title: Disruption of protein complexes containing protein phosphatase 2B and Munc18c reduces the secretion of von Willebrand factor from endothelial cells.
abstract: Essentials Endothelial secretion of von Willebrand factor (VWF) promotes inflammation and thrombosis. We studied the role of protein phosphatase 2B (PP2B) and Munc18c protein complex in VWF secretion. Disruption of PP2B-Munc18c complex in endothelial cells reduced agonist-induced VWF secretion. PP2B-Munc18c complex represents a potential target for thrombotic and inflammatory conditions.
  
  
  
  Background Aberrant secretion of von Willebrand factor (VWF) from endothelial cells contributes to inflammation and vascular thrombosis. Agonist-induced VWF secretion is facilitated by protein kinase and phosphatase-mediated signaling. Although the catalytic subunit of protein phosphatase 2B (PP2B-Aα) is targeted to the secretory machinery via an interaction with the vesicle trafficking protein Munc18c in endothelial cells, the functional relevance of this phosphatase complex is unclear. Objective To assess the contribution of the PP2B-Aα-Munc18c complex to endothelial VWF secretion. Results Here, we show that amino acids 120-130 of PP2B-Aα are important to support an interaction with Munc18c. A synthetic myristylated cell-permeable peptide, which is derived from amino acids 121-130 of PP2B-Aα, disrupted endogenous PP2B-Aα-Munc18c complexes in human umbilical vein endothelial cells, and decreased low-dose histamine-stimulated and thrombin-stimulated VWF secretion. Conclusion These studies indicate that PP2B-Aα-Munc18c complex supports agonist-induced VWF secretion, and suggest the potential of targeting this phosphatase complex in thrombotic and inflammatory conditions.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, TX, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Da
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Shaw
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pradhan
authors.affiliation: National Cancer Institute, Bethesda, MD, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Roche
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.|Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Cruz
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.|Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: K Vinod
authors.initials: KV
authors.lastname: Vijayan
mesh_terms: D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D006632:Histamine / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D051938:Munc18 Proteins / Q000378:metabolism*; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013917:Thrombin / Q000494:pharmacology; D014162:Transfection; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D051938:Munc18 Proteins; D010446:Peptide Fragments; D014841:von Willebrand Factor; D006632:Histamine; D019703:Calcineurin; D013917:Thrombin
keywords: Munc18c protein; SNAP23 protein human; exocytosis; protein phosphatase 2B; von Willebrand factor