Date Published: May 29, 2014
Publisher: Public Library of Science
Author(s): Mathieu Vanderstraete, Nadège Gouignard, Katia Cailliau, Marion Morel, Steffen Hahnel, Silke Leutner, Svenja Beckmann, Christoph G. Grevelding, Colette Dissous, Stephen John Davies.
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.
Trematode parasites of the Schistosoma genus are responsible for schistosomiasis or bilharzia, one of the most important parasitic endemias worldwide in terms of mortality and morbidity. According to the World Health Organisation, more than 240 million people are currently infected by schistosomes, with about 200 000 deaths per year .
VKR is an uncommon RTK that bears a VFT ligand-binding domain not found in any other RTK . Since its first discovery ten years ago in S. mansoni, VKR has been found in a large variety of organisms. It is preferentially expressed in larval stages and in gonads of several organisms, suggesting its role in development and reproduction . This work is centered on the functions of VKR in S. mansoni, and specially on the demonstration of its role in reproduction. We performed a comparative analysis of the two members SmVKR1 and SmVKR2 expressed in S. mansoni, studying their respective tissue distribution, the morphological and physiological impact of their knock-down expression in parasites, molecular aspects of receptor activation and cellular signalling pathways.