Cellular interactions of actin regulatory proteins
Final Report Abstract
Proteins associated with the actin cytoskeleton have many and diverse roles. They are involved in signal transduction processes, cell motility, chemotaxis and intracellular transport. Their multi-functionality is achieved by a multi-domain structure which enables them to become part of protein complexes which link cellular structures to the cytoskeleton and to act in a wider cellular context. In this project we focused on proteins which interact with actin and regulate its assembly status. On the other hand they are involved in further processes such as functioning of the centrosome, myosin assembly and the regulation of cell adhesion. Among the proteins investigated were CAP (cyclase-associated protein) and coronin and coronin7. The studies were carried out in "Dictyostelium discoideum" which gave us the opportunity of performing biochemical as well as genetic studies. CAP consists of an N-terminal domain, whose structure was determined, and a highly conserved C-terminal domain thought to mediate actin binding. By mutant analysis we could show that the protein is intimately involved in the regulation of the actin cytoskeleton and in cAMP signaling in "D. discoideum". A search for novel interaction partners revealed several components of the centrosome, among them CP250, a pericentriolar protein, and CEP161, the "Dictyostelium" ortholog of CDK5RAP2. Mutations in the human "CDK5RAP2" gene can give rise to primary microcephaly. Further studies showed that CEP161 links the centrosome to the Hippo signaling pathway. Coronins are a highly conserved family of proteins that are important regulators of actin-dependent processes. They have a WD40 repeat domain containing seven repeats that form a beta propeller. Coronin from "Dictyostelium discoideum" is the founding member of this family. It localizes to actin rich structures, is present in leading fronts and pseudopodia and has roles in phagocytosis, cell motility and development. Coronin7 contains two beta propellers. It binds directly to F-actin and protects actin filaments from depolymerization. In vivo analysis showed that it functions in phagocytosis and chemotaxis. All coronins have a Cdc42/Rac interactive binding (CRIB) motif. For coronin and coronin7 we could show that this motif is responsible for Rac binding and that through this interaction coronin and coronin7 have an impact on Rac downstream effectors like PAK, WASP and SCAR and influence the actin cytoskeleton.
Publications
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2009. CP250, a novel acidic coiled coil protein of the Dictyostelium centrosome, affects growth, chemotaxis and the nuclear envelope. Molecular Biology of the Cell, Vol. 20. 2009, no. 20, pp. 4348-4361.
Blau-Wasser, R., Euteneuer, U., Xiong, H., Gassen, B. Schleicher, M., Noegel, A. A.
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2009. Microarray phenotyping places cyclase associated protein CAP at the crossroad of signaling pathways reorganizing the actin cytoskeleton in Dictyostelium. Experimental Cell Research, Vol. 315. 2009, Issue 2, pp 127–140.
Sultana, H., Neelakanta, G., Eichinger, L., Rivero, F., Noegel, A. A.
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2010. A coronin7 homolog with functions in actin-driven processes.
Journal of Biological Chemistry, Vol. 285. 2010, pp. 9249-9261.
Shina, M. C., Ünal, C., Eichinger, L., Müller-Taubenberger, A., Schleicher, M., Steinert, M., Noegel, A. A.
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2010. A cytohesin homolog in Dictyostelium amoebae. PLoS One, Vol. 5. 2010, Issue 2: e9378.
Shina, M. C., Müller, R., Blau-Wasser, R., Glöckner, G., Schleicher, M., Eichinger, L., Noegel, A. A., Kolanus, W.
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2010. Regulation of the actin cytoskeleton by an interaction of IQGAP related protein GAPA with filamin and cortexillin I. PloS ONE, Vol. 5. 2010 ,Issue 11: e15440.
Mondal, S., Burgute, B., Rieger, D., Müller, R., Rivero, F., Faix, J., Schleicher, M., Noegel, A. A.
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2011. ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nature Reviews Molecular Cell Biology, Vol. 12.2011, 362-375.
Donaldson J.G., Jackson C.L.
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2011. Redundant and unique roles of coronin proteins in Dictyostelium. Cellular and Molecular Life Sciences, Vol. 68. 2011, Issue 2, pp 303-313.
Shina, M. C. Müller-Taubenberger, A., Ünal, C., Schleicher, M., Steinert, M., Eichinger, L., Müller, R., Blau-Wasser, R., Glöckner, G., Noegel, A. A.
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2012. Ectopic expression of Cyclase associated protein CAP restores the streaming and aggregation defects of Adenylyl Cyclase A deficient Dictyostelium discoideum cells. BMC Developmental Biology, Vol. 12. 2012:3.
Sultana, H., Neelakanta, G., Rivero, F., Blau-Wasser, R., Schleicher, M., Noegel, A. A.
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2013. Ablation of Cyclase Associated Protein 2 (CAP2) leads to cardiomyopathy. Cellular and Molecular Life Sciences, Vol. 70. 2013, Issue 3, pp 527-543.
Peche VS, Holak TA, Burgute BD, Kosmas K, Kale SPF, Wunderlich T, Elhamine F, Stehle R, Pfitzer G, Nohroudi K, Addicks K, Stöckigt F, Schrickel JW, Gallinger J, Schleicher M, Noegel AA.
