|Institut für Biochemie I||Printer friendly|
Role of the actin cytoskeleton and its associated proteins
CAP (Cyclase associated protein)
The actin cytoskeleton participates in many fundamental cellular aspects including the regulation of cell shape, cell motility, and cell adhesion. Its remodeling depends on actin binding proteins which organize actin filaments into specific structures that are a prerequisite of various specialized functions. CAP is an evolutionary conserved protein with roles in regulating the actin cytoskeleton and in signal transduction. Mammals have two CAP genes encoding the related CAP1 and CAP2. CAP1 is widely distributed and present in all organs. At the subcellular level it is found in the cytosol and localizes to actin-rich structures. In contrast, CAP2 expression is limited to skeletal and heart muscle, to the brain and skin. Its subcellular distribution differs also from the one of CAP1. In undifferentiated myoblasts and in keratinocyte cell lines CAP2 is primarily found in the nucleus, in differentiated myotubes it is present at the M-line. A recent report showed that CAP2 is specifically upregulated in hepatocellular carcinoma.
Sultana H, Neelakanta G, Eichinger L, Rivero F, Noegel AA. (2009) Microarray phenotyping places cyclase associated protein CAP at the crossroad of signaling pathways reorganizing the actin cytoskeleton in Dictyostelium. Exp Cell Res. 315, 127-40.
Peche, V., Shekar, S., Leichter, M., Korte, H., Schröder, R., Schleicher, M., Holak, T. A., Clemen, C. S., Ramanath-Y., B., Pfitzer, G., Karakesisoglou, I., Noegel, A. A. (2007). CAP2, Cyclase Associated Protein 2, is a dual compartment protein. Cell Mol. Life Sci. 64, 2702-2715.
Yusof, A. M., Jaenicke, E., Pedersen, J. S., Noegel, A. A., Schleicher, M., Hofmann, A. (2006). Studies on oligomerisation of cyclase-associated protein from Dictyostelium discoideum in solution. J. Mol. Biol. 362, 1072-1081.
Sultana, H., Rivero, F., Blau-Wasser, R., Schwager, S., Balbo, A., Bozzaro, S., Schleicher, M., Noegel, A. A. (2005). CAP is essential for the functioning of the endo-lysosomal system and provides a link to the actin cytoskeleton. Traffic 6, 930-946.
Mavoungou, C., Israel, L., Rehm, T., Ksiazek, D., Krajewski, M., Popowicz, G., Noegel, A. A., Schleicher, M., Holak, T. A. (2004). NMR structural characterization of the N-terminal domain of the adenylyl cyclase-associated protein (CAP) from Dictyostelium discoideum. J. Biomol. NMR 29, 73-84.
Ksiazek, D., Brandstetter, H., Israel L., Bourenkov, G. B., Katchalova, G., Janssen, K.-P., Bartunik, H. D., Noegel, A. A., Schleicher, M., Holak, T. A. (2003). Structure of the N-terminal domain of the adenylyl cyclase associated protein (CAP) form Dictyostelium discoideum. Structure 11, 1171-1178.
Generation of cell polarity
Polarity in Dictyostelium discoideum is controlled by external signals. Upon a chemotactic signal cells polarize. Signalling molecules and components of the cytoskeleton are involved in the polarization process. Cell polarization in Dictyostelium is essential for motility, development and morphogenesis. Development starts with the formation of highly elongated cells during aggregation when cells use chemotaxis towards cAMP to form a multicellular organism. Chemotactic motility continues to be the determining factor during all subsequent morphogenetic events and is essential for formation of an asymmetric anterior/posterior body axis. We study the requirements for cell polarization with emphasis on the characterization of the cytoskeletal components of the cells that provide the basis for cell polarization. In addition to the analysis of single components which relies on Dictyostelium mutants deficient in cell polarization we make use of the possibilities offered by the Dictyostelium genome project and examine the roles of candidate genes.
Khaire, N., Müller, R., Blau-Wasser, R., Eichinger, L., Schleicher, M., Rief, M., Holak, T. A., Noegel A. A. (2007). Filamin regulated F-actin assembly is essential for morphogenesis and controls phototaxis in Dictyostelium. J. Biol. Chem. 282, 1948-1955.
Noegel, A. A., Blau-Wasser, R., Sultana, H., Müller, R., Israel, L., Schleicher, M., Patel, H., Weijer, C. J. (2004). CAP/ASP56 as regulator of cell polarity and cAMP signaling in Dictyostelium. Mol. Biol. Cell 15, 934-945.
Functional analysis of the actin cytoskeleton and of the G-protein-coupled receptor (GPCR) family
The actin cytoskeleton and the family of GPCRs show an unexpected complexity in D. discoideum. This might be the basis of its complex life cycle and its temporary multicellularity, which both rely on motility and signalling. We are studying the presence of these components in other Dictyostelids as well and try to attribute specific functions to the individual genes.
Wilkins, A., Szafranski, K., Fraser, D. J., Bakthavatsalam, D., Müller, R., Fisher, P. R., Glöckner, G., Eichinger, L., Noegel, A., Insall, R. H. (2005). Numerous RasGEFs with non-redundant functions in Dictyostelium. Genome Biol. 6:R68
Bakthavatsalam, D., Brazill, D., Gomer, R. H., Eichinger, L., Rivero, F., Noegel, A. A. (2007). A G protein coupled receptor with a lipid kinase domain is involved in cell density sensing. Curr. Biol. 17, 892-897.
Prabhu, Y., Müller, R., Anjard, C., Noegel, A. A. (2007). GrlJ, a Dictyostelium GABAB-like receptor with roles in post-aggregation development. BMC Developmental Biology, 7:44.
Prabhu, Y., Mondal, S., Eichinger, L., Noegel, A.A. (2007). A GPCR involved in post aggregation events in Dictyostelium discoideum. Dev. Biol. 312, 29-34.
Figure 1: Expression of cell type specific markers in mutants lacking grlJ, a G protein coupled receptor in D. discoideum.
September 13, 2013
Center for Biochemistry, Joseph-Stelzmann-Straße 52, D50931 Cologne
Suggestions and wishes: Gudrun Konertz