23 results on '"Lissitzky, Jean-Claude"'
Search Results
2. Resistance to cisplatin-induced cell death conferred by the activity of organic anion transporting polypeptides (OATP) in human melanoma cells
- Author
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Silvy, Françoise, Lissitzky, Jean-Claude, Bruneau, Nadine, Zucchini, Nathalie, Landrier, Jean-François, Lombardo, Dominique, and Verrando, Patrick
- Published
- 2013
- Full Text
- View/download PDF
3. αvβ5/β6 integrin suppression leads to a stimulation of α2β1 dependent cell migration resistant to PI3K/Akt inhibition
- Author
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Defilles, Céline, Lissitzky, Jean-Claude, Montero, Marie-Pierre, André, Frédéric, Prévot, Charles, Delamarre, Estelle, Marrakchi, Naziha, Luis, José, and Rigot, Véronique
- Published
- 2009
- Full Text
- View/download PDF
4. IL-6 and IL-8 Production from Cultured Human Endothelial Cells Stimulated by Infection with Rickettsia conorii via a Cell-associated IL-1 alpha-dependent Pathway
- Author
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Kaplanski, Gilles, Teysseire, Nadine, Farnarier, Catherine, Kaplanski, Solange, Lissitzky, Jean-Claude, Durand, Jean-Marc, Soubeyrand, Jacques, Dinarello, Charles A., and Bongrand, Pierre
- Published
- 1995
5. Serge Lissitzky
- Author
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Torresani, Janine, Lissitzky, Jean-Claude, and Carayon, Pierre
- Published
- 2007
- Full Text
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6. Genetic, structural, and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis.
- Author
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Cartier-Michaud, Amandine, Bailly, Anne-Laure, Betzi, Stéphane, Shi, Xiaoli, Lissitzky, Jean-Claude, Zarubica, Ana, Sergé, Arnauld, Roche, Philippe, Lugari, Adrien, Hamon, Véronique, Bardin, Florence, Derviaux, Carine, Lembo, Frédérique, Audebert, Stéphane, Marchetto, Sylvie, Durand, Bénédicte, Borg, Jean-Paul, Shi, Ning, Morelli, Xavier, and Aurrand-Lions, Michel
- Subjects
GENETICS of spermatogenesis ,GERM cells ,GOLGI apparatus ,ACROSOME reaction ,MEIOTIC drive ,PHYSIOLOGY - Abstract
Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and Sertoli cells. Germ cells express the Junctional Adhesion Molecule-C (JAM-C, encoded by Jam3), which localizes to germ/Sertoli cell contacts. JAM-C is involved in germ cell polarity and acrosome formation. Using a proteomic approach, we demonstrated that JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55, encoded by Gorasp2) in developing germ cells. Generation and study of Gorasp2
-/- mice revealed that knock-out mice suffered from spermatogenesis defects. Acrosome formation and polarized localization of JAM-C in spermatids were altered in Gorasp2-/- mice. In addition, Golgi morphology of spermatocytes was disturbed in Gorasp2-/- mice. Crystal structures of GRASP55 in complex with JAM-C or JAM-B revealed that GRASP55 interacted via PDZ-mediated interactions with JAMs and induced a conformational change in GRASP55 with respect of its free conformation. An in silico pharmacophore approach identified a chemical compound called Graspin that inhibited PDZ-mediated interactions of GRASP55 with JAMs. Treatment of mice with Graspin hampered the polarized localization of JAM-C in spermatids, induced the premature release of spermatids and affected the Golgi morphology of meiotic spermatocytes. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
7. Anti-β4 integrin antibodies enhance migratory and invasive abilities of human colon adenocarcinoma cells and their MMP-2 expression.
- Author
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Daemi, Noucha, Thomasset, Nicole, Lissitzky, Jean-Claude, Dumortier, Jérôme, Jacquier, Marie-France, Pourreyron, Céline, Rousselle, Patricia, Chayvialle, Jean-Alain, and Remy, Lionel
- Published
- 2000
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8. Biogenesis of α6β4 integrin in a human colonic adenocarcinoma cell line.
- Author
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Rigot, Véronique, André, Frédéric, Lehmann, Maxime, Lissitzky, Jean-Claude, Marvaldi, Jacques, and Luis, José
- Subjects
INTEGRINS ,ADENOCARCINOMA ,EPITHELIAL cells - Abstract
Examines the biogenesis of a major integrin in human colonic adenocarcinoma cell line. Involvement of calnexin at different temperatures; Responsibility for the adhesion of epithelial cells to laminins; Description of the biosynthesis of the integrin.
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- 1999
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9. Regulation of expression of opioid peptide genes.
- Author
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Douglass, James O., Civelli, Olivier, Birnberg, Neal, Comb, Michael, Ubler, Michael, Lissitzky, Jean-Claude, and Herbert, Edward
- Published
- 1984
- Full Text
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10. α1β1-integrin engagement to distinct laminin-1 domains orchestrates spreading, migration and survival of neural crest cells through independent signaling pathways.
- Author
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Desban, Nathalie, Lissitzky, Jean-Claude, Rousselle, Patricia, and Duband, Jean-Loup
- Subjects
- *
INTEGRINS , *CELL migration , *CELL adhesion , *CELL differentiation , *ACTIN - Abstract
Integrin engagement regulates cell adhesion, shape, migration, growth, and differentiation, but molecular mechanisms coordinating these functions in cells remain unclear. Because of their migratory and differentiation potential, neural crest cells constitute a powerful paradigm to address this question. Here, we describe that laminin-1, a major component of their migration routes, promotes crest cell spreading, migration and survival through two distinct integrin-binding domains that are situated on both sides of its α1 subunit and can be separated in the LN-1 elastase proteolytic fragments E1′ and E8. Interaction with either domain was mediated by the same integrin α1β1 but produced distinct, complementary responses through specific signaling cascades. FAK activation upon E8 binding induced spreading, formation of actin bundles and focal adhesions, stimulated oriented migration, but failed to support survival. Conversely, Erk activation upon E1′ binding promoted long-term survival and random migration without actin reorganization. Consistent with this, interaction with laminin-5 or laminin-10/11, which do not harbor integrin-binding domains in the N-terminal side of their α chains, failed to support survival. Thus, the signaling activity and function of integrins might depend on binding domains in their ligands, thereby revealing ligand control of integrin function as a possible mechanism for the modulation and coordination of cell response to adhesive signals. [ABSTRACT FROM AUTHOR]
- Published
- 2006
11. Modulable Southern and Northern blot hybridization apparatus for routine screening of gene amplification and expression
- Author
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Bignon, Christophe, Roux-Dosseto, Magali, Lissitzky, Jean-Claude, and Martin, Pierre-Marie
- Published
- 1990
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12. Effect of nicotine on in vivo secretion of melanocorticotropic hormones in the rat
- Author
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Conte-Devolx, Bernard, Oliver, Charles, Giraud, Pierre, Gillioz, Pierre, Castanas, Elias, Lissitzky, Jean-Claude, Boudouresque, Françoise, and Millet, Yves
- Published
- 1981
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13. GRASP55 Is Dispensable for Normal Hematopoiesis but Necessary for Myc-Dependent Leukemic Growth.
- Author
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Bailly, Anne-Laure, Grenier, Julien M. P., Cartier-Michaud, Amandine, Bardin, Florence, Balzano, Marielle, Goubard, Armelle, Lissitzky, Jean-Claude, De Grandis, Maria, Mancini, Stéphane J. C., Serge, Arnauld, and Aurrand-Lions, Michel
- Subjects
- *
HEMATOPOIETIC stem cells , *SPERMATOGENESIS , *HEMATOPOIESIS , *CARRIER proteins , *PROTEIN transport ,BONE marrow cancer - Abstract
Grasp55 is a ubiquitous Golgi stacking protein involved in autophagy, protein trafficking, and glucose deprivation sensing. The function of Grasp55 in protein trafficking has been attributed to its PDZ-mediated interaction with the C-terminal PDZ-binding motifs of protein cargos. We have recently shown that such an interaction occurs between Grasp55 and the adhesion molecule Jam-C, which plays a central role in stemness maintenance of hematopoietic and spermatogenic cells. Accordingly, we have found that Grasp55-deficient mice suffer from spermatogenesis defects similar to Jam-C knockout mice. However, whether Grasp55 is involved in the maintenance of immunohematopoietic homeostasis through regulation of protein transport and Jam-C expression remains unknown. In this study, we show that Grasp55 deficiency does not affect hematopoietic stem cell differentiation, engraftment, or mobilization, which are known to depend on expression of Grasp55-dependent protein cargos. In contrast, using an Mycdependent leukemic model addicted to autophagy, we show that knockdown of Grasp55 in leukemic cells reduces spleen and bone marrow tumor burden upon i.v. leukemic engraftment. This is not due to reduced homing of Grasp55-deficient cells to these organs but to increased spontaneous apoptosis of Grasp55-deficient leukemic cells correlated with increased sensitivity of the cells to glucose deprivation. These results show that Grasp55 plays a role in Myc-transformed hematopoietic cells but not in normal hematopoietic cells in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
14. Soluble Melanoma Cell Adhesion Molecule (sMCAM/sCD146) Promotes Angiogenic Effects on Endothelial Progenitor Cells through Angiomotin.
- Author
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Stalin, Jimmy, Harhouri, Karim, Hubert, Lucas, Subrini, Caroline, Lafitte, Daniel, Lissitzky, Jean-Claude, Elganfoud, Nadia, Robert, Stéphane, Foucault-Bertaud, Alexandrine, Kaspi, Elise, Sabatier, Florence, Aurrand-Lions, Michel, Bardin, Nathalie, Holmgren, Lars, Dignat-George, Françoise, and Blot-Chabaud, Marcel
- Subjects
- *
CANCER cells , *CELL adhesion , *ENDOTHELIAL cells , *ENZYME-linked immunosorbent assay , *MASS spectrometry , *NEOVASCULARIZATION - Abstract
The melanoma cell adhesion molecule (CD146) contains a circulating proteolytic variant (sCD146), which is involved in inflammation and angiogenesis. Its circulating level is modulated in different pathologies, but its intracellular transduction pathways are still largely unknown. Using peptide pulldown and mass spectrometry, we identified angiomotin as a sCD146-associated protein in endothelial progenitor cells (EPC). Interaction between angiomotin and sCD146 was confirmed by enzyme-linked immunosorbent assay (ELISA), homogeneous time-resolved fluorescence, and binding of sCD146 on both immobilized recombinant angiomotin and angiomotin-transfected cells. Silencing angiomotin in EPC inhibited sCD146 angiogenic effects, i.e. EPC migration, proliferation, and capacity to form capillary-like structures in Matrigel. In addition, sCD146 effects were inhibited by the angiomotin inhibitor angiostatin and competition with recombinant angiomotin. Finally, binding of sCD146 on angiomotin triggered the activation of several transduction pathways that were identified by antibody array. These results delineate a novel signaling pathway where sCD146 binds to angiomotin to stimulate a proangiogenic response. This result is important to find novel target cells of sCD146 and for the development of therapeutic strategies based on EPC in the treatment of ischemic diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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15. MVL-PLA2, a phospholipase A2 from Macrovipera lebetina transmediterranea venom, inhibits tumor cells adhesion and migration
- Author
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Bazaa, Amine, Luis, José, Srairi-Abid, Najet, Kallech-Ziri, Olfa, Kessentini-Zouari, Raoudha, Defilles, Céline, Lissitzky, Jean-Claude, El Ayeb, Mohamed, and Marrakchi, Naziha
- Subjects
- *
PHOSPHOLIPASE A2 , *CELL adhesion , *CELL migration , *SNAKE venom - Abstract
Abstract: Here, we report the purification and characterization of an acidic Asp49 phospholipase A2, named MVL-PLA2, with a molecular mass of 13,626.64 Da. The complete MVL-PLA2 cDNA was cloned from Macrovipera lebetina transmediterranea venom gland cDNA library. MVL-PLA2 possesses 122 amino acid residues, including 14 cysteines, and belongs to group II snake venom phospholipase A2 enzymes. MVL-PLA2 was not cytotoxic up to 2 μM and completely abolished cell adhesion and migration of various human tumor cells. Chemical modification with p-bromophenacyl bromide abolished the enzymatic activity of MVL-PLA2 without affecting its anti-tumor effect, suggesting the presence of ‘pharmacological sites’ distinct from the catalytic site in snake venom phospholipase A2. We demonstrated for the first time that the anti-tumor effect of MVL-PLA2 was mediated by α5β1 and αv-containing integrins. This finding may serve as starting point for structure–function relationship studies leading to design a new generation of specific anti-cancer drugs. [Copyright &y& Elsevier]
- Published
- 2009
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16. Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.
- Author
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Milhas S, Raux B, Betzi S, Derviaux C, Roche P, Restouin A, Basse MJ, Rebuffet E, Lugari A, Badol M, Kashyap R, Lissitzky JC, Eydoux C, Hamon V, Gourdel ME, Combes S, Zimmermann P, Aurrand-Lions M, Roux T, Rogers C, Müller S, Knapp S, Trinquet E, Collette Y, Guillemot JC, and Morelli X
- Subjects
- Crystallography, X-Ray, Protein Interaction Mapping, Drug Discovery, Proteins chemistry, Small Molecule Libraries
- Abstract
Protein-protein interactions (PPIs) represent an enormous source of opportunity for therapeutic intervention. We and others have recently pinpointed key rules that will help in identifying the next generation of innovative drugs to tackle this challenging class of targets within the next decade. We used these rules to design an oriented chemical library corresponding to a set of diverse "PPI-like" modulators with cores identified as privileged structures in therapeutics. In this work, we purchased the resulting 1664 structurally diverse compounds and evaluated them on a series of representative protein-protein interfaces with distinct "druggability" potential using homogeneous time-resolved fluorescence (HTRF) technology. For certain PPI classes, analysis of the hit rates revealed up to 100 enrichment factors compared with nonoriented chemical libraries. This observation correlates with the predicted "druggability" of the targets. A specific focus on selectivity profiles, the three-dimensional (3D) molecular modes of action resolved by X-ray crystallography, and the biological activities of identified hits targeting the well-defined "druggable" bromodomains of the bromo and extraterminal (BET) family are presented as a proof-of-concept. Overall, our present study illustrates the potency of machine learning-based oriented chemical libraries to accelerate the identification of hits targeting PPIs. A generalization of this method to a larger set of compounds will accelerate the discovery of original and potent probes for this challenging class of targets.
- Published
- 2016
- Full Text
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17. The human PDZome: a gateway to PSD95-Disc large-zonula occludens (PDZ)-mediated functions.
- Author
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Belotti E, Polanowska J, Daulat AM, Audebert S, Thomé V, Lissitzky JC, Lembo F, Blibek K, Omi S, Lenfant N, Gangar A, Montcouquiol M, Santoni MJ, Sebbagh M, Aurrand-Lions M, Angers S, Kodjabachian L, Reboul J, and Borg JP
- Subjects
- Amino Acid Sequence, Animals, Binding Sites, Cell Line, Cell Movement, Embryo, Nonmammalian metabolism, Enzyme-Linked Immunosorbent Assay, Fluorescence, Gene Knockdown Techniques, Humans, Intracellular Signaling Peptides and Proteins chemistry, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins chemistry, Membrane Proteins metabolism, Mice, Molecular Sequence Data, Morphogenesis, Oncogene Proteins, Viral metabolism, Protein Interaction Mapping, Protein Kinases chemistry, Protein Kinases metabolism, Reproducibility of Results, Sorting Nexins metabolism, Tumor Suppressor Proteins metabolism, Two-Hybrid System Techniques, Xenopus embryology, Xenopus metabolism, PDZ Domains, Proteome metabolism
- Abstract
Protein-protein interactions organize the localization, clustering, signal transduction, and degradation of cellular proteins and are therefore implicated in numerous biological functions. These interactions are mediated by specialized domains able to bind to modified or unmodified peptides present in binding partners. Among the most broadly distributed protein interaction domains, PSD95-disc large-zonula occludens (PDZ) domains are usually able to bind carboxy-terminal sequences of their partners. In an effort to accelerate the discovery of PDZ domain interactions, we have constructed an array displaying 96% of the human PDZ domains that is amenable to rapid two-hybrid screens in yeast. We have demonstrated that this array can efficiently identify interactions using carboxy-terminal sequences of PDZ domain binders such as the E6 oncoviral protein and protein kinases (PDGFRβ, BRSK2, PCTK1, ACVR2B, and HER4); this has been validated via mass spectrometry analysis. Taking advantage of this array, we show that PDZ domains of Scrib and SNX27 bind to the carboxy-terminal region of the planar cell polarity receptor Vangl2. We also have demonstrated the requirement of Scrib for the promigratory function of Vangl2 and described the morphogenetic function of SNX27 in the early Xenopus embryo. The resource presented here is thus adapted for the screen of PDZ interactors and, furthermore, should facilitate the understanding of PDZ-mediated functions.
- Published
- 2013
- Full Text
- View/download PDF
18. αv integrin processing interferes with the cross-talk between αvβ5/β6 and α2β1 integrins.
- Author
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Defilles C, Montero MP, Lissitzky JC, Rome S, Siret C, Luis J, André F, and Rigot V
- Subjects
- Cell Adhesion, Cell Movement, Collagen Type I metabolism, Focal Adhesion Protein-Tyrosine Kinases metabolism, Humans, Mitogen-Activated Protein Kinases metabolism, Phosphatidylinositol 3-Kinase metabolism, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, alpha 1-Antitrypsin biosynthesis, Antigens, Neoplasm metabolism, Integrin alpha2beta1 metabolism, Integrin alphaV metabolism, Integrins metabolism, Receptors, Vitronectin metabolism
- Abstract
Background Information: Previous studies have reported that cross-talk between integrins may be an important regulator of integrin-ligand binding and subsequent signalling events that control a variety of cell functions in many tissues. We previously demonstrated that αvβ5/β6 integrin represses α2β1-dependent cell migration. The αv subunits undergo an endoproteolytic cleavage by protein convertases, whose role in tumoral invasion has remained controversial., Results: Inhibition of convertases by the convertase inhibitor α1-PDX (α1-antitrypsin Portland variant), leading to the cell-surface expression of an uncleaved form of the αv integrin, stimulated cell migration toward type I collagen. Under convertase inhibition, α2β1 engagement led to enhanced phosphorylation of both FAK (focal adhesion kinase) and MAPK (mitogen-activated protein kinase). This outside-in signalling stimulation was associated with increased levels of activated β1 integrin located in larger than usual focal-adhesion structures and a cell migration that was independent of the PI3K (phosphoinositide 3-kinase)/Akt (also called protein kinase B) pathway., Conclusions: The increase in cell migration observed upon convertases inhibition appears to be due to the up-regulation of β1 integrins and to their location in larger focal-adhesion structures. The endoproteolytic cleavage of αv subunits is necessary for αvβ5/β6 integrin to control α2β1 function and could thus play an essential role in colon cancer cell migration.
- Published
- 2011
- Full Text
- View/download PDF
19. Expression of integrin alpha6beta1 enhances tumorigenesis in glioma cells.
- Author
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Delamarre E, Taboubi S, Mathieu S, Bérenguer C, Rigot V, Lissitzky JC, Figarella-Branger D, Ouafik L, and Luis J
- Subjects
- Animals, Apoptosis, Brain Neoplasms metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation, Female, Glioblastoma metabolism, Humans, Male, Mice, Mice, Inbred BALB C, Neoplasm Invasiveness, Brain Neoplasms pathology, Glioblastoma pathology, Integrin alpha6beta1 biosynthesis
- Abstract
The integrin alpha6beta1 and its main ligand laminin-111 are overexpressed in glioblastoma, as compared with normal brain tissue, suggesting they may be involved in glioblastoma malignancy. To address this question, we stably expressed the alpha6 integrin subunit in the U87 cell line via retroviral-mediated gene transfer. We show that cell surface expression of the alpha6beta1 integrin led to dramatic changes in tumor U87 cell behavior, both in vitro and in vivo. Nude mice receiving either subcutaneous or intracerebral inoculation of alpha6beta1-expressing cells developed substantially more voluminous tumors than mice injected with control cells. The difference in tumor growth was associated with a marked increase in vascularization in response to alpha6beta1 integrin expression and may also be related to changes in the balance between cell proliferation and survival. Indeed, expression of alpha6beta1 enhanced proliferation and decreased apoptosis of U87 cells both in the tumor and in vitro. Additionally, we demonstrate that alpha6beta1 is implicated in glioblastoma cell migration and invasion and that laminin-111 might mediate dissemination of alpha6beta1-positive cells in vivo. Our results highlight for the first time the considerable role of the integrin alpha6beta1 in glioma progression.
- Published
- 2009
- Full Text
- View/download PDF
20. alphavbeta5/beta6 integrin suppression leads to a stimulation of alpha2beta1 dependent cell migration resistant to PI3K/Akt inhibition.
- Author
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Defilles C, Lissitzky JC, Montero MP, André F, Prévot C, Delamarre E, Marrakchi N, Luis J, and Rigot V
- Subjects
- Antigens, Neoplasm genetics, Antigens, Neoplasm physiology, Cell Line, Tumor, Cell Movement drug effects, Collagen Type I metabolism, Focal Adhesions, Humans, Integrin alpha2beta1 antagonists & inhibitors, Integrin alpha2beta1 genetics, Integrins genetics, Integrins physiology, Oncogene Protein v-akt genetics, Oncogene Protein v-akt physiology, Phosphatidylinositol 3-Kinases physiology, Protein Kinase Inhibitors pharmacology, RNA, Small Interfering genetics, Receptors, Vitronectin genetics, Receptors, Vitronectin physiology, Signal Transduction, Cell Movement physiology, Integrin alpha2beta1 physiology, Integrins antagonists & inhibitors, Oncogene Protein v-akt antagonists & inhibitors, Phosphoinositide-3 Kinase Inhibitors, Receptors, Vitronectin antagonists & inhibitors
- Abstract
Crosstalk between integrins is involved in the regulation of various cell functions including cell migration. Here we identify the interplay between the integrins alphavbeta5/beta6 and alpha2beta1 during cell migration toward type I collagen. Human colon cancer cell lines HT29-D4 and SW480 were used as cell models. To improve our understanding of the consequences of alphavbeta5/beta6 function on alpha2beta1, we decreased the expression of alphav integrins by either siRNA or lysosomal targeting strategies or inhibited their function using, as antagonists, blocking antibodies or disintegrins. In all cases, we observed a greatly enhanced alpha2beta1 integrin-dependent cell migration associated with focal adhesion rearrangements and increased outside-in signaling as demonstrated by elevated phosphorylation of focal adhesion kinase and MAPKinase (ERK1 and ERK2). The alphavbeta5/beta6-dependent limitation of alpha2beta1 function could be overridden by TS2/16, an activating anti-beta1 antibody. Interestingly, compared to control cells, the pharmacological inhibition of PI3Kinase or the siRNA-mediated knockdown of AKT had little effect on the high alpha2beta1-mediated cell migration observed in the absence of alphav integrins or following activation of alpha2beta1 integrins by the TS2/16. These results suggest that integrins alphavbeta5/beta6 repress alpha2beta1 possibly by interfering with their activation process and thereby modify the cell signaling regulation of alpha2beta1-mediated migration.
- Published
- 2009
- Full Text
- View/download PDF
21. Cyclic AMP signaling as a mediator of vasculogenic mimicry in aggressive human melanoma cells in vitro.
- Author
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Lissitzky JC, Parriaux D, Ristorcelli E, Vérine A, Lombardo D, and Verrando P
- Subjects
- 1-Methyl-3-isobutylxanthine pharmacology, Cell Line, Tumor, Colforsin pharmacology, Guanine Nucleotide Exchange Factors metabolism, Humans, Ligands, MAP Kinase Signaling System drug effects, Melanoma blood supply, Microvessels drug effects, Microvessels metabolism, Microvessels pathology, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Receptors, G-Protein-Coupled metabolism, Shelterin Complex, Signal Transduction drug effects, Telomere-Binding Proteins metabolism, Vasoactive Intestinal Peptide pharmacology, alpha-MSH pharmacology, Cyclic AMP metabolism, Melanoma metabolism, Melanoma pathology
- Abstract
Aggressive melanoma cells can engage in a process termed vasculogenic mimicry (VM) that reflects the ability of tumor cells to express a multipotent, stem cell-like phenotype. Melanoma cell plasticity contributes to the lack of efficient therapeutic strategies targeting metastatic tumors. This study reveals cyclic AMP as a mediator of VM in vitro. In uveal and cutaneous metastatic aggressive human melanoma cells, an increase in cyclic AMP by forskolin, dibutyryl cyclic AMP, or G protein-coupled receptor (GPCR) ligands such as adrenaline and vasoactive intestinal peptide inhibited VM to different extents. Although chemical modulators of protein kinase A (PKA) had no effect, a specific pharmacologic activator of Exchange protein directly activated by cyclic AMP (Epac) impaired VM. Ras-associated protein-1 (Rap1) activation assays revealed that cyclic AMP-elevating agents induce a PKA-independent activation of Epac/Rap1. Pharmacologic inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity abolished VM. Phosphorylation of ERK1/2 was PKA-independently inhibited by forskolin but not inhibited by Epac/Rap1 signaling, PKA modulation, or GPCR ligands. Furthermore, the forskolin also inhibited phosphatidyl inositol-3-kinase (PI3K)-mediated activation of protein kinase Akt, as monitored by Ser473