Schistosoma mansoni: Structural and biochemical characterization of two distinct Venus Kinase Receptors

Gouignard, Nadège; Vanderstraete, Mathieu; Cailliau, Kátia; Lescuyer, Arlette; Browaeys, Edith; Dissous, Colette

doi:10.1016/j.exppara.2011.05.007

Cited by 28 publications

(81 citation statements)

References 27 publications

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“…SmTK6-SH2SH3 alone was also unable to induce GVBD, in contrast to the SmTK6-TK catalytic domain, which induced 100% GVBD (Tables 1 and 2). The expression of SmVKR1 YYRE alone also led to GVBD, whereas wild-type SmVKR1 in the absence of ligand had no effect as shown previously (25). The results showed that the co-expression of SmTK6-fl with SmVKR1 YYRE did not affect GVBD induced by the SmVKR1 active kinase.…”

Section: Co-immunoprecipitation Experiments Confirm Smtk6-smtk3 and Ssupporting

confidence: 61%

“…cRNA was also produced from a pcDNA 3.1 plasmid encoding full-length SmVKR1 (23) rendered constitutively active by an exchange of the Phe-1167 (close to the potential YY1064 -1065 autophosphorylation site) to a glutamic acid residue (SmVKR1 YYRE ) performed by site-directed mutagenesis as described before (24,25). SmVKR1 YYRE -C-term was amplified by PCR from SmVKR1 YYRE in pcDNA 3.1 using the primer pair SmVKR1-C-term-5Ј (5Ј-CCCTGCAGTCAAGGTAGAA-ACGCTAAACTGTTATC-3Ј; containing a PstI site) and SmVKR1-C-term-3Ј (5Ј-GGGAATTCCGACGTAAACTGA-AAGAAATTGAAAATCG-3Ј; containing an EcoRI site) and subcloned in the T7-containing plasmid PGBKT7 that also contains the Myc tag.…”

Section: Methodsmentioning

confidence: 99%

“…As shown before, schistosome kinases can be efficiently expressed in this system, and kinase activities were proven by their capacity to induce GVBD as a resumption of meiosis (13,21,22,25,33). To be enzymatically active, kinases have to adopt an open conformation, which is usually acquired following interaction with an activated partner molecule such as a receptor.…”

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

confidence: 99%

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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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Section: Co-immunoprecipitation Experiments Confirm Smtk6-smtk3 and Ssupporting

confidence: 61%

Section: Methodsmentioning

confidence: 99%

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

confidence: 99%

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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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“…Preliminary experiments indicated that VKRs were preferentially expressed in larvae and in gonads of several species [28], suggesting a role in development and reproduction. A single vkr gene was usually found in each invertebrate genome but exceptionally the genome of S. mansoni , as that of another trematode Clonorchis , contains two genes vkr1 and vkr2 with a similar organization but encoding distinct proteins [29], [30]. The expression of Smvkr1 and Smvkr2 was shown to be variable in the different parasitic stages, likely indicating their independent regulation [30].…”

Section: Introductionmentioning

confidence: 99%

Venus Kinase Receptors Control Reproduction in the Platyhelminth Parasite Schistosoma mansoni

et al. 2014

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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.

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“…Another class of schistosome RTKs is represented by the venus kinase receptors (VKR) SmVKR1 and SmVKR2, which belong to a novel family of transmembrane receptors [70,86,87]. VKRs have also been found in insects, where they are mainly expressed in female gonads indicating functional roles for reproduction [87].…”

Section: Kinase Signaling In Schistosomesmentioning

confidence: 99%

Protein Kinases as Potential Targets for Novel Anti-Schistosomal Strategies

Beckmann

Leutner²,

Gouignard³

et al. 2012

cpd

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Schistosome parasites are the causative pathogens of schistosomiasis (bilharzia), a disease of worldwide significance. In terms of patient numbers, schistosomiasis ranks second to malaria as a parasitosis affecting more than 200 million people of the tropics and subtropics. Since the 1970s Praziquantel (PZQ) is the drug of choice and nearly exclusively used for treatment. However, drug resistance is an increasing threat, particularly with respect to large-scale PZQ administration programs. Last decade´s research indicated that resistance against PZQ can be induced under laboratory conditions, and field studies provided first indications for the possibility of reduced PZQ efficacy. Furthermore, clear evidence for the molecular armamentarium of schistosomes with multidrug transporters was found, one of which was responding to PZQ challenge. Also the development of a vaccine still represents an elusive goal, although effort and time have been invested in this subject. In light of these facts it is commonly accepted that new drugs are urgently needed. Research on signal transduction processes in Schistosoma mansoni has provided an unexpected and novel perspective towards this end. Molecular, biochemical, and physiological studies elucidating principles of schistosome development have demonstrated the essential role of protein kinases (PKs). In humans, PKs are known to be involved in cancer development. Since a variety of approved anticancer drugs targeting PKs exist, first studies have been performed to investigate whether these drugs are able to also inhibit schistosome PKs. Indeed, promising results have been obtained indicating the potential of PKs as privileged targets for new concepts in fighting schistosomes.

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Schistosoma mansoni: Structural and biochemical characterization of two distinct Venus Kinase Receptors

Cited by 28 publications

References 27 publications

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

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

Venus Kinase Receptors Control Reproduction in the Platyhelminth Parasite Schistosoma mansoni

Protein Kinases as Potential Targets for Novel Anti-Schistosomal Strategies

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