authors: Satya P
authors: SP
authors: Kunapuli
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects*; D005434:Flow Cytometry / Q000379:methods; D006467:Hemophilia A / Q000188:drug therapy; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D037181:Lectins, C-Type / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects; D011134:Polysaccharides / Q000737:chemistry*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000925:Anticoagulants; C529518:CLEC-2 protein, mouse; C104778:CLEC2B protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011134:Polysaccharides; C007789:fucoidan; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases