Jérôme Vicogne

Institut de Biologie de Lille, Lille, Nord-Pas-de-Calais, France

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Publications (24)87.96 Total impact

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    ABSTRACT: The regulation of PfPP1 phosphatase activity in Plasmodium falciparum remains to be deciphered. Data from homologous eukaryotic PP1 phosphatases suggest that several protein regulators should be involved in this essential process. One such regulator, named PfI2 based on its primary sequence homology with eukaryotic I2, was recently shown to be able to interact with PfPP1 and to inhibit its phosphatase activity, mainly through the canonical “RVxF” binding motif. The details of the structural and functional characteristics of this interaction are investigated here. Using NMR spectroscopy, a second site of interaction is suggested to reside between residues D94-T117 and contains the “FxxR/KxR/K” binding motif present in other I2 proteins. This site seems to play in concert/synergy with the “RVxF” motif to bind PP1, as only mutations in both motifs were able to abolish completely this interaction. However, regarding the structure/function relationship, the mutation of either “RVxF” or “FxxR/KxR/K” motif is more drastic, as each mutation prevents the capacity of PfI2 to trigger GVBD in micro-injected Xenopus oocytes. This indicates that the tight association of the PfI2 regulator to the PP1 phosphatase, mediated by a two-site interaction, is necessary to exert its function. Based on these results, the use of a peptide derived from the “FxxR/KxR/K” PfI2 motif was investigated for its potential effect on Plasmodium growth. This peptide, fused at its N-terminus to a penetrating sequence, was shown to accumulate specifically in infected erythrocytes and to have an anti-plasmodial effect.This article is protected by copyright. All rights reserved.Structured digital abstractPfPP1 and PfI2 bind by nuclear magnetic resonance (1, 2)PP1 physically interacts with PfPP1 by anti tag coimmunoprecipitation (View interaction)PfI2 binds to PfPP1 by enzyme linked immunosorbent assay (View interaction)PfI2 binds to PfPP1 by surface plasmon resonance (1, 2, 3, 4)
    FEBS Journal 08/2014; · 4.25 Impact Factor
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    ABSTRACT: The capacity of many proteins to interact with natural or synthetic polyanions has been exploited for modulating their biological action. However, the polydispersity of these macromolecular polyanions as well as their poor specificity is a severe limitation to their use as drugs. An emerging trend in this field is the synthesis of homogeneous and well-defined polyanion-peptide conjugates which act as bivalent ligands with the peptide part bringing the selectivity of the scaffold. Alternately, this strategy can be used for improving the binding of short peptides to polyanion-binding protein targets. This work describes the design and first synthesis of homogeneous polysulfonate-peptide conjugates using thiocarbamate ligation for binding to the extracellular domain of MET tyrosine kinase receptor for hepatocyte growth factor.
    Bioconjugate Chemistry 04/2014; · 4.58 Impact Factor
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    ABSTRACT: BACKGROUND: Receptor tyrosine kinases (RTK) form a family of transmembrane proteins widely conserved in Metazoa, with key functions in cell-to-cell communication and control of multiple cellular processes. A new family of RTK named Venus Kinase Receptor (VKR) has been described in invertebrates. The VKR receptor possesses a Venus Fly Trap (VFT) extracellular module, a bilobate structure that binds small ligands to induce receptor kinase activity. VKR was shown to be highly expressed in the larval stages and gonads of several invertebrates, suggesting that it could have functions in development and/or reproduction. RESULTS: Analysis of recent genomic data has allowed us to extend the presence of VKR to five bilaterian phyla (Platyhelminthes, Arthropoda, Annelida, Mollusca, Echinodermata) as well as to the Cnidaria phylum. The presence of NveVKR in the early-branching metazoan Nematostella vectensis suggested that VKR arose before the bilaterian radiation. Phylogenetic and gene structure analyses showed that the 40 receptors identified in 36 animal species grouped monophyletically, and likely evolved from a common ancestor. Multiple alignments of tyrosine kinase (TK) and VFT domains indicated their important level of conservation in all VKRs identified up to date. We showed that VKRs had inducible activity upon binding of extracellular amino-acids and molecular modeling of the VFT domain confirmed the structure of the conserved amino-acid binding site. CONCLUSIONS: This study highlights the presence of VKR in a large number of invertebrates, including primitive metazoans like cnidarians, but also its absence from nematodes and chordates. This little-known RTK family deserves to be further explored in order to determine its evolutionary origin, its possible interest for the emergence and specialization of Metazoa, and to understand its function in invertebrate development and/or reproductive biology.
    BMC Genomics 05/2013; 14(1):361. · 4.40 Impact Factor
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    ABSTRACT: Hepatocyte growth factor/scatter factor (HGF/SF) is the high affinity ligand of MET tyrosine kinase receptor. We report here the total synthesis of a biotinylated analogue of human HGF/SF N domain. Functionally, N domain is part of the HGF/SF high affinity binding site for MET and also the main HGF/SF binding site for heparin. The 97 Aa linear chain featuring a C-terminal biotin group was assembled in high yield using an N-to-C one-pot three segments assembly strategy relying on a sequential Native Chemical Ligation (NCL)/bis(2-sulfanylethyl)amido (SEA) native peptide ligation process. The folded protein displayed the native disulfide bond pattern and showed the ability to bind heparin.
    Bioorganic & medicinal chemistry 03/2013; · 2.82 Impact Factor
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    ABSTRACT: The GRB2-associated binder 1 (GAB1) docking/scaffold protein is a key mediator of the MET-tyrosine kinase receptor activated by hepatocyte growth factor/scatter factor (HGF/SF). Activated MET promotes recruitment and tyrosine phosphorylation of GAB1, which in turn recruits multiple proteins and mediates MET signaling leading to cell survival, motility, and morphogenesis. We previously reported that, without its ligand, MET is a functional caspase target during apoptosis, allowing the generation of a p40-MET fragment that amplifies apoptosis. In this study we established that GAB1 is also a functional caspase target by evidencing a caspase-cleaved p35-GAB1 fragment that contains the MET binding domain. GAB1 is cleaved by caspases before MET, and the resulting p35-GAB1 fragment is phosphorylated by MET upon HGF/SF binding and can interact with a subset of GAB1 partners, PI3K, and GRB2 but not with SHP2. This p35-GAB1 fragment favors cell survival by maintaining HGF/SF-induced MET activation of AKT and by hindering p40-MET pro-apoptotic function. These data demonstrate an anti-apoptotic role of caspase-cleaved GAB1 in HGF/SF-MET signaling.
    Journal of Biological Chemistry 08/2012; 287(42):35382-96. · 4.65 Impact Factor
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    ABSTRACT: The receptor tyrosine kinase Met and its ligand, the hepatocyte growth factor/scatter factor, are essential for embryonic development, whereas deregulation of Met signaling pathways is associated with tumorigenesis and metastasis. The presenilin-regulated intramembrane proteolysis (PS-RIP) is involved in ligand-independent downregulation of Met. This proteolytic process involves shedding of the Met extracellular domain followed by γ-secretase cleavage, generating labile intracellular fragments degraded by the proteasome. We demonstrate here that upon shedding both generated Met N- and C-terminal fragments are degraded directly in the lysosome, with C-terminal fragments escaping γ-secretase cleavage. PS-RIP and lysosomal degradation are complementary, because their simultaneous inhibition induces synergistic accumulation of fragments. Met N-terminal fragments associate with the high-affinity domain of HGF/SF, confirming its decoy activity which could be reduced through their routing to the lysosome at the expense of extracellular release. Finally, the DN30 monoclonal antibody inducing Met shedding promotes receptor degradation through induction of both PS-RIP and the lysosomal pathway. Thus, we demonstrate that Met shedding initiates a novel lysosomal degradation which participates to ligand-independent downregulation of the receptor.
    Traffic 06/2012; 13(9):1261-72. · 4.65 Impact Factor
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    ABSTRACT: Growing evidence indicates that the protein regulators governing protein phosphatase 1 (PP1) activity have crucial functions because their deletion drastically affects cell growth and division. PP1 has been found to be essential in Plasmodium falciparum, but little is known about its regulators. In this study, we have identified a homolog of Inhibitor-3 of PP1, named PfI3. NMR analysis shows that PfI3 belongs to the disordered protein family. High affinity interaction of PfI3 and PfPP1 is demonstrated in vitro using several methods, with an apparent dissociation constant KD of 100 nm. We further show that the conserved 41KVVRW45 motif is crucial for this interaction as the replacement of the Trp45 by an Ala45 severely decreases the binding to PfPP1. Surprisingly, PfI3 was unable to rescue a yeast strain deficient in I3 (Ypi1). This lack of functional orthology was supported as functional assays in vitro have revealed that PfI3, unlike yeast I3 and human I3, increases PfPP1 activity. Reverse genetic approaches suggest an essential role of PfI3 in the growth and/or survival of blood stage parasites because attempts to obtain knock-out parasites were unsuccessful, although the locus of PfI3 is accessible. The main localization of a GFP-tagged PfI3 in the nucleus of all blood stage parasites is compatible with a regulatory role of PfI3 on the activity of nuclear PfPP1.
    Journal of Biological Chemistry 01/2012; 287(2):1306-1321. · 4.65 Impact Factor
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    ABSTRACT: The interaction of polysaccharides with proteins modulates or triggers many biological effects. In particular, heparan sulphate proteoglycans (HSPGs) have multiple regulatory interactions with growth factors, enzymes, enzyme inhibitors, and some components of the extracellular matrix. The important role played by HSPGs has motivated the synthesis and selection of HSPG mimetics for modulating the biological activity of HS-binding proteins. We present hereinafter an efficient polysaccharide microarray method that allows the screening of HS-mimetic libraries towards HS-binding growth factors, a major class of polypeptides whose inhibition or potentiation is of high medical interest.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 808:231-40. · 1.29 Impact Factor
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    ABSTRACT: Growing evidence indicates that the protein regulators governing protein phosphatase 1 (PP1) activity have crucial functions because their deletion drastically affects cell growth and division. PP1 has been found to be essential in Plasmodium falciparum, but little is known about its regulators. In this study, we have identified a homolog of Inhibitor-3 of PP1, named PfI3. NMR analysis shows that PfI3 belongs to the disordered protein family. High affinity interaction of PfI3 and PfPP1 is demonstrated in vitro using several methods, with an apparent dissociation constant K(D) of 100 nm. We further show that the conserved (41)KVVRW(45) motif is crucial for this interaction as the replacement of the Trp(45) by an Ala(45) severely decreases the binding to PfPP1. Surprisingly, PfI3 was unable to rescue a yeast strain deficient in I3 (Ypi1). This lack of functional orthology was supported as functional assays in vitro have revealed that PfI3, unlike yeast I3 and human I3, increases PfPP1 activity. Reverse genetic approaches suggest an essential role of PfI3 in the growth and/or survival of blood stage parasites because attempts to obtain knock-out parasites were unsuccessful, although the locus of PfI3 is accessible. The main localization of a GFP-tagged PfI3 in the nucleus of all blood stage parasites is compatible with a regulatory role of PfI3 on the activity of nuclear PfPP1.
    Journal of Biological Chemistry 11/2011; 287(2):1306-21. · 4.65 Impact Factor
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    ABSTRACT: Three in one: Native chemical ligation (NCL) and bis(2-sulfanylethyl)amido (SEA) ligation allow the one-pot assembly of three peptide segments in the N-to-C direction. The SEA group is switched off by intramolecular disulfide bond formation during NCL. Then, a phosphine switches it on to trigger the second SEA ligation step. The K1 domain of the hepatocyte growth factor was synthesized and found to be biologically active.
