Novel aspects of signal transduction through Rho GTPases: cGMP, proteasomal degradation and mitochondrial homeostasis
Final Report Abstract
Rho GTPases have emerged as pivotal signaling elements for the control, directly or indirectly, of almost all cellular activities. Perhaps one of the most extensively studied functional aspects of these proteins deals with the Chemotaxis response: how are signals originating from the plasma membrane in response to chemoattractants transmitted to effector proteins and how do these effectors regulate the assembly and disassembly of actin networks in order to elicit directed cell migration? Our current knowledge of many fundamental aspects of Chemotaxis and the role of Rho GTPases in this process has benefited from studies in neutrophils and in Dictyostelium discoideum. A similar argumentation can be used to address signaling during several stages of vesicle trafficking, where some members of the Rho family have emerged as important regulators. Our broad goal was to better understand the complex mechanisms of signaling to the cytoskeleton mediated by Rho-like GTPases using mainly, but not exclusively, Dictyostelium discoideum as a genetically tractable model organism. We have investigated the specific contribution of four Rho GTPases of Dictyostelium, RacG, RacH, RacC and RacA using knockout strains as well as of strains that overexpress mutated variants of these proteins. RacA is particularly interesfing because it belongs to the subfamily of RhoBTB proteins likely involved in the formation of ubiquitin ligase complexes. We have more generally addressed the mechanism of action of RhoBTB proteins in mammalian cells and have developed a model in which these proteins exist as autoinhibited dimers. We have extended our studies to regulators of Rho signaling like those of the RhoGEF and Dock families and bacterial virulence factors with GAP activity (like Yersinia YopE). We have also contributed to the study of Rho signaling in the ectomycorhizal fungus Tuber borchii with the characterization of a Cdc42 and a RhoGDI ortholog. Finally, we have started to investigate the function of Miro, a Rasrelated GTPase of the outer mitochondrial membrane that appears to be involved in movement of mitochondria along microtubules. Taken together our results will contribute to a better understanding of signaling pathways dependent of small GTPases in multiple systems.
Publications
- Dictyostelium discoideum protocols. Methods in Molecular Biology, vol. 346. Humana Press. Totowa, New Jersey. 2006
L. Eichinger and F. Rivero
- Dictyostelium RacH regulates endocytic vesicular trafficking and is required for localizafion of vacuolin. Traffic 7, 1194-1212 (2006)
B. P. Somesh, C. Neffgen, M. Iijima, P. Devreotes, F. Rivero
- Quantitative and microscopic methods for studying the endocytic pathway. Methods in Molecular Biology 346, 423-438 (2006)
F. Rivero, M. Maniak
- RacG regulates morphology, phagocytosis and Chemotaxis in Dictyostelium through novel signaling pathways. Eukaryotic Cell 6, 1648-1663 (2006)
B. P. Somesh, G. Vlahou, M. Iijima, R. Insall, P. Devreotes, F. Rivero
- Rho GTPase signaling in Dictyostelium discoideum: insights from the genome. European Journal of Cell Biology 85, 947-959 (2006)
G. Vlahou, F. Rivero
- Role of RacC for the regulafion of WASP and PI3 kinase during Chemotaxis of Dictyostelium. Journal of Biological Chemistry 281, 35224-35234 (2006)
J. W. Han, L. Leeper, F. Rivero, C. Y. Chung
- GxcDD, a putative RacGEF, is important for Dictyostelium development. BMC Cell Biology 8, 23 (2007)
S. Mondal, D. Neelamegan, F. Rivero, A. A. Noegel
- Molecular characterisation of the small GTPase CDC42 in the ectomycorrhizal fungus Tuber borchii Vittad. Protoplasma 231, 227-237 (2007)
M. Menotta, A. Amicucci, G. Basili, F. Rivero, E. Polidori, D. Sisfi, V. Stocchi
- Origins and evolution of the actin cytoskeleton. Advances in Experimental Medicine and Biology 607, 7-110 (2007)
F. Rivero, F. Cvrckova
- Characterization of RhoBTB-dependent Cul3 ubiquitin ligase complexes - Evidence for an autoregulatory mechanism. Experimental Cell Research 314, 4353-3465 (2008)
J. Berthold, K. Schenkova, S. Ramos, Y. Miura, M. Furukawa, P. Aspenström, F. Rivero
- Endocytosis and the actin cytoskeleton in Dictyostelium discoideum. International Review of Cell and Molecular Biology 267, 343-397 (2008)
F. Rivero
- Identification of a Rho GDP dissociation inhibitor in the filamentous fungus Tuber borchii: molecular and functional characterization. BMC Microbiology 8:57 (2008)
M. Menotta, A. Amicucci, G. Basili, E. Polidori, V. Stocchi, F. Rivero
- Linking Ras to myosin function: RasGEF Q, a Dictyostelium exchange factor for RasB, affects myosin II function. Journal of Cell Biology 181, 747-760 (2008)
S. Mondal, D. Bakthavatsalam, P. Steimle, B. Gassen, F. Rivero, A.A. Noegel
- Rho GTPases of the RhoBTB family and tumorigenesis. Acta Pharmacologica Sinica 29, 285-295 (2008)
J. Berthold, K. Schenkova, F. Rivero
- RHOBTB1 (Rho-related BTB domain containing 1). Atlas Genet Cytogenet Oncol Haematol. 2008
K. Schenkova, F. Rivero
- RHOBTB2 (Rho-related BTB domain containing 2). Atlas Genet Cytogenet Oncol Haematol. 2008
K. Schenkova, F. Rivero
