Disruption of protein complexes containing protein phosphatase 2B and Munc18c reduces the secretion of von Willebrand factor from endothelial cells

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-A alpha) 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-A alpha-Munc18c complex to endothelial VWF secretion. Results: Here, we show that amino acids 120-130 of PP2B-A alpha are important to support an interaction with Munc18c. A synthetic myristylated cell-permeable peptide, which is derived from amino acids 121-130 of PP2B-A alpha, disrupted endogenous PP2B-A alpha-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-A alpha-Munc18c complex supports agonist-induced VWF secretion, and suggest the potential of targeting this phosphatase complex in thrombotic and inflammatory conditions.