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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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Specific induction of migration and invasion of pancreatic carcinoma cells by RhoC, which differs from RhoA in its localisation and activity

Karin-Almut Dietrich1, a / Rene Schwarz1 / Martina Liska1 / Stefanie Graß1 / Andre Menke2 / Michael Meister1, 3 / Gesa Kierschke1 / Claudia Längle2 / Felicitas Genze1, 4 / Klaudia Giehl2

1Institute of Pharmacology and Toxicology, University of Ulm, D-89070 Ulm, Germany

2Internal Medicine I, University of Ulm, D-89070 Ulm, Germany

3Translational Research Unit, Thoraxklinik-Heidelberg GmbH, University of Heidelberg, D-69126 Heidelberg, Germany

4Department of Urology, University of Ulm, D-89070 Ulm, Germany

aPresent address: Department of Dermatology and Allergology, Ludwig Maximilians University of Munich, Frauenlobstr. 9-11, D-80337 München, Germany.

Corresponding author

Citation Information: Biological Chemistry. Volume 390, Issue 10, Pages 1063–1077, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2009.110, July 2009

Publication History

Received:
2009-01-21
Accepted:
2009-05-18
Published Online:
2009-07-30

Abstract

RhoA and RhoC are highly related Rho GTPases, but differentially control cellular behaviour. We combined molecular, cellular, and biochemical experiments to characterise differences between these highly similar GTPases. Our findings demonstrate that enhanced expression of RhoC results in a striking increase in the migration and invasion of pancreatic carcinoma cells, whereas forced expression of RhoA decreases these actions. These isoform-specific functions correlate with differences in the cellular activity of RhoA and RhoC in human cells, with RhoC being more active than RhoA in activity assays and serum-response factor-dependent gene transcription. Subcellular localisation studies revealed that RhoC is predominantly localised in the membrane-containing fraction, whereas RhoA is mainly localised in the cytoplasmic fraction. These differences are not mediated by a different interaction with RhoGDIs. In vitro GTP/GDP binding analyses demonstrate different affinity of RhoC for GTP[S] and faster intrinsic and guanine nucleotide exchange factor (GEF)-stimulated GDP/GTP exchange rates compared to RhoA. Moreover, the catalytic domains of SopE and Dbs are efficacious GEFs for RhoC. mRNA expression of RhoC is markedly enhanced in advanced pancreatic cancer stages, and thus the differences discovered between RhoA and RhoC might provide explanations for their different influences on cell migration and tumour invasion.

Keywords: Dbs; GTP binding; invasion; migration; RhoC; SopE

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