My group is interested in non-inhibitory functions of serine protease inhibitors (serpins), especially in functions in cell signaling. Serpins are a family of glycoproteins, which includes inhibitors of serine proteases as well as non-inhibitory members. We are focusing on protein C inhibitor (PCI, serpinA5), a serpin with wide tissue distribution and broad protease reactivity. We are investigating to which extent additional, non-inhibitory functions/properties of PCI are physiologically relevant. We have established and analyzed PCI-knockout mice and have shown that male PCI-deficient mice are infertile due to abnormal spermatogenesis. We have also shown that in adult mice – unlike in men – PCI is almost exclusively expressed in the reproductive tract. During embryonic development, however, PCI is expressed in several organs and at specific developmental stages suggesting a role in morphogenesis. Furthermore we have shown that PCI binds retinoids as well as certain phospholipids, and that these phospholipids mediate the internalization of PCI into cells, where it can translocate to the nucleus. Based on these results we are currently analyzing the mechanism of PCI-internalization as well as the effect of PCI on phospholipid-dependent intracellular signaling. Furthermore we are aiming to identify intracellular, nuclear and/or cell membrane associated proteins interacting with PCI and to determine the functional relevance of these interactions.
The role of serine protease inhibitors (serpins) in cell signalling
techniques and infrastructure of the research group:
Diverse basic molecular and cellular biology techniques, immunological and functional assays, subcellular fractionation, 2D-electrophoresis, flow cytometry, immunohistochemistry, confocal microscopy, analysis of protein-phospholipid interactions, phagocytosis assays, expression and purification of recombinant proteins, transgenic animals.
Prendes MJ, Bielek E, Zechmeister-Machhart M, Vanyek-Zavadil E,. Carroll VA, Breuss J, Binder BR, and Geiger M. Synthesis and ultratructural localization of protein C inhibitor in human platelets and megakaryocytes. Blood 94: 1300-1312, 1999.
Uhrin P, Dewerchin M, Hilpert M, Chrenek P, Schöfer C, Zechmeister-Machhart M, Krönke G, Vales A, Carmeliet P, Binder BR, and Geiger M. Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility. J Clin Invest 106:1531-1539, 2000.
Malleier JM, Oskolkova O, Bochkov V, Jerabek I, Sokolikova B, Perkmann T, Breuss J, Binder BR, and Geiger M. Regulation of protein C inhibitor (PCI) activity by specific oxidized and negatively charged phospholipids. Blood 109: 4769-4776, 2007.
Baumgärtner P., Geiger M., Zieseniss S., Malleier J., Huntington J.A., Hochrainer K., Bielek E., Stoeckelhuber M., Lauber K., Scherfeld D., Schwille P., Wäldele K., Beyer K., Engelmann B. Phosphatidylethanolamine critically supports internalization of cell penetrating protein C inhibitor. J. Cell Biol. 179:793-804, 2007.
Prohaska TA, Wahlmüller FC, Furtmüller M, Geiger M. Interaction of protein C inhibitor with the type II transmembrane serine protease enteropeptidase. Plos One 7: e39262, 2012.