Past Research (a Selection)
The atypical Rho GTPase RhoBTB3
RhoBTB proteins are widely distributed in eukaryotes and display an atypical architecture that enables them to function as scaffolds for target recognition for ubiquitination and degradation of signalling components. RhoBTB proteins participate in regulation of vesicle transport and of the cell cycle, and they have been also described as tumour suppressors. We proposed that RhoBTB proteins may exist in an autoinhibited conformation that prevents formation of cullin-dependent ubiquitin ligase complexes. We have studied the pattern of expression of rhobtb3 (one of the three mammalian isoforms) in a gene trap mouse strain. Characterization of this strain has revealed a variety of interesting phenotypes, e.g. platelet aggregation defects, neurological alterations and deficient fertility.
Key papers:
Lutz et al. (2014) Expression analysis of mouse Rhobtb3 using a LacZ reporter and preliminary characterization of a knockout strain. Histochemistry and Cell Biology, 142:511-528.
Berthold et al. (2008) Characterization of RhoBTB-dependent Cul3 ubiquitin ligase complexes – Evidence for an autoregulatory mechanism. Experimental Cell Research, 314:3453-3465.
Plastin 1
Plastin 1 (fimbrin) is an abundant actin bundling protein of the intestinal brush border microvilli and inner ear hair cell stereocilia. In collaboration with the lab of Dr. Sylvie Robin (Institut Curie, Paris) we have shown that plastin 1 plays a key role in the organization of the intestinal brush border, as its absence results in mechanical fragility and alterations in delivery of membrane-associated enzymes to the microvillus. In collaboration with Dr. Nicolas Daudet and Prof. Dr. Andy Forge (Ear Institute London) and Dr. Walter Marcotti (University of Sheffield) we showed that plastin 1 is important for the maintenance of the architecture of stereocilia of inner ear cells.
Key papers:
Taylor et al. (2015) Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a progressive form of hearing loss in mice. Human Molecular Genetics, 24:37-49.
Grimm-Günter et al. (2009). Plastin 1 binds to keratin and is required for terminal web assembly in the intestinal epithelium. Molecular Biology of the Cell, 20:2549-2562.
Rho signaling
My lab has investigated the specific contribution of several Rho GTPases and other components of the Rho signalling pathway mainly in the model organism Dictyostelium discoideum using knockout and overexpressor strains. The repertoire of Rho signalling components in D. discoideum is more similar to metazoa and fungi than to plants, making this organism an excellent model for the study of Rho-dependent signalling. The list of components investigated directly or indirectly by my lab (and the list of colaborators) is long and includes several Racs, a RhoGDI, some GEFs and effectors like formins, PAK kinases, a WASP-related protein and coronin. A comprehensive review of the field is due in 2016.
Key papers:
Swaminathan et al. (2014) A CRIB domain mediates functions of coronin. Proceedings of the National Academy of Sciences USA, 111:E25-33.
Rivero et al. (2001) The Dictyostelium family of Rho-related proteins. Nucleic Acids Research 29, 1068-1079.
Genomics
My lab has contributed to the analysis of the components of the actin cytoskeleton and the proteins involved in Rho signaling in the fram of the Dictyostelium discoideum genome project. The completion of the Dictyostelium genome sequencing opened a new era for the research with this organism. We have also contributed to the analysis of other dictyostelids more recently.
Key papers:
Heidel et al. (2011) Phylogeny-wide analysis of social amoeba genomes highlights ancient origins for complex intercellular communication. Genome Research, 21:1882-1891.
Eichinger et al. (2005) The genome of the social amoeba Dictyostelium discoideum. Nature 435, 43-57.
Actin-binding proteins
A significant amount of work has focused on studies of the actin cytoskeleton using Dictyostelium discoideum as a model organism. Remodelling of the cytoskeleton plays a pivotal role in both cell motility and phagocytosis, and a variety of proteins are involved in the assembly and disassembly of the actin cytoskeleton. At the Max-Planck Institute in Martinsried first, and later at the University of Cologne we investigated the role of alpha-actinin, filamin, the 34 kDa actin bundling protein (ABP-34) and fimbrin, which are among the most abundant F-actin binding proteins of D. discoideum. Homologous recombination was used to generate single and multiple mutants of those proteins.
In a search for novel members of the alpha-actinin superfamily we identified interaptin, a protein that associates with membranes of intracellular compartments, i.e. the nuclear envelope and the ER. In fact, interaptin has turned out to be homologous to the nesprins of higher eukaryotes that are important for maintaining the architecture of the nuclear envelope, and have been linked to the pathogenesis of severe diseases, e.g. progeria and Emery-Dreifuss muscular dystrophy.
Key papers:
Rivero, et al. (1999). Three actin cross-linking proteins, the 34 kDa actin-bundling protein, a-actinin and ABP-120, have both unique and redundant roles in the growth and development of Dictyostelium. Journal of Cell Science 112, 2737-2751.
Rivero et al. (1998) Interaptin, an actin-binding protein of the a-actinin superfamily in Dictyostelium discoideum, is developmentally and cAMP regulated and associates with intracellular membrane compartments. Journal of Cell Biology 142, 735-750.
