Öppna denna publikation i ny flik eller fönster >>Örebro universitet, Institutionen för medicinska vetenskaper.
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Örebro universitet, Institutionen för medicinska vetenskaper.
Division of Organic Chemistry, Linköping University, Linköping, Sweden.
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom; Division of Biomolecular Science and Medicinal Chemistry, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
Division of Organic Chemistry, Linköping University, Linköping, Sweden.
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
Örebro universitet, Institutionen för medicinska vetenskaper.
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2019 (Engelska)Ingår i: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 3, nr 3, s. 275-287Artikel i tidskrift (Refereegranskat) Published
Abstract [en]
Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.
Ort, förlag, år, upplaga, sidor
American Society of Hematology, 2019
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Hematologi
Identifikatorer
urn:nbn:se:oru:diva-72478 (URN)10.1182/bloodadvances.2018024950 (DOI)000458442500007 ()30700416 (PubMedID)2-s2.0-85060943358 (Scopus ID)
Forskningsfinansiär
KK-stiftelsen
Anmärkning
Funding Agencies:
BHF PG/16/53/32242 RG/13/18/30563
Deutsche Forschungsgemeinschaft DFG: Eb 177/14-1
Fonds voor Wetenschappelijk Onderzoek Vlaanderen grant G0A6514N
2019-02-142019-02-142024-03-06Bibliografiskt granskad