Tyrosine kinase and cooperative TGFβ signaling in the reproductive organs of Schistosoma mansoni

Knobloch, Jürgen; Beckmann, Svenja; Burmeister, Cora; Quack, Thomas; Grevelding, Christoph G.

doi:10.1016/j.exppara.2007.04.006

Cited by 62 publications

(85 citation statements)

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“…Convincing studies have demonstrated the importance of protein kinases in schistosome growth and development (Dissous et al 2006, Knobloch et al 2007, Beckmann et al 2010a. The effect of anti-cancer drugs on the reproductive activity of parasites as well as on their survival in in vitro culture (shown recently for the Abl-kinase inhibitor Imatinib by Beckmann and Grevelding 2010) reinforces the hypothesis that parasite protein kinases could represent new targets for antischistosomal strategies, but also that piggy-backing cancer drugs for treatment of schistosomiasis is really worth considering (Dissous and Grevelding 2011).…”

Section: Discussionmentioning

confidence: 99%

Schistosoma mansoni polo-like kinases and their function in control of mitosis and parasite reproduction

Dissous

Grevelding

Long

2011

An. Acad. Bras. Ciênc.

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Polo-like kinases are important regulators of cell cycle progression and mitosis. They constitute a family of conserved serine/threonine kinases which are highly related in their catalytic domains and contain polo boxes involved in protein-protein interactions and subcellular localization. In mammals, five Plks (Plk 1-5) encompass diverse roles in centrosome dynamics, spindle formation, intra S-phase and G2/M checkpoints and DNA damage response. Plk1 is a key positive regulator of mitosis and is overexpressed in various types of cancers. Plk4 is a divergent member of the Plk family, with essential functions in centriole duplication. Homozygous disruption of Plk1 or Plk4 in mice is lethal in embryos. Two Plk members SmPlk1 and SmSak, homologous to Plk1 and Plk4 respectively, are present in the parasitic platyhelminth Schistosoma mansoni. Structural and functional analyses of SmPlk1 have demonstrated its conserved function in the regulation of cell cycle G2/M transition in Xenopus oocytes. The anti-cancer drug BI 2536 (the most potent and selective Plk1 inhibitor) inhibits specifically the catalytic activity of SmPlk1 and induced profound alterations in schistosome gonads, indicating a role of SmPlk1 in parasite gametogenesis and its potential as a novel chemotherapeutic target against schistosomiasis. Functions of SmSak in cell cycle regulation and schistosome gonad development are currently investigated.Key words: cell cycle, Polo-like kinases, reproduction, Schistosoma mansoni. SCHISTOSOME BIOLOGY AND PROTEIN KINASESSchistosomiasis is a water-borne disease and one of the most important parasitic diseases worldwide, with more than 200 million people infected. Transmission of schistosomes is endemic in over 70 tropical and subtropical countries. Control of schistosomiasis relies in priority on mass treatment of human populations with Praziquantel (PZQ), a drug which has been proven for decades to be efficient to reduce morbidity and mortality due to schistosomiasis. However, its widespread use and its inefficacy on juvenile parasites raise fears that schistosomes will develop resistance to PZQ, and there is an urgent need to Correspondence to: Colette Dissous E-mail: colette.dissous@pasteur-lille.fr find alternative drugs and novel concepts to fight schistosomes (Doenhoff et al. 2008).Mating and sexual maturation of adult male and female worms of S. mansoni in the human host lead to the production of numerous eggs which are responsible for transmission, but also for the pathology of schistosomiasis. Eggs are eliminated in faeces, and they assure parasite transmission through the infection of fresh water molluscs as intermediate hosts. Aside, a large proportion of eggs become trapped into human tissues, and granulomas formed around these eggs have serious pathogenic consequences (Ross et al. 2002). In this context, any strategy that aims to reduce worm fecundity and schistosome reproduction represents a valuable concept to combat schistosomiasis.An Acad Bras Cienc (2011) 83 (2) 628 COLETTE DISSOUS, CHRISTO...

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Section: Discussionmentioning

confidence: 99%

Schistosoma mansoni polo-like kinases and their function in control of mitosis and parasite reproduction

Dissous

Grevelding

Long

2011

An. Acad. Bras. Ciênc.

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“…(19) These three kinases have retained particular attention, due to their presence in the reproductive tissues of the parasite and therefore their possible implication in development of gonad and multiplication of germinal and vitelline cells. (20) Indeed, Sykkinases, which are mainly expressed in hematopoietic cells in mammals, have primordial activities in cell development (21) and Src kinases, among their multiple functions, regulate mitogenic activity, by affecting cell growth and proliferation in response to growth factor stimulation, particularly through the activation of RTK and Ras/MAPK (Mitogen-Activated Protein Kinase) downstream signalling pathways. (16) Recent data have demonstrated that Herbimycin A, a potent inhibitor of Src kinase activities, blocked mitotic activity and egg production in female schistosomes.…”

Section: Cytoplasmic Tyrosine Kinases Of Schistosomesmentioning

confidence: 99%

Protein tyrosine kinases as new potential targets against human schistosomiasis

2007

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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.

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“…Results showed that the expression of SmTK6-TK protein induced 100% GVBD in oocytes demonstrating the kinase activity of SmTK6-TK (Table 1). This activity was completely abolished when the Src kinase-specific inhibitor herbimycin A was added at a concentration of 10 M. herbimycin A was shown before to be able to block the activity of the Src kinase SmTK3 and to reduce male-induced mitotic activity in paired females as well as egg production in worms cultured in vitro (16,34). In the Xenopus oocyte assays, we confirmed that herbimycin A was a potent inhibitor of SmTK3 that completely blocked its activity already at a concentration of 0.01 M (Table 1).…”

Section: Smtk6 Full-length Cdna Sequence Reveals Src and Ablmentioning

confidence: 99%

Characterization of the Src/Abl Hybrid Kinase SmTK6 of Schistosoma mansoni

Beckmann

Hahnel

Cailliau

et al. 2011

Journal of Biological Chemistry

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Background: SmTK6 was identified as interaction partner of SmTK4. Results: SmTK6 is a Src/Abl hybrid kinase and interacts also with the uncommon SmVKR1 and SmTK3. Conclusion: SmTK6 is suggested to be part of a complex of receptors, Syk and Src kinases, which are involved in gonad development. Significance: SmTK6 represents an Abl kinase progenitor, for which a function in reproduction could be assigned.

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Tyrosine kinase and cooperative TGFβ signaling in the reproductive organs of Schistosoma mansoni

Cited by 62 publications

References 142 publications

Schistosoma mansoni polo-like kinases and their function in control of mitosis and parasite reproduction

Schistosoma mansoni polo-like kinases and their function in control of mitosis and parasite reproduction

Protein tyrosine kinases as new potential targets against human schistosomiasis

Characterization of the Src/Abl Hybrid Kinase SmTK6 of Schistosoma mansoni

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