David Tulasne
Pasteur Institute
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by David Tulasne.
Journal of Biological Chemistry | 2004
Jérôme Vicogne; Katia Cailliau; David Tulasne; Edith Browaeys; Yu Tao Yan; Véronique Fafeur; Jean Pierre Vilain; Dominique Legrand; Jacques Trolet; Colette Dissous
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 (Shoemaker, C. B., Ramachandran, H., Landa, A., dos Reis, M. G., and Stein, L. D. (1992) Mol. Biochem. Parasitol. 53, 17–32). 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. 125I-EGF binding experiments performed on SER-expressing oocytes revealed high affinity (2.9 × 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.
Molecular Biology of the Cell | 2009
Bénédicte Foveau; Frédéric Ancot; Catherine Leroy; Annalisa Petrelli; Karina Reiss; Valérie Vingtdeux; Silvia Giordano; Véronique Fafeur; David Tulasne
Hepatocyte growth factor/scatter factor (HGF/SF) acts through the membrane-anchored Met receptor tyrosine kinase to induce invasive growth. Deregulation of this signaling is associated with tumorigenesis and involves, in most cases, overexpression of the receptor. We demonstrate that Met is processed in epithelial cells by presenilin-dependent regulated intramembrane proteolysis (PS-RIP) independently of ligand stimulation. The proteolytic process involves sequential cleavage by metalloproteases and the gamma-secretase complex, leading to generation of labile fragments. In normal epithelial cells, although expression of cleavable Met by PS-RIP is down-regulated, uncleavable Met displayed membrane accumulation and induced ligand-independent motility and morphogenesis. Inversely, in transformed cells, the Met inhibitory antibody DN30 is able to promote Met PS-RIP, resulting in down-regulation of the receptor and inhibition of the Met-dependent invasive growth. This demonstrates the original involvement of a proteolytic process in degradation of the Met receptor implicated in negative regulation of invasive growth.
Cell Death & Differentiation | 2008
David Tulasne; Bénédicte Foveau
The MET tyrosine kinase receptor is a high-affinity receptor for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF-MET system is necessary for embryonic development, and aberrant MET signalling favours tumorigenesis and metastasis. MET is a prototype of tyrosine kinase receptor, which is able to counteract apoptosis through the initiation of a survival signal involving notably the PI3K–Akt pathway. Paradoxically, the MET receptor is also able to promote apoptosis when activated by HGF/SF or independently of ligand stimulation. The molecular mechanisms underlying this uncommon response have been recently investigated and revealed dual antiapoptotic or proapoptotic property of MET according to the cell type or stress conditions. Although the involvement of MET in the regulation of integrated biological responses mostly took into account its efficient antiapoptotic function, its proapoptotic responses could also be important for regulation of the survival/apoptosis balance and play a role during the development or tumour progression.
Molecular and Cellular Biology | 2004
David Tulasne; Julien Deheuninck; Filipe Calheiros Lourenço; Fabienne Lamballe; Zongling Ji; Catherine Leroy; Emilie Puchois; Anice Moumen; Flavio Maina; Patrick Mehlen; Véronique Fafeur
ABSTRACT The MET tyrosine kinase, the receptor of hepatocyte growth factor-scatter factor (HGF/SF), is known to be essential for normal development and cell survival. We report that stress stimuli induce the caspase-mediated cleavage of MET in physiological cellular targets, such as epithelial cells, embryonic hepatocytes, and cortical neurons. Cleavage occurs at aspartic residue 1000 within the SVD site of the juxtamembrane region, independently of the crucial docking tyrosine residues Y1001 or Y1347 and Y1354. This cleavage generates an intracellular 40-kDa MET fragment containing the kinase domain. The p40 MET fragment itself causes apoptosis of MDCK epithelial cells and embryonic cortical neurons, whereas its kinase-dead version is impaired in proapoptotic activity. Finally, HGF/SF treatment does not favor MET cleavage and apoptosis, confirming the known survival role of ligand-activated MET. Our results show that stress stimuli convert the MET survival receptor into a proapoptotic factor.
Cell Death & Differentiation | 2007
Bénédicte Foveau; Catherine Leroy; F Ancot; Julien Deheuninck; Zongling Ji; Véronique Fafeur; David Tulasne
Activation of the MET tyrosine kinase receptor by hepatocyte growth factor/scatter factor is classically associated with cell survival. Nonetheless, stress stimuli can lead to a caspase-dependent cleavage of MET within its juxtamembrane region, which generate a proapoptotic 40 kDa fragment (p40 MET). We report here that p40 MET is in fact generated through an additional caspase cleavage of MET within its extreme C-terminal region, which removes only few amino acids. We evidenced a hierarchical organization of these cleavages, with the C-terminal cleavage favoring the juxtamembrane one. As a functional consequence, the removal of the last amino acids of p40 MET increases its apoptotic capacity. Finally, cells expressing a MET receptor mutated at the C-terminal caspase site are unable to generate p40 MET and are resistant to apoptosis, indicating that generation of p40 MET amplifies apoptosis. These results revealed a two-step caspase cleavage of MET resulting in the reshaping of this survival receptor to a proapoptotic factor.
Molecular Cancer Research | 2010
Aurélie Cazet; Jonathan Lefebvre; Eric Adriaenssens; Sylvain Julien; Marie Bobowski; Anita Grigoriadis; Andrew Tutt; David Tulasne; Xuefen Le Bourhis; Philippe Delannoy
The disialoganglioside GD3 is overexpressed in ∼50% of invasive ductal breast carcinoma, and the GD3 synthase gene (ST8SIA1) displays higher expression among estrogen receptor–negative breast cancer tumors, associated with a decreased overall survival of breast cancer patients. However, no relationship between ganglioside expression and breast cancer development and aggressiveness has been reported. We have previously shown that overexpression of GD3 synthase induces the accumulation of b- and c-series gangliosides (GD3, GD2, and GT3) at the cell surface of MDA-MB-231 breast cancer cells together with the acquisition of a proliferative phenotype in the absence of serum. Here, we show that phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways are constitutively activated in GD3 synthase–expressing cells. Analysis of phosphorylation of tyrosine kinase receptors shows a specific c-Met constitutive activation in GD3 synthase–expressing cells, in the absence of its ligand, hepatocyte growth factor/scatter factor. In addition, inhibition of c-Met or downstream signaling pathways reverses the proliferative phenotype. We also show that GD3 synthase expression enhances tumor growth in severe combined immunodeficient mice. Finally, a higher expression of ST8SIA1 and MET in the basal subtype of human breast tumors are observed. Altogether, our results show that GD3 synthase expression is sufficient to enhance the tumorigenicity of MDA-MB-231 breast cancer cells through a ganglioside-dependent activation of the c-Met receptor. Mol Cancer Res; 8(11); 1526–35. ©2010 AACR.
Oncogene | 2007
Zongling Ji; C. Degerny; N. Vintonenko; Julien Deheuninck; Bénédicte Foveau; Catherine Leroy; J. Coll; David Tulasne; J. L. Baert; Véronique Fafeur
Sumoylation and ubiquitinylation reversibly regulate the activity of transcription factors through covalent attachment to lysine residues of target proteins. We examined whether the Ets-1 transcription factor is modified by sumoylation and/or ubiquitinylation. Among four potential SUMO motifs in Ets-1, we identified lysines 15 and 227 within the LK15YE and IK227QE motifs, as being the sumoylation acceptor sites. Using transfection of Ets-1 wildtype (WT) or its sumoylation deficient version (Ets-1 K15R/K227R), as well as WT or mutant proteins of the SUMO pathway, we further demonstrated that the E2 SUMO-conjugating enzyme Ubc9 and a E3 SUMO ligase, PIASy, can enhance Ets-1 sumoylation, while a SUMO protease, SENP1, can desumoylate Ets-1. We also found that Ets-1 is modified by K48-linked polyubiquitinylation independently of the sumoylation acceptor sites and is degraded through the 26S proteasome pathway, while sumoylation of Ets-1 does not affect its stability. Finally, sumoylation of Ets-1 leads to reduced transactivation and we demonstrated that previously identified critical lysine residues in Synergistic Control motifs are the sumoylation acceptor sites of Ets-1. These data show that Ets-1 can be modified by sumoylation and/or ubiquitinylation, with sumoylation repressing transcriptional activity of Ets-1 and having no clear antagonistic action on the ubiquitin-proteasome degradation pathway.
Cancer Research | 2014
Alessandro Furlan; Zoulika Kherrouche; Rémi Montagne; Marie-Christine Copin; David Tulasne
Met receptor tyrosine kinase was discovered in 1984 as an oncogene. Thirty years later, Met and its ligand hepatocyte growth factor/scatter factor are promising targets for the novel therapies developed to fight against cancers, with more than 240 clinical trials currently conducted. In this review, we offer to trace and highlight the most recent findings of the exemplary track record of research on Met receptor, which allowed moving this biomarker from bench to bedside. Indeed, three decades of basic research unravelled the structural basis of the ligand/receptor interaction and their complex downstream signaling network. During this period, animal models highlighted their crucial role in the development and homeostasis of epithelial organs. In parallel, involvement of Met in tumorigenesis was confirmed by the direct association of its deregulation to poor prognosis in numerous cancers. On the basis of these data, pharmaceutical companies developed many Met inhibitors, some of which are in phase III clinical trials. These impressive achievements should not detract from many questions that still remain, such as the precise Met signaling involvement in development or homeostasis of specific epithelial structures. In addition, the processes involving Met in resistance to current therapies or the appearance of resistances to Met-targeted therapies are far from being fully understood.
Glycobiology | 2012
Aurélie Cazet; Marie Bobowski; Yoann Rombouts; Jonathan Lefebvre; Agata Steenackers; Iuliana Popa; Yann Guerardel; Xuefen Le Bourhis; David Tulasne; Philippe Delannoy
We have recently established and characterized cellular clones deriving from MDA-MB-231 breast cancer cells that express the human G(D3) synthase (GD3S), the enzyme that controls the biosynthesis of b- and c-series gangliosides. The GD3S positive clones show a proliferative phenotype in the absence of serum or growth factors and an increased tumor growth in severe immunodeficient mice. This phenotype results from the constitutive activation of the receptor tyrosine kinase c-Met in spite of the absence of ligand and subsequent activation of mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/Akt pathways. Here, we show by mass spectrometry analysis of total glycosphingolipids that G(D3) and G(D2) are the main gangliosides expressed by the GD3S positive clones. Moreover, G(D2) colocalized with c-Met at the plasma membrane and small interfering RNA silencing of the G(M2)/G(D2) synthase efficiently reduced the expression of G(D2) as well as c-Met phosphorylation and reversed the proliferative phenotype. Competition assays using anti-G(D2) monoclonal antibodies also inhibit proliferation and c-Met phosphorylation of GD3S positive clones in serum-free conditions. Altogether, these results demonstrate the involvement of the disialoganglioside G(D2) in MDA-MB-231 cell proliferation via the constitutive activation of c-Met. The accumulation of G(D2) in c-Met expressing cells could therefore reinforce the tumorigenicity and aggressiveness of breast cancer tumors.
Oncogene | 2009
F Ancot; Bénédicte Foveau; J Lefebvre; Catherine Leroy; David Tulasne
Receptor tyrosine kinases (RTK) constitute a large family of membrane receptors which, in response to their respective ligand, transmit information into cells. RTK regulate multiple biological responses, and their deregulation is often associated with tumourigenesis. The intracellular signalling pathways initiated by full-length membrane RTK are studied extensively, but many RTK fragments showing unexpected cellular localization have been observed. These fragments are generated by proteolytic cleavages, catalyzed notably by caspases, membrane metalloproteases or γ-secretase. Interestingly, these cleavages, in addition to regulating membrane receptor levels, generate active fragments that can regulate biological processes, such as transcription or the survival/apoptosis balance. Thus, proteolytic cleavages release RTK from the membrane and extend their functions. Furthermore, the RTK proteolysis are involved in regulating cell transformation, which highlights their potential as attractive targets for therapeutic strategies.