Da Q, Shaw T, Pradhan S, Roche P A, Cruz M A, Vijayan K Vinod
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.
J Thromb Haemost. 2017 May;15(5):1032-1039. doi: 10.1111/jth.13671. Epub 2017 Apr 13.
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.
血管性血友病因子（VWF）的内皮分泌促进炎症和血栓形成。我们研究了蛋白磷酸酶2B（PP2B）和Munc18c蛋白复合物在VWF分泌中的作用。内皮细胞中PP2B-Munc18c复合物的破坏减少了激动剂诱导的VWF分泌。PP2B-Munc18c复合物是血栓形成和炎症性疾病的一个潜在靶点。
背景 内皮细胞中血管性血友病因子（VWF）的异常分泌导致炎症和血管血栓形成。激动剂诱导的VWF分泌由蛋白激酶和磷酸酶介导的信号传导促进。尽管蛋白磷酸酶2B（PP2B-Aα）的催化亚基通过与内皮细胞中囊泡运输蛋白Munc18c的相互作用靶向分泌机制，但这种磷酸酶复合物的功能相关性尚不清楚。目的 评估PP2B-Aα-Munc18c复合物对内皮VWF分泌的贡献。结果 在这里，我们表明PP2B-Aα的120-130位氨基酸对于支持与Munc18c的相互作用很重要。一种合成的肉豆蔻酰化细胞可渗透肽，其衍生自PP2B-Aα的121-130位氨基酸，破坏了人脐静脉内皮细胞中的内源性PP2B-Aα-Munc18c复合物，并降低了低剂量组胺刺激和凝血酶刺激的VWF分泌。结论 这些研究表明PP2B-Aα-Munc18c复合物支持激动剂诱导的VWF分泌，并提示在血栓形成和炎症性疾病中靶向这种磷酸酶复合物的潜力。
