Identifizierung und Charakterisierung Ovar-exprimierter Rezeptormoleküle und Transposon-basierte Keimbahntransformation in Schistosoma mansoni
Final Report Abstract
With respect to the scientific questions and aims of the project we reached most of the targets. A number of cytoplasmic and membrane-bound molecues was identified and characterized that contribute to gonad differentiation processes in adult S. mansoni. In this context molecular and biochemical evidence were obtained for a complex interaction between Smβ-Int1 and SmVKR1. Besides the identification of downstream binding partners and ligands activating SmVKRs, we demonstrated the ligand-independent activation of SmVKR1 by Smβ-Int1 which is supported by the bridging molecules SmILK, SmPINCH, and SmNck2. Furthermore, we unraveled the functional meaning of Smβ-Int1/SmVKR1 cooperation, which is involved in differentiation processes during oogenesis also by controlling directed apoptosis in oogonia and further processes leading to cell death in primary oocytes. Alongside we recognized why schistosome genes are often problematic to be expressed in heterologous systems. Based on our findings a solution was developed to overcome these problems, which will be of high value in the future – not only for schistosome research. Although a protocol for germline transformation was successfully developed, generating stably transformed schistosomes by a transposon-based approach is still in progress. With respect to applied aspects of this basic research approaches, our results characterizing molecules that control the reproductive biology of schistosomes elucidated the prominent role of kinases. They represent Acilles´ heels for schistosomes - not only with respect to reproduction. This fact vouches for exploitable biology against the background of the roles of kinases for diverse human diseases, their druggability, the high number of kinase inhibitors being available, and the increasing molecular and structural knowledge about kinases in schistosomes.
Publications
- (2009) The formin-homology protein SmDia1 interacts with the Src kinase SmTK3 and the GTPase SmRho1 in the gonads of Schistosoma mansoni. PLoS ONE 4(9): e6998
Quack, T., Knobloch, J., Münnich, M., Beckmann, S., Vicogne, J., Dissous, C., Grevelding C.G.
- (2010) Schistosoma mansoni: Signal transduction processes during the development of the reproductive organs. Parasitology 137, 497-520
Beckmann, S., Quack, T., Burmeister, C., Buro, C., Long, T., Dissous, C., Grevelding C.G.
- (2010) The Syk kinase SmTK4 of Schistosoma mansoni is involved in the regulation of spermatogenesis and oogenesis. PLoS Pathogens 6(2): e1000769
Beckmann, S., Buro, C., Dissous, C., Hirzmann, J., Grevelding, C.G.
- (2011) Characterization of the Src/Abl hybrid-kinase SmTK6 of Schistosoma mansoni. The Journal of Biological Chemistry 286, 42325-42336
Beckmann, S., Hahnel, S., Dissous, C., Cailliau, K., Browaeys, E., Grevelding, C.G.
- (2011) What’s about sex in schistosomes? - Signaling mechanisms in the female gonads. In: H. Mehlhorn (ed.) Progress in Parasitology, Parasitology Research Monographs 2, Springer-Verlag Berlin Heidelberg; 181-200
Beckmann, S., Quack, T., Burmeister, C., Buro, C., Hahnel, S., Long, T., Dissous, C., Grevelding C.G.
- (2012) Novel α, β families of invertebrate integrin receptors: identification and characterization in Schistosoma mansoni. PLoS ONE 7(12): e52519
Beckmann, S., Quack, T., Lang, G., Grevelding, C.G.
- (2012) Paving the way for transgenic schistosomes. Parasitology 139, 651-668
Beckmann, S., Grevelding C.G.
(See online at https://doi.org/10.1017/S0031182011001466) - (2013) Transcriptome analyses of inhibitor-treated schistosome females provide evidence for cooperating Src-kinase and TGFβ receptor pathways controlling mitosis and eggshell formation. PLoS Pathogens 9(6): e1003448
Buro, C., Oliveira, K.C., Leutner, S., Beckmann, S., Lu, Z., Dissous, C., Cailliau, K., Verjovski-Almeida, S., Grevelding, C.G.
(See online at https://doi.org/10.1371/journal.ppat.1003448) - (2014) Receptor tyrosine kinase signaling and drug targeting in schistosomes. In: Protein phosphorylation in eukaryotic parasites: potential for chemotherapy. Edited by Christian Doerig, Martin Wiese, Gerald Spaeth; Wiley-Blackwell; p. 337-356
Dissous, C., Vanderstraete, M., Beckmann, S., Gouignard, N., Leutner, S., Buro, C., Grevelding C.G.
- (2014) Receptor tyrosine kinases and schistosome reproduction: new targets for chemotherapy. Frontiers in Genetics 5: 238
Morel, M., Vanderstraete, M., Hahnel, S., Grevelding, C.G., Dissous, C.
(See online at https://doi.org/10.3389/fgene.2014.00238) - (2014) Venus kinase receptors control reproduction in the platyhelminth parasite Schistosoma mansoni. PLoS Pathogens 10(5): e1004138
Vanderstraete, M., Gouignard, N., Cailliau, K., Morel, M., Hahnel, S., Leutner, S., Beckmann, S., Grevelding, C.G., Dissous, C.
(See online at https://doi.org/10.1371/journal.ppat.1004138) - (2015) Cryptic 3' mRNA processing signals hinder the expression of Schistosoma mansoni integrins in yeast. Molecular and Biochemical Parasitology 199, 51-57
Parker-Manuel, R.P., Grevelding C.G., Gelmedin, V.
(See online at https://doi.org/10.1016/j.molbiopara.2015.03.005)
