Catherine Leroy

Publications (11)49.45 Total impact

• Source

  Available from: David Tulasne

  Article: Shedding-generated Met receptor fragments can be routed to either the proteasomal or the lysosomal degradation pathway.

  Frédéric Ancot, Catherine Leroy, Ghaffar Muharram, Jonathan Lefebvre, Jérôme Vicogne, Arnaud Lemiere, Zoulika Kherrouche, Bénédicte Foveau, Albin Pourtier, Oleg Melnyk, Silvia Giordano, Anne Chotteau-Lelievre, David Tulasne
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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. · 4.92 Impact Factor
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  Available from: David Tulasne

  Article: Met degradation: more than one stone to shoot a receptor down.

  Jonathan Lefebvre, Frédéric Ancot, Catherine Leroy, Ghaffar Muharram, Arnaud Lemière, David Tulasne
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  ABSTRACT: The receptor tyrosine kinase Met and its high-affinity ligand, the hepatocyte growth factor/scatter factor (HGF/SF), are essential to embryonic development. Deregulation of their signaling is associated with tumorigenesis and metastasis, notably through receptor overexpression. It is thus important to understand the mechanisms controlling Met expression. The ligand-dependent internalization of Met and its subsequent degradation in the lysosomal compartment are well described. This process is known to attenuate downstream Met signaling pathways. Yet internalized Met takes part directly in intracellular signaling by chaperoning signaling factors in the course of its trafficking. Furthermore, recent studies describe various new degradation mechanisms of membrane-anchored Met, involving proteolytic cleavages or association with novel partners. Although all these degradations are ligand-independent, they share, to different extents, some common features with canonical HGF/SF-dependent degradation. Interestingly, activated Met variants display resistance to degradation, suggesting defective degradation is involved in tumorigenesis. Conversely, forced degradation of Met through reinduction of one or more degradation pathways is a promising therapeutic strategy.
  The FASEB Journal 01/2012; 26(4):1387-99. · 5.71 Impact Factor
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  Available from: David Tulasne

  Article: Caspase cleavage of Ets-1 p51 generates fragments with transcriptional dominant-negative function.

  Souhaila Choul-Li, Catherine Leroy, Gabriel Leprivier, Clélia Laitem, David Tulasne, Marc Aumercier
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  ABSTRACT: Ets-1 is a transcription factor that plays an important role in various physiological and pathological processes, such as development, angiogenesis, apoptosis and tumour invasion. In the present study, we have demonstrated that Ets-1 p51, but not the spliced variant Ets-1 p42, is processed in a caspase-dependent manner in Jurkat T-leukaemia cells undergoing apoptosis, resulting in three C-terminal fragments Cp20, Cp17 and Cp14 and a N-terminal fragment, Np36. In vitro cleavage of Ets-1 p51 by caspase 3 produces fragments consistent with those observed in cells undergoing apoptosis. These fragments are generated by cleavage at three sites located in the exon VII-encoded region of Ets-1 p51. This region is absent from the Ets-1 p42 isoform, which therefore cannot be cleaved by caspases. In Ets-1 p51, cleavage generates C-terminal fragments containing the DNA-binding domain, but lacking the transactivation domain. The Cp17 fragment, the major cleavage product generated during apoptosis, is devoid of transcriptional activity and inhibits Ets-1 p51-mediated transactivation of target genes by competing with Ets-1 p51 for binding to Ets-binding sites present in the target promoters. In the present study, we have demonstrated that caspase cleavage of Ets-1 within the exon VII-encoded region leads to specific down-regulation of the Ets-1 p51 isoform during apoptosis. Furthermore, our results establish that caspase cleavage generates a stable C-terminal fragment that acts as a natural dominant-negative form of the full-length Ets-1 p51 protein.
  Biochemical Journal 12/2009; 426(2):229-41. · 4.90 Impact Factor
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  Available from: David Tulasne

  Article: Phosphorylation of the MET receptor on juxtamembrane tyrosine residue 1001 inhibits its caspase-dependent cleavage.

  Julien Deheuninck, Gautier Goormachtigh, Bénédicte Foveau, Zongling Ji, Catherine Leroy, Frédéric Ancot, Vincent Villeret, David Tulasne, Véronique Fafeur
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  ABSTRACT: The MET tyrosine kinase is the hepatocyte growth factor/scatter factor (HGF/SF) receptor, which elicits multiple biological responses in epithelial cells, including cell survival. We previously demonstrated that in stress conditions, the MET receptor is cleaved by caspases within its juxtamembrane region, generating a pro-apoptotic intracellular fragment of 40 kDa. The caspase cleavage site at aspartic acid D1000 is adjacent to tyrosine Y1001, which when phosphorylated upon MET activation, is involved in CBL recruitment, allowing receptor ubiquitination and down regulation. Scanning mutagenesis of the MET juxtamembrane region led us to demonstrate that V999 and D1000 are essential for the caspase cleavage, while D1000 and Y1001 are essential for CBL recruitment. By examining whether overlapping of these sites leads to a functional interference, an inverse relationship was found between generation of p40 MET and phosphorylation of MET, with a direct involvement of phosphorylated Y1001 in protecting MET against its caspase cleavage. A molecular modeling analysis of caspase 3 interaction with the juxtamembrane region of MET confirmed that phosphorylation of this tyrosine is not compatible with its recognition by active caspase 3. These data demonstrate a direct protection mechanism of an activated phosphorylated MET receptor, against its caspase-dependent cleavage.
  Cellular signalling 06/2009; 21(9):1455-63. · 4.09 Impact Factor
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  Available from: David Tulasne

  Article: Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis.

  Bénédicte Foveau, Frédéric Ancot, Catherine Leroy, Annalisa Petrelli, Karina Reiss, Valérie Vingtdeux, Silvia Giordano, Véronique Fafeur, David Tulasne
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  ABSTRACT: 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.
  Molecular biology of the cell 04/2009; 20(9):2495-507. · 5.98 Impact Factor
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  Available from: David Tulasne

  Article: Caspase cleavage of the MET receptor generates an HGF interfering fragment.

  Julien Deheuninck, Bénédicte Foveau, Gautier Goormachtigh, Catherine Leroy, Zongling Ji, David Tulasne, Véronique Fafeur
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  ABSTRACT: The MET tyrosine kinase receptor activated by its ligand HGF/SF, induces several cellular responses, including survival. Nonetheless, the MET receptor is cleaved in stress conditions by caspases within its intracellular region, generating a 40kDa fragment, p40 MET, with pro-apoptotic properties. Here, we established that this cleavage splits the receptor at the juxtamembrane ESVD site, causing the concomitant generation of p100 MET, corresponding to the entire extracellular region of the MET receptor still spanning the membrane. This fragment is able to bind HGF/SF and to prevent HGF-dependent signaling downstream of full MET, demonstrating its function as a decoy receptor.
  Biochemical and Biophysical Research Communications 04/2008; 367(3):573-7. · 2.48 Impact Factor
• Article: HGF/SF regulates expression of apoptotic genes in MCF-10A human mammary epithelial cells.

  Catherine Leroy, Julien Deheuninck, Sylvie Reveneau, Bénédicte Foveau, Zongling Ji, Céline Villenet, Sabine Quief, David Tulasne, Jean-Pierre Kerckaert, Véronique Fafeur
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  ABSTRACT: Hepatocyte growth factor/scatter factor (HGF/SF) induces scattering, morphogenesis, and survival of epithelial cells through activation of the MET tyrosine kinase receptor. HGF/SF and MET are involved in normal development and tumor progression of many tissues and organs, including the mammary gland. In order to find target genes of HGF/SF involved in its survival function, we used an oligonucleotide microarray representing 1,920 genes known to be involved in apoptosis, transcriptional regulation, and signal transduction. MCF-10A human mammary epithelial cells were grown in the absence of serum and treated or not with HGF/SF for 2 h. Total RNA was reverse-transcribed to cDNA in the presence of fluorescent Cy3-dUTP or Cy5-dUTP to generate fluorescently labeled cDNA probes. Microarrays were performed and the ratios of Cy5/Cy3 fluorescence were determined. The expression of three apoptotic genes was modified by HGF/SF, with A20 being upregulated, and DAXX and SMAC being downregulated. These changes of expression were confirmed by real-time quantitative PCR. According to current-knowledge, A20 is antiapoptotic and SMAC is proapoptotic, while a pro- or antiapoptotic function of DAXX is controversial. The fact that HGF/SF upregulates an antiapoptotic gene (A20) and downregulates a proapoptotic gene (SMAC) is in agreement with its survival effect in MCF-10A cells. This study identified novel apoptotic genes regulated by HGF/SF, which can contribute to its survival effect.
  Annals of the New York Academy of Sciences 01/2007; 1090:188-202. · 3.15 Impact Factor
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  Available from: David Tulasne

