A New Family of Receptor Tyrosine Kinases with a Venus Flytrap Binding Domain in Insects and Other Invertebrates Activated by Aminoacids

Background: Tyrosine kinase receptors (RTKs) comprise a large family of membrane receptors that regulate various cellular processes in cell biology of diverse organisms. We previously described an atypical RTK in the platyhelminth parasite Schistosoma mansoni, composed of an extracellular Venus flytrap module (VFT) linked through a single transmembrane domain to an intracellular tyrosine kinase domain similar to that of the insulin receptor. Methods and Findings: Here we show that this receptor is a member of a new family of RTKs found in invertebrates, and particularly in insects. Sixteen new members of this family, named Venus Kinase Receptor (VKR), were identified in many insects. Structural and phylogenetic studies performed on VFT and TK domains showed that VKR sequences formed monophyletic groups, the VFT group being close to that of GABA receptors and the TK one being close to that of insulin receptors. We show that a recombinant VKR is able to autophosphorylate on tyrosine residues, and report that it can be activated by L-arginine. This is in agreement with the high degree of conservation of the alpha amino acid binding residues found in many amino acid binding VFTs. The presence of high levels of vkr transcripts in larval forms and in female gonads indicates a putative function of VKR in reproduction and/or development. Conclusion: The identification of RTKs specific for parasites and insect vectors raises new perspectives for the control of human parasitic and infectious diseases

Eukaryotic Protein Kinases (ePKs) of the Helminth Parasite Schistosoma mansoni

<p>Abstract</p> <p>Background</p> <p>Schistosomiasis remains an important parasitic disease and a major economic problem in many countries. The <it>Schistosoma mansoni </it>genome and predicted proteome sequences were recently published providing the opportunity to identify new drug candidates. Eukaryotic protein kinases (ePKs) play a central role in mediating signal transduction through complex networks and are considered druggable targets from the medical and chemical viewpoints. Our work aimed at analyzing the <it>S. mansoni </it>predicted proteome in order to identify and classify all ePKs of this parasite through combined computational approaches. Functional annotation was performed mainly to yield insights into the parasite signaling processes relevant to its complex lifestyle and to select some ePKs as potential drug targets.</p> <p>Results</p> <p>We have identified 252 ePKs, which corresponds to 1.9% of the <it>S. mansoni </it>predicted proteome, through sequence similarity searches using HMMs (Hidden Markov Models). Amino acid sequences corresponding to the conserved catalytic domain of ePKs were aligned by MAFFT and further used in distance-based phylogenetic analysis as implemented in PHYLIP. Our analysis also included the ePK homologs from six other eukaryotes. The results show that <it>S. mansoni </it>has proteins in all ePK groups. Most of them are clearly clustered with known ePKs in other eukaryotes according to the phylogenetic analysis. None of the ePKs are exclusively found in <it>S. mansoni </it>or belong to an expanded family in this parasite. Only 16 <it>S. mansoni </it>ePKs were experimentally studied, 12 proteins are predicted to be catalytically inactive and approximately 2% of the parasite ePKs remain unclassified. Some proteins were mentioned as good target for drug development since they have a predicted essential function for the parasite.</p> <p>Conclusions</p> <p>Our approach has improved the functional annotation of 40% of <it>S. mansoni </it>ePKs through combined similarity and phylogenetic-based approaches. As we continue this work, we will highlight the biochemical and physiological adaptations of <it>S. mansoni </it>in response to diverse environments during the parasite development, vector interaction, and host infection.</p

PENGARUH BAURAN PROMOSI TERHADAP KEPUTUSAN PEMBELIAN PADA TOKO INDOSAMAJAYA UTAMA TANAH GROGOT

Tujuan penelitian ini adalah untuk mengetahui pengaruh dari bauran promosi yang meliputi variabel periklanan (X1), penjualan tatap muka (X2), promosi penjualan (X3), dan publisitas (X4) terhadap keputusan pembelian (Y). Jenis penelitian ini adalah penelitian lapangan (field work research), penelitian ini meliputi konsumen yang membeli pada toko Indosamajaya Utama Tanah Grogot. Teknik pengambilan sampel menggunakan teknik aksidental maksudnya yakni teknik penentuan sampel berdasarkan kebetulan, yaitu siapa saja yang secara kebetulan ditemui dan cocok sebagai sumber data. Berdasarkan analisis di peroleh&nbsp; nilai koefisien korelasi (R) 0,707, yang artinya terdapat keeratan hubungan yang kuat antara variabel periklanan, penjualan tatap muka promosi penjualan dan Publisitas terhadap keputusan pembelian pada toko Indosamajaya Utama Tanah Grogot. Nilai koefisien determinasi (R2) sebesar 0,500 atau 50%, artinya bahwa variabel keputusan pembelian (Y) dapat dijelaskan oleh variabel periklanan, penjualan tatap muka, promosi penjualan, dan publisitas sebesar 50% sedangkan sisanya 50%&nbsp; adalah pengaruh variabel lainnya diluar penelitian ini. Pengujian secara parsial diketahui bahwa variabel periklanan (X1) memberikan pengaruh dominan, hal ini dibuktikan oleh nilai thitung&nbsp; terbesar dibandingkan dengan variabel bebas lainnya, sesuai dengan hasil SPSS pada tabel 14 yaitu 7,159. Dan t hitung &nbsp;&gt;&nbsp; t tabel&nbsp; yakni 7,159 &gt; 1,6669, dan di dukung oleh tingkat signifikansi 0,000 &lt; 0,05 serta standardizerd coefficient beta yaitu 0,638

Etude de l'adaptation de schistosoma mansoni à son environnement nutritif (rôles de la glutanime dans le métabolisme énergétique du sporocyste et analyse de la diversification de la famille des récepteurs de l'insuline chez le parasite)

La schistosomiase est un problème majeur de santé publique dans de nombreux pays émergents d Afrique, d Amérique latine et d Asie du sud Est, causant près de 300 000 décès par an. Cette maladie est due au schistosome qui est un ver parasite possédant un cycle de vie complexe durant lequel il passe par deux hôtes différents et six stades de développement distincts. Au cours de ma thèse je me suis penché sur la remarquable capcité d adaptation du parasite à ses hôtes successifs et notamment à l environnement nutritif qu il rencontre. Le sporocyste hébergé par l hôte intermédiaire mollusque, se trouve dans un milieu moins favorable que les stades évoluant dans les veines mésentériques riches en glucose, de l hôte vertébré. Nous avons pu montrer que la glutamine pouvait être une source d énergie alternative pour le sporocyste, ainsi qu un précurseur dans la voie de la glycéronéogénèse dépendante de la PEPCK. Cette voie métabolique qui n avait jusqu alors été observée que chez les mammifères, pourrait jouer un rôle important dans la physiologie du parasite. D autre part nous avons caractérisé chez S. mansoni, deux membres de la famille des récepteurs de l insuline (IR), connue pour être un régulateur clé du métabolisme énergétique chez les métazoaires. L étude des structures géniques et protéiques de SmIR-1 et SmIR-2 et leur capacité à lier la pro-insuline humaine, suggèrent fortement leur appartenance à la famille des IR. Cependant les différences du profil d expression de ces deux IR et les résultats de l analyse phylogénétique indiquent que SmIR-1 et SmIR-2 joueraient ds roôles distincts dans le développement du schistosome, contrastant ainsi avec la présence d un IR unique chez les autres invertébrés. Ces résultats suggèrent également l émergence et le maintient de SmIR-1 chez le schistosome afin d y exercer une fonction biologique spécifique ce que confirme des expériences d ARN interférence dans lesquels nous montrons l implication de ce récepteur dans la régulation de la prise de glucose, source d énergie majeure, par le parasiteLILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Protein tyrosine kinases as new potential targets against human schistosomiasis

In spite of the numerous efforts made to control their transmission, parasite schistosomes still represent a serious public health concern and a major economic problem in many developing countries. Praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis and the only one that is available for mass chemotherapy. However, its widespread use and its inefficacy on juvenile parasites raise fears that schistosomes will develop drug resistance, and make the development of alternative drugs highly desirable. Protein tyrosine kinases (PTKs) are key molecules that control cell differentiation and proliferation and they already represent important targets for molecular cancer therapy. The recent characterization in Schistosoma mansoni of several cytosolic and receptor PTKs, with properties similar but also divergent from their vertebrate counterparts, opens new perspectives for the development of novel strategies in chemotherapy of schistosomiasis, which could be based on the use of parasite-specific tyrosine phosphorylation inhibitors

Insulin receptors and glucose uptake in the human parasite Schistosoma mansoni

Very little is known about insulin signalling in schistosomes despite its potential importance in host-parasite molecular dialogue and parasite growth and development. The recent characterization of two insulin receptors (SmIR-1 and SmIR-2) in Schistosoma mansoni has led us to reconsider the question of the potential importance of insulin in host-schistosome interactions. In this work, we demonstrated that insulin could regulate glucose uptake in schistosomes and we investigated the implication of SmIR-1 and SmIR-2 in this process. The possibility that specific inhibitors of SmIR-1 and SmIR-2 tyrosine kinase activities could be developed to target schistosomes is discussed

Insulin receptors and glucose uptake in the human parasite Schistosoma mansoni

Very little is known about insulin signalling in schistosomes despite its potential importance in host-parasite molecular dialogue and parasite growth and development. The recent characterization of two insulin receptors (SmIR-1 and SmIR-2) in Schistosoma mansoni has led us to reconsider the question of the potential importance of insulin in host-schistosome interactions. In this work, we demonstrated that insulin could regulate glucose uptake in schistosomes and we investigated the implication of SmIR-1 and SmIR-2 in this process. The possibility that specific inhibitors of SmIR-1 and SmIR-2 tyrosine kinase activities could be developed to target schistosomes is discussed