Kristina Gegenbauer

Publications of Kristina Gegenbauer

• Synaptotagmin-like protein 1 interacts with the GTPase-activating protein Rap1GAP2 and regulates dense granule secretion in platelets.

  Authors: Olga Neumuller, Meike Hoffmeister, Jan Babica, Carola Prelle, Kristina Gegenbauer, Albert P Smolenski

  Blood. 07/2009;

  The small guanine-nucleotide-binding protein Rap1 plays a key role in platelet aggregation and hemostasis and we recently identified Rap1GAP2 as the only GTPase-activating protein of Rap1 inThe small guanine-nucleotide-binding protein Rap1 plays a key role in platelet aggregation and hemostasis and we recently identified Rap1GAP2 as the only GTPase-activating protein of Rap1 in platelets. In search of Rap1GAP2-associated proteins we performed yeast-two-hybrid screening and found synaptotagmin-like protein 1 (Slp1) as new binding partner. We confirmed the interaction of Rap1GAP2 and Slp1 in transfected COS-1 and HeLa cells and at endogenous level in human platelets. Mapping studies showed that Rap1GAP2 binds through amino acids T524-K525-X-T527 within its C-terminus to the C2A domain of Slp1. Slp1 contains a Rab27-binding domain and we demonstrate that Rap1GAP2, Slp1 and Rab27 form a trimeric complex in transfected cells and in platelets. Purified Slp1 dose-dependently decreased dense granule secretion in streptolysin-O permeabilized platelets stimulated with calcium or GTPgammaS. The isolated C2A domain of Slp1 had a stimulatory effect on granule secretion and reversed the inhibitory effect of full-length Slp1. Purified Rap1GAP2 augmented dense granule secretion of permeabilized platelets, whereas deletion of the Slp1-binding TKXT motif abolished the effect of Rap1GAP2. We conclude that Slp1 inhibits dense granule secretion in platelets and that Rap1GAP2 modulates secretion by binding to Slp1.

• Nitric Oxide-Independent Vasodilator Rescues Heme-Oxidized Soluble Guanylate Cyclase From Proteasomal Degradation.

  Authors: Sabine Meurer, Sylke Pioch, Tatjana Pabst, Nils Opitz, Peter M Schmidt, Tobias Beckhaus, Kristina Wagner, Simone Matt, Kristina Gegenbauer, Sandra Geschka, Michael Karas, Johannes-Peter Stasch, Harald H H W Schmidt, Werner Müller-Esterl

  Circulation research. 06/2009;

  Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and downregulation of its majorNitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and downregulation of its major intracellular receptor, the alphabeta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of the heme of sGC, as well as the responsiveness of sGC to NO. sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here, we show that oxidation-induced downregulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand BAY 58-2667 prevented sGC ubiquitination and stabilized both alpha and beta subunits. Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC.

• Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteosomal degradation

  Authors: Sabine Meurer, Sylke Pioch, Tatjana Pabst, Nils Opitz, Peter Schmidt, Tobias Beckhaus, Kristina Wagner, Simone Matt, Kristina Gegenbauer, Sandra Geschka, Michael Karas, Johannes-Peter Stasch, Harald Schmidt, Werner Müller-Esterl

  BMC Pharmacology. 01/2009;

• Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells.

  Authors: Sabine H Wimmer-Kleikamp, Eva Nievergall, Kristina Gegenbauer, Samantha Adikari, Mariam Mansour, Trina Yeadon, Andrew W Boyd, Neill R. Patani, Martin Lackmann

  Blood. 05/2008;

  Signalling by Eph receptors and cell-surface ephrin ligands modulates adhesive cell properties and thereby co-ordinates cell movement and positioning in normal and oncogenic development. WhileSignalling by Eph receptors and cell-surface ephrin ligands modulates adhesive cell properties and thereby co-ordinates cell movement and positioning in normal and oncogenic development. While cell-contact dependent Eph activation frequently leads to cell-cell repulsion, also the diametrically-opposite response, cell-cell adhesion, is a probable outcome. However, the molecular principles regulating such disparate functions have remained controversial. We have examined cell-biological mechanisms underlying this switch by analysing ephrin-A5 induced cell morphological changes of EphA3-positive LK63 pre-B acute lymphoblastic leukaemia cells. Their exposure to ephrin-A5 surfaces leads to a rapid conversion from a suspended/nonpolarized to adherent/polarized cell type, a transition which relies on EphA3 functions operating in the absence of Eph-kinase signalling. Cell morphology change and adhesion of LK63 cells are effectively attenuated by endogenous protein tyrosine phosphatase (PTP) activity, whereby PTP inhibition and productive EphA3-phosphotyrosine signalling reverse the phenotype to non-adherent cells with a condensed cytoskeleton. Our findings suggest that Eph-associated PTP activities not only control receptor phosphorylation levels, but as a result switch the response to ephrin-contact from repulsion to adhesion, which may play a role in the pathology of haematopoietic tumours.