New lipid interaction partners stimulate the inhibition of activated protein C by cell-penetrating protein C inhibitor

Felix Christof Wahlmüller; Barbora Sokolikova; Daniela Rieger; Margarethe Geiger

doi:10.1160/TH13-06-0478

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2014; 111(01): 41-52
DOI: 10.1160/TH13-06-0478

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

New lipid interaction partners stimulate the inhibition of activated protein C by cell-penetrating protein C inhibitor

Authors

Felix Christof Wahlmüller
Barbora Sokolikova
Daniela Rieger
Margarethe Geiger

Abstract

Summary

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.

Keywords

Protease inhibitors - phospholipids - coagulation factors - signal transduction - SERPINs

Full Text

References

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