gms | German Medical Science

62nd Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Polish Society of Neurosurgeons (PNCH)

German Society of Neurosurgery (DGNC)

7 - 11 May 2011, Hamburg

Beta-Arrestin 1 is a key player in the regulation of glioma cell migration and invasion

Meeting Abstract

  • F. Geßler - Experimentelle Neurochirurgie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • S. Dützmann - Klinik für Neurochirurgie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • V. Voss - Experimentelle Neurochirurgie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • V. Seifert - Klinik für Neurochirurgie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
  • R. Gerlach - Klinik für Neurochirurgie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main; Klinik für Neurochirurgie, Helios Klinikum Erfurt, Erfurt
  • D. Kögel - Experimentelle Neurochirurgie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main

Deutsche Gesellschaft für Neurochirurgie. Polnische Gesellschaft für Neurochirurgen. 62. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgen (PNCH). Hamburg, 07.-11.05.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. DocMO.05.06

DOI: 10.3205/11dgnc025, URN: urn:nbn:de:0183-11dgnc0254

Published: April 28, 2011

© 2011 Geßler et al.
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Outline

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Objective: Tissue Factor (TF) expression is observed in gliomas and various malignant tumors and is positively correlated with the grade of malignancy. Next to its function in initiating the coagulation cascade, TF has been recently discovered to function as a signalling protein leading to activation of MAP kinase. Beta-Arrestin has been described as a scaffolding protein in cellular signalling. In glioma, the extent of beta-Arrestin phosphorylation inversely correlates with tumor grading. Our previous studies have demonstrated an important role of the TF/PAR-2 pathway in glioma cell migration and invasion. Here, we describe a novel crosslink between TF/PAR-2 and beta-Arrestin signalling and its impact on downstream signalling and invasive behaviour of malignant glioma cells.

Methods: Western Blotting with glioma cell lines MZ-18 and Hs 683 was used for expression analysis of TF, PAR-2, PP2A, beta-Arrestin, p-beta-Arrestin, ERK and p-ERK. Inhibition of TF-induced signalling was achieved via a lentiviral knockdown of TF. PAR-2 signalling was activated by a synthetic, agonistic peptide (SLIGKV-NH2). Migration and cellular invasion were analyzed in scratch- and modified Boyden-chamber-assays, respectively. PP2A was inhibited by either an oligonucleotide-mediated knockdown or by the phosphatase inhibitor Okadaic Acid.

Results: We previously demonstrated reduced activation of ERK signalling and reduced migration and invasion in glioma cells with a stable knockdown of TF. Restoration of this pathway by addition of the selective PAR-2 agonist SLIGKV completely abrogated the effects of the TF knockdown and restored migration, invasion and activated ERK signalling. Furthermore, TF knockdown cells revealed a higher extent of phosphorylated beta-Arrestin. In contrast, SLIGKV treatment resulted in beta-Arrestin dephosphorylation. Knockdown of beta-Arrestin reduced cellular migration to an extent comparable to that of the TF-knockdown, an effect that could not be reversed by SLIGKV treatment. The PP2A inhibitor Okadaic Acid prevented dephosphorylation of beta-Arrestin and reduced migration and invasion in MZ-18 and Hs 683 glioma cells.

Conclusions: The major findings of our study point out the crosslink between the TF/PAR-2 pathway and beta-Arrestin signalling and highlight the pathway as an interesting target for tumor therapy aimed at limiting invasion of gliomas. We were furthermore able to describe the role of PP2A as the phosphatase mediating beta-Arrestin dephosphorylation in glioma cells.