ArticleArteriosclerosis, thrombosis, and vascular biology2016
Intracellular Trafficking, Localization, and Mobilization of Platelet-Borne Thiol Isomerases.
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Article in Arteriosclerosis, thrombosis, and vascular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38citing papers in PubMed
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38 citing papers in PubMed, 60 citations in OpenAlex.
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- Recent advances in vascular thiol isomerases: insights into structures, functions in thrombosis and antithrombotic inhibitor development.Thrombosis journal · 2025Review
- Looking Under the Hood at the Cytoskeletal Engine of Platelet Production.Arteriosclerosis, thrombosis, and vascular biology · 2025Review
- HSP47 at the Crossroads of Thrombosis and Collagen Dynamics: Unlocking Therapeutic Horizons and Debates.TH open : companion journal to thrombosis and haemostasis · 2025Review
- Targeting cargo to an unconventional secretory system within megakaryocytes allows the release of transgenic proteins from platelets.Journal of thrombosis and haemostasis : JTH · 2024Article
- Human platelets contain a pool of free zinc in dense granules.Research and practice in thrombosis and haemostasis · 2024Article
- Megakaryocytes possess a STING pathway that is transferred to platelets to potentiate activation.Life science alliance · 2024Article
- Role of heat shock protein 47 in platelet glycoprotein VI dimerization and signaling.Research and practice in thrombosis and haemostasis · 2023Article
- ADP receptor P2Y12 is the capstone of the cross-talk between CaResearch and practice in thrombosis and haemostasis · 2023Article
- Platelet-Derived Exosomes in Atherosclerosis.International journal of molecular sciences · 2022Review
- Article
- ERp57/PDIA3: new insight.Cellular & molecular biology letters · 2022Review
- Selective Secretion of KDEL-Bearing Proteins: Mechanisms and Functions.Frontiers in cell and developmental biology · 2022Review
- Protein disulfide isomerase-A1 regulates intraplatelet reactive oxygen species-thromboxane AJournal of thrombosis and haemostasis : JTH · 2022Article
- Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors.Antioxidants (Basel, Switzerland) · 2021Article
- Article
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Authors and funding
15 authors at 3 institutions in 2 countries.
Marilena CrescenteFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Fred G PlutheroFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Ling LiFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Richard W LoFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Tony G WalshFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Michael P SchenkFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Lisa M HolbrookFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Silvia LourieroFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Marfoua S AliFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Sakthivel VaiyapuriFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Hervé FaletFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Ian M JonesFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Alastair W PooleFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.).
Walter H A KahrFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.). j.m.gibbins@reading.ac.uk walter.kahr@sickkids.ca.
Jonathan M GibbinsFrom the School of Biological Sciences, University of Reading, Reading, United Kingdom (M.C., M.P.S., L.M.H., S.L., M.S.A., S.V., I.M.J., J.M.G.); Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (F.G.P., L.L., R.W.L., W.H.A.K.); Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, Ontario, Canada (R.W.L., W.H.A.K.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (T.G.W., A.W.P.); and Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA (H.F.). j.m.gibbins@reading.ac.uk walter.kahr@sickkids.ca.
University of Toronto · CAUniversity of Bristol · GBUniversity of Reading · GB
Funding
Endocytosis in platelet and megakaryocyte biologyR01HL126743 · NHLBI · VERSITI WISCONSIN, INC. · PI FALET, HERVE · 2016 to 2019
$1.7MBritish Heart Foundation PG/11/125/29320British Heart Foundation PG/13/14/30023British Heart Foundation RG/10/006/28299British Heart Foundation RG/15/16/31758CIHR MOP-259952Medical Research Council MR/J002666/1Medical Research Council MR/J008796/1NHLBI NIH HHS R01 HL126743
Abstract
objectiveThiol isomerases facilitate protein folding in the endoplasmic reticulum, and several of these enzymes, including protein disulfide isomerase and ERp57, are mobilized to the surface of activated platelets, where they influence platelet aggregation, blood coagulation, and thrombus formation. In this study, we examined the synthesis and trafficking of thiol isomerases in megakaryocytes, determined their subcellular localization in platelets, and identified the cellular events responsible for their movement to the platelet surface on activation. APPROACH AND
resultsImmunofluorescence microscopy imaging was used to localize protein disulfide isomerase and ERp57 in murine and human megakaryocytes at various developmental stages. Immunofluorescence microscopy and subcellular fractionation analysis were used to localize these proteins in platelets to a compartment distinct from known secretory vesicles that overlaps with an inner cell-surface membrane region defined by the endoplasmic/sarcoplasmic reticulum proteins calnexin and sarco/endoplasmic reticulum calcium ATPase 3. Immunofluorescence microscopy and flow cytometry were used to monitor thiol isomerase mobilization in activated platelets in the presence and absence of actin polymerization (inhibited by latrunculin) and in the presence or absence of membrane fusion mediated by Munc13-4 (absent in platelets from Unc13d(Jinx) mice).
conclusionsPlatelet-borne thiol isomerases are trafficked independently of secretory granule contents in megakaryocytes and become concentrated in a subcellular compartment near the inner surface of the platelet outer membrane corresponding to the sarco/endoplasmic reticulum of these cells. Thiol isomerases are mobilized to the surface of activated platelets via a process that requires actin polymerization but not soluble N-ethylmaleimide-sensitive fusion protein attachment receptor/Munc13-4-dependent vesicular-plasma membrane fusion.
Indexed as
Platelet ActivationActinsAnimalsBlood PlateletsBlood ProteinsCalnexinCell MembraneGenotypeHumansMegakaryocytesMembrane FusionMembrane ProteinsMiceMice, Inbred C57BLMice, KnockoutPhenotypeActinsBlood ProteinsCalnexinMembrane ProteinsNbeal2 protein, mousePDIA3 protein, humanPdia3 protein, mouseProtein Disulfide-IsomerasesSarcoplasmic Reticulum Calcium-Transporting ATPasesUNC13D protein, humanUnc13d protein, mouseblood plateletsmegakaryocytesmembrane fusionprotein disulfide isomerasessecretory vesicles
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