title: New lipid interaction partners stimulate the inhibition of activated protein C by cell-penetrating protein C inhibitor.
abstract: Protein C inhibitor (PCI, SerpinA5) is a heparin-binding serpin which can penetrate through cellular membranes. Selected negatively charged phospholipids like unsaturated phosphatidylserine and oxidised phosphatidylethanolamine bind to PCI and stimulate its inhibitory activity towards different proteases. The interaction of phospholipids with PCI might also alter the lipid distribution pattern of blood cells and influence the remodelling of cellular membranes. Here we showed that PCI is an additional binding partner of phosphatidic acid (PA), cardiolipin (CL), and phosphoinositides (PIPs). Protein lipid overlay assays exhibited a unique binding pattern of PCI towards different lipid species. In addition PA, CL, and unsaturated, monophosphorylated PIPs stimulated the inhibitory property of PCI towards activated protein C in a heparin like manner. As shown for kallistatin (SerpinA4) and vaspin (SerpinA12), the incubation of cells with PCI led to the activation of protein kinase B (AKT), which could be achieved through direct interaction of PCI with PIPs. This model is supported by the fact that PCI stimulated the PIP-dependent 5-phosphatase SHIP2 in vitro, which would result in AKT activation. Hence the interaction of PCI with different lipids might not only stimulate the inhibition of potential target protease by PCI, but could also alter intracellular lipid signalling.
authors.forename: Felix Christof
authors.initials: FC
authors.lastname: Wahlmüller
authors.forename: Barbora
authors.initials: B
authors.lastname: Sokolikova
authors.forename: Daniela
authors.initials: D
authors.lastname: Rieger
authors.affiliation: Margarethe Geiger, Center of Physiology and Pharmacology, Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstraße 17, A-1090 Vienna, Austria, Tel.: +43 1 40160 31106, Fax: +43 1 40160 931129, E-mail: margarethe.geiger@meduniwien.ac.at.
authors.forename: Margarethe
authors.initials: M
authors.lastname: Geiger
mesh_terms: D001777:Blood Coagulation; D002308:Cardiolipins / Q000737:chemistry; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004075:Diglycerides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000737:chemistry; D057809:HEK293 Cells; D006493:Heparin / Q000737:chemistry; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D010712:Phosphatidic Acids / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010718:Phosphatidylserines / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry*; D011485:Protein Binding; D011486:Protein C / Q000037:antagonists & inhibitors*; D018046:Protein C Inhibitor / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D015843:Serpins / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D002308:Cardiolipins; D004075:Diglycerides; D005227:Fatty Acids; D008055:Lipids; D010712:Phosphatidic Acids; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines; D010743:Phospholipids; D011486:Protein C; D018046:Protein C Inhibitor; D011994:Recombinant Proteins; C534934:SERPINA5 protein, human; D015843:Serpins; C051324:kallistatin; C483858:phosphatidylethanolamine; D006493:Heparin; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
keywords: Protease inhibitors; SERPINs; coagulation factors; phospholipids; signal transduction