  Article: Proapoptotic function of the MET tyrosine kinase receptor through caspase cleavage.

  David Tulasne, Julien Deheuninck, Filipe Calheiros Lourenco, Fabienne Lamballe, Zongling Ji, Catherine Leroy, Emilie Puchois, Anice Moumen, Flavio Maina, Patrick Mehlen, Véronique Fafeur
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  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.
  Molecular and Cellular Biology 01/2005; 24(23):10328-39. · 5.53 Impact Factor
• Article: Inhibition of JNK by HGF/SF prevents apoptosis induced by TNF-alpha.

  Sylvie Reveneau, Réjane Paumelle, Julien Deheuninck, Catherine Leroy, Yvan De Launoit, Véronique Fafeur
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  ABSTRACT: We investigated whether repression of JNK by hepatocyte growth factor/scatter factor (HGF/SF) in MDCK epithelial cells is linked to its ability to protect cells from apoptosis. To this purpose, cells were treated by TNF-alpha, a well-known inducer of JNK and of cell death, and the effects of HGF/SF were investigated under these conditions. We identified repression of JNK as a signaling target of HGF/SF for protection against TNF-alpha-induced cell death. This effect of HGF/SF occurs via the activation of the PI3K and MEK1 pathways.
  Annals of the New York Academy of Sciences 01/2004; 1010:100-3. · 3.15 Impact Factor
• Article: Involvement of RAS-ERK signaling in multiple biological responses to HGF/SF.

  David Tulasne, Rejane Paumelle, Catherine Leroy, Sylvie Reveneau, Bernard Vandenbunder, Veronique Fafeur
  Annals of the New York Academy of Sciences 12/2002; 973:105-8. · 3.15 Impact Factor
• Article: Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway.

  Rejane Paumelle, David Tulasne, Zoulika Kherrouche, Serge Plaza, Catherine Leroy, Sylvie Reveneau, Bernard Vandenbunder, Veronique Fafeur, David Tulashe, Syline Reveneau
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  ABSTRACT: Hepatocyte growth factor/scatter factor (HGF/SF) induces scattering and morphogenesis of epithelial cells through the activation of the MET tyrosine kinase receptor. Although the activated MET receptor recruits a number of signaling proteins, little is known of the downstream signaling pathways activated by HGF/SF. In this study, we wished to examine the signaling pathway leading to activation of the ETS1 transcription factor. Using in vitro and in vivo kinase assays, we found that HGF/SF activates the ERK1 MAP kinase, leading to the phosphorylation of the threonine 38 residue of ETS1 within a putative MAP kinase phosphorylation site (PLLT38P). This threonine residue was neither phosphorylated by JNK1, nor by p38 MAP kinases and was required for the induction of transcriptional activity of ETS1 by HGF/SF. Using kinase and transcription assays, we further demonstrated that phosphorylation and activation of ETS1 occurs downstream of a RAS-RAF-MEK-ERK pathway. The functional involvement of this pathway in HGF/SF action was demonstrated using U0126, a pharmacological inhibitor of MEK, which blocked phosphorylation and activation of ETS1, RAS-dependent transcriptional responses, cell scattering and morphogenesis. These data demonstrated that ETS1 is a downstream target of HGF/SF acting through a RAS-RAF-MEK-ERK pathway and provides a signaling pathway leading to the regulation of gene expression by HGF/SF.
  Oncogene 05/2002; 21(15):2309-19. · 6.37 Impact Factor