Protein tyrosine kinases in Schistosoma mansoni

Bahia, Diana; Andrade, Luiza F.; Ludolf, Fernanda; Mortara, Renato Arruda; Oliveira, Guilherme

doi:10.1590/s0074-02762006000900022

Cited by 21 publications

(15 citation statements)

References 56 publications

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“…Potential importance of tyrosine phosphorylation in a few of cellular processes in S. mansion had been proposed [26][27][28]. In the present study, we identified two tyrosine phosphorylations in two proteins (tubulin beta-2C chain and cell division protein kinase 10).…”

Section: Discussionsupporting

confidence: 54%

Identification of in vivo protein phosphorylation sites in human pathogen Schistosoma japonicum by a phosphoproteomic approach

Luo

Zhou

Lin

et al. 2012

Journal of Proteomics

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Section: Discussionsupporting

confidence: 54%

Identification of in vivo protein phosphorylation sites in human pathogen Schistosoma japonicum by a phosphoproteomic approach

Luo

Zhou

Lin

et al. 2012

Journal of Proteomics

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“…PTKs can be classified, based on the presence or absence of transmembrane domains, into receptor tyrosine kinase (RTK) that relay intracellular signals [74], and cytoplasmatic tyrosine kinase (CTK). S. mansoni kinome contains 15 RTKs and 19 CTKs.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2011

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BackgroundSchistosomiasis remains an important parasitic disease and a major economic problem in many countries. The Schistosoma mansoni 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 S. mansoni 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.ResultsWe have identified 252 ePKs, which corresponds to 1.9% of the S. mansoni 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 S. mansoni 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 S. mansoni or belong to an expanded family in this parasite. Only 16 S. mansoni 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.ConclusionsOur approach has improved the functional annotation of 40% of S. mansoni ePKs through combined similarity and phylogenetic-based approaches. As we continue this work, we will highlight the biochemical and physiological adaptations of S. mansoni in response to diverse environments during the parasite development, vector interaction, and host infection.

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“…elegans [ 46 ]. Moreiver the RNAi-induced phenotype of Sm- Protein Kinase C together with the highlighted potential of kinases as key targets for drug design in schistosomes [ 28 , 47 , 48 ] led us to focus on kinases in our bioinformatics list. We also identified some other potential targets known to interact with known small molecule, drug-like compounds (i.e.…”

Section: Introductionmentioning

confidence: 99%

Application of RNAi to Genomic Drug Target Validation in Schistosomes

et al. 2015

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Concerns over the possibility of resistance developing to praziquantel (PZQ), has stimulated efforts to develop new drugs for schistosomiasis. In addition to the development of improved whole organism screens, the success of RNA interference (RNAi) in schistosomes offers great promise for the identification of potential drug targets to initiate drug discovery. In this study we set out to contribute to RNAi based validation of putative drug targets. Initially a list of 24 target candidates was compiled based on the identification of putative essential genes in schistosomes orthologous of C. elegans essential genes. Knockdown of Calmodulin (Smp_026560.2) (Sm-Calm), that topped this list, produced a phenotype characterised by waves of contraction in adult worms but no phenotype in schistosomula. Knockdown of the atypical Protein Kinase C (Smp_096310) (Sm-aPKC) resulted in loss of viability in both schistosomula and adults and led us to focus our attention on other kinase genes that were identified in the above list and through whole organism screening of known kinase inhibitor sets followed by chemogenomic evaluation. RNAi knockdown of these kinase genes failed to affect adult worm viability but, like Sm-aPKC, knockdown of Polo-like kinase 1, Sm-PLK1 (Smp_009600) and p38-MAPK, Sm-MAPK p38 (Smp_133020) resulted in an increased mortality of schistosomula after 2-3 weeks, an effect more marked in the presence of human red blood cells (hRBC). For Sm-PLK-1 the same effects were seen with the specific inhibitor, BI2536, which also affected viable egg production in adult worms. For Sm-PLK-1 and Sm-aPKC the in vitro effects were reflected in lower recoveries in vivo. We conclude that the use of RNAi combined with culture with hRBC is a reliable method for evaluating genes important for larval development. However, in view of the slow manifestation of the effects of Sm-aPKC knockdown in adults and the lack of effects of Sm-PLK-1 and Sm-MAPK p38 on adult viability, these kinases may not represent suitable drug targets.

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Protein tyrosine kinases in Schistosoma mansoni

Cited by 21 publications

References 56 publications

Identification of in vivo protein phosphorylation sites in human pathogen Schistosoma japonicum by a phosphoproteomic approach

Identification of in vivo protein phosphorylation sites in human pathogen Schistosoma japonicum by a phosphoproteomic approach

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

Application of RNAi to Genomic Drug Target Validation in Schistosomes

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