    Angewandte Chemie International Edition 11/2011; 51(1):209-13. · 11.34 Impact Factor
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    ABSTRACT: Schistosomiasis (bilharzia) is a parasitic disease of worldwide significance affecting human and animals. As schistosome eggs are responsible for pathogenesis, the understanding of processes controlling gonad development might open new perspectives for intervention. The Src-like tyrosine-kinase SmTK3 of Schistosoma mansoni is expressed in the gonads, and its pharmacological inhibition reduces mitogenic activity and egg production in paired females in vitro. Since Src kinases are important signal transduction proteins it is of interest to unravel the signaling cascades SmTK3 is involved in to understand its cellular role in the gonads. Towards this end we established and screened a yeast two-hybrid (Y2H) cDNA library of adult S. mansoni with a bait construct encoding the SH3 (src homology) domain and unique site of SmTK3. Among the binding partners found was a diaphanous homolog (SmDia), which was characterized further. SmDia is a single-copy gene transcribed throughout development with a bias towards male transcription. Its deduced amino acid sequence reveals all diaphanous-characteristic functional domains. Binding studies with truncated SmDia clones identified SmTK3 interaction sites demonstrating that maximal binding efficiency depends on the N-terminal part of the FH1 (formin homology) domain and the inter-domain region of SmDia located upstream of FH1 in combination with the unique site and the SH3 domain of SmTK3, respectively. SmDia also directly interacted with the GTPase SmRho1 of S. mansoni. In situ hybridization experiments finally demonstrated that SmDia, SmRho1, and SmTK3 are transcribed in the gonads of both genders. These data provide first evidence for the existence of two cooperating pathways involving Rho and Src that bridge at SmDia probably organizing cytoskeletal events in the reproductive organs of a parasite, and beyond that in gonads of eukaryotes. Furthermore, the FH1 and inter domain region of SmDia have been discovered as binding sites for the SH3 and unique site domains of SmTK3, respectively.
    PLoS ONE 01/2009; 4(9):e6998. · 3.53 Impact Factor
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    A Ahier, N Khayath, J Vicogne, C Dissous
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    ABSTRACT: 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.
    Parasite 01/2009; 15(4):573-9. · 0.82 Impact Factor
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    ABSTRACT: Insulin signalling is a very ancient and well conserved pathway in metazoan cells, dependent on insulin receptors (IR) which are transmembrane proteins with tyrosine kinase activity. A unique IR is usually present in invertebrates whereas two IR members are found with different functions in vertebrates. This work demonstrates the existence of two distinct IR homologs (SmIR-1 and SmIR-2) in the parasite trematode Schistosoma mansoni. These two receptors display differences in several structural motifs essential for signalling and are differentially expressed in parasite tissues, suggesting that they could have distinct functions. The gene organization of SmIR-1 and SmIR-2 is similar to that of the human IR and to that of the IR homolog from Echinococcus multilocularis (EmIR), another parasitic platyhelminth. SmIR-1 and SmIR-2 were shown to interact with human pro-insulin but not with pro-insulin-like growth factor-1 in two-hybrid assays. Phylogenetic results indicated that SmIR-2 and EmIR might be functional orthologs whereas SmIR-1 would have emerged to fulfil specific functions in schistosomes.
    FEBS Journal 03/2007; 274(3):659-76. · 4.25 Impact Factor
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    ABSTRACT: In order to characterize protein cofactors of the Schistosoma mansoni nuclear receptor SmFtz-F1, we have screened a yeast two-hybrid adult worm cDNA library using a construct expressing the D, E and F domains of SmFtz-F1 as bait. One of the selected clones encoded a sequence without homologues in any other species, apart from Schistosoma japonicum. The complete sequence was obtained by 5' and 3' rapid amplification of cDNA ends (RACE) and comprised 3660 nucleotides with an open reading frame of 788 amino acids. The gene is expressed at all schistosome life cycle stages at a 5-11-fold higher level than SmFtz-f1. The protein, named SmFIP-1, interacted with SmFtz-F1 in a GST pull-down assay and in a mammalian two-hybrid assay in CV-1 cells. Although SmFIP-1 contains a consensus NR box (LXXLL) this was not involved in the interaction with SmFtz-F1. However, interaction did depend on the AF2-AD motif in the nuclear receptor ligand binding domain. Deletion analysis showed that the C-terminal moiety of SmFIP-1 was involved in the binding, but this could not be localized to a particular motif, suggesting that the binding may be conformation-dependent. Finally, SmFIP-1 markedly repressed SmFtz-F1-mediated transcription in a dose-dependent manner from the SmFtz-f1 gene promoter demonstrating that SmFIP-1 is a schistosome-specific transcriptional corepressor.
    Molecular and Biochemical Parasitology 08/2006; 148(1):10-23. · 2.73 Impact Factor
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    ABSTRACT: To date, glyceroneogenesis has only been described in mammals but we demonstrate in this paper that it could exist in the invertebrate Schistosoma mansoni, the parasitic helminth transmitted by fresh water molluscs and responsible for the major human endemic disease, schistosomiasis. Glyceroneogenesis is a phosphoenolpyruvate carboxykinase (PEPCK)-dependent process by which glycerol can be produced from precursors like glutamine and therefore represents a truncated gluconeogenic pathway. We have previously demonstrated the possible central role of glutamine in mollusc-schistosome interactions. In this work, we show that glutamine effectively promotes in vitro survival and protein synthesis in sporocysts, the intramolluscan larval stages of S. mansoni, possibly through its role as an energy source. However, the demonstration that PEPCK is massively expressed in these larval forms as compared to adult parasites, together with the observation that 3-mercaptopicolinate, a specific inhibitor of PEPCK, significantly reduces the effect of glutamine on sporocyst growth, suggest that glutamine could also be used for glucose or glycerol production. Results of [14C] glutamine incorporation confirmed that neosynthesis of glucose and mainly of glycerol occurred in sporocysts and was dependent on PEPCK activity. Therefore, our results strongly indicate that glyceroneogenesis could exist in schistosomes. Several hypotheses can be proposed concerning the importance of glycerol for the adaptation of this helminth to its host osmotic and energetic environment.
    Molecular and Biochemical Parasitology 07/2006; 147(2):145-53. · 2.73 Impact Factor
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    ABSTRACT: Parasitic helminths remain major pathogens of both humans and animals throughout the world. The success of helminth infections depends on the capacity of the parasite to counteract host immune responses but also to exploit host-derived signal molecules for its development. Recent progress has been made in the characterization of growth factor receptors of various nematode and flatworm parasites with the demonstration that transforming growth factor beta (TGF-beta), epidermal growth factor (EGF) and insulin receptor signalling pathways are conserved in helminth parasites and potentially implicated in the host-parasite molecular dialogue and parasite development.
    FEBS Letters 06/2006; 580(12):2968-75. · 3.58 Impact Factor
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    ABSTRACT: Interleukin (IL-)7 and thyroxin (T4) favor Schistosoma mansoni development. Their effect is similar, rather than identical; moreover, cotreatment acts synergistically on parasites. This questioned a common mediator to their action, which we hypothesized was host glucose metabolism. Infection with S. mansoni resulted in an early peak in glycemia immediately followed by a peak of insulinemia (D7-21). In IL-7 + T4 cotreated infected animals, the peak of insulin was abrogated. We further assessed the consequences of experimentally induced glucose- or insulin-level variations on parasite development. Insulin treatment from day 14 to day 21 post-infection (PI) led to increased worm burden and parasite size, thus mimicking the effect of T4 on schistosome development. Interestingly, insulin treatment did not modify glycemia yet abrogated the hyperinsulinemia, normally occurring during infection. Finally, these treatments were associated with an alteration of the expression of parasite genes involved in glucose uptake. These experiments characterize the elaborate links between parasite and host metabolism and their reciprocal influences.
    Journal of Parasitology 09/2005; 91(4):737-44. · 1.32 Impact Factor
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    ABSTRACT: The epidermal growth factor receptor (EGF-R) plays an important role in development and cell differentiation, and homologues of EGF-R have been identified in a broad range of vertebrate and invertebrate organisms. This work concerns the functional characterization of SER, the EGF-R-like molecule previously identified in the helminth parasite Schistosoma mansoni. Transactivation assays performed in epithelial Madin-Darby canine kidney cells co-transfected with SER and a Ras-responsive reporter vector indicated that SER was able to trigger a Ras/ERK pathway in response to human epidermal growth factor (EGF). These results were confirmed in Xenopus oocytes showing that human EGF induced meiosis reinitiation characterized by germinal vesicle breakdown in SER-expressing oocytes. Germinal vesicle breakdown induced by EGF was dependent on receptor kinase activity and shown to be associated with phosphorylation of SER and of downstream ERK proteins. (125)I-EGF binding experiments performed on SER-expressing oocytes revealed high affinity (2.9 x 10(-9) M) of the schistosome receptor for human EGF. Phosphorylation of the native SER protein present in S. mansoni membranes was also shown to occur upon binding of human EGF. These data demonstrate the ability of the SER schistosome receptor to be activated by vertebrate EGF ligands as well as to activate the classical ERK pathway downstream, indicating the conservation of EGF-R function in S. mansoni. Moreover, human EGF was shown to increase protein and DNA synthesis as well as protein phosphorylation in parasites, supporting the hypothesis that host EGF could regulate schistosome development. The possible role of SER as a receptor for host EGF peptides and its implication in host-parasite signaling and parasite development are discussed.
    Journal of Biological Chemistry 10/2004; 279(36):37407-14. · 4.65 Impact Factor
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    ABSTRACT: Cytosine-phosphate-guanine (CpG) motifs in bacterial DNA are known to activate the mammalian immune system, and this activation is thought to depend on the Toll-like receptor 9 (TLR9) signaling pathway. Previous studies strongly suggested that TLR9 is involved as the specific receptor for CpG motifs but did not provide direct evidence of their interaction. In this study, we demonstrate for the first time that murine TLR9 binds an unmethylated CpG-containing plasmid. This interaction is sequence-specific and is influenced by the methylation status of the plasmid. Furthermore, we demonstrate that this interaction leads to the activation of the NF-kappaB pathway in mTLR9-expressing cells. Our results provide a molecular basis for the interaction between CpG-DNA and TLR9.
    Journal of Biological Chemistry 05/2004; 279(15):15124-9. · 4.65 Impact Factor
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    ABSTRACT: Biomphalaria glabrataembryonic (Bge) cells have been shown to provide favourable environmental conditions for the development of Schistosoma mansoni sporocysts. We investigated the effect of Bge excretory-secretory products on metabolic activity and gene transcription in S. mansoni mother sporocysts. Using the differential-display technique, we identified several sporocyst transcripts regulated by exposure to Bge soluble components. Research in databases indicated that six of the eight differential products analysed were homologous to sequences already present in databases. Two transcripts appeared of interest for schistosome development since they could be associated with cell division and protein synthesis in developing sporocysts. Their up-regulation following contact with cell products was confirmed by semi-quantitative RT-PCR. The first fragment coded for a part of the chaperonin containing T-complex protein gamma subunit-like protein of S. mansoni (SmTCP 1-C). The second one represented a new S. mansoni expressed sequence tag encoding a protein homologous to various glutaminyl-tRNA synthetases (GlnRS). The full-length sequence of SmGlnRS was cloned from adult schistosomes and its primary sequence was compared to other GlnRS. The overexpression of SmTCP-1 and SmGlnRS could be correlated with the metabolic changes observed in Bge-exposed sporocysts.
    Parasitology Research 02/2003; 89(2):113-9. · 2.85 Impact Factor