title: Venus kinase receptors control reproduction in the platyhelminth parasite Schistosoma mansoni.
abstract: The Venus kinase receptor (VKR) is a single transmembrane molecule composed of an intracellular tyrosine kinase domain close to that of insulin receptor and an extracellular Venus Flytrap (VFT) structure similar to the ligand binding domain of many class C G protein coupled receptors. This receptor tyrosine kinase (RTK) was first discovered in the platyhelminth parasite Schistosoma mansoni, then in a large variety of invertebrates. A single vkr gene is found in most genomes, except in S. mansoni in which two genes Smvkr1 and Smvkr2 exist. VKRs form a unique family of RTKs present only in invertebrates and their biological functions are still to be discovered. In this work, we show that SmVKRs are expressed in the reproductive organs of S. mansoni, particularly in the ovaries of female worms. By transcriptional analyses evidence was obtained that both SmVKRs fulfill different roles during oocyte maturation. Suppression of Smvkr expression by RNA interference induced spectacular morphological changes in female worms with a strong disorganization of the ovary, which was dominated by the presence of primary oocytes, and a defect of egg formation. Following expression in Xenopus oocytes, SmVKR1 and SmVKR2 receptors were shown to be activated by distinct ligands which are L-Arginine and calcium ions, respectively. Signalling analysis in Xenopus oocytes revealed the capacity of SmVKRs to activate the PI3K/Akt/p70S6K and Erk MAPK pathways involved in cellular growth and proliferation. Additionally, SmVKR1 induced phosphorylation of JNK (c-Jun N-terminal kinase). Activation of JNK by SmVKR1 was supported by the results of yeast two-hybrid experiments identifying several components of the JNK pathway as specific interacting partners of SmVKR1. In conclusion, these results demonstrate the functions of SmVKR in gametogenesis, and particularly in oogenesis and egg formation. By eliciting signalling pathways potentially involved in oocyte proliferation, growth and migration, these receptors control parasite reproduction and can therefore be considered as potential targets for anti-schistosome therapies.
authors.affiliation: Center for Infection and Immunity of Lille, Inserm U1019, CNRS-UMR 8204, University Lille Nord de France, Institut Pasteur de Lille, Lille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vanderstraete
authors.affiliation: Center for Infection and Immunity of Lille, Inserm U1019, CNRS-UMR 8204, University Lille Nord de France, Institut Pasteur de Lille, Lille, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Gouignard
authors.affiliation: EA 4479, IFR 147, Universite Lille 1 Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Cailliau
authors.affiliation: Center for Infection and Immunity of Lille, Inserm U1019, CNRS-UMR 8204, University Lille Nord de France, Institut Pasteur de Lille, Lille, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Morel
authors.affiliation: Institute for Parasitology, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hahnel
authors.affiliation: Institute for Parasitology, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Leutner
authors.affiliation: Institute for Parasitology, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Beckmann
authors.affiliation: Institute for Parasitology, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Grevelding
authors.affiliation: Center for Infection and Immunity of Lille, Inserm U1019, CNRS-UMR 8204, University Lille Nord de France, Institut Pasteur de Lille, Lille, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Dissous
mesh_terms: D000818:Animals; D000947:Antigens, Helminth; D005260:Female; D007448:Invertebrates / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D012098:Reproduction / Q000235:genetics; D012550:Schistosoma mansoni / Q000378:metabolism*; D014981:Xenopus
chemical_list: D000947:Antigens, Helminth; D020794:Receptor Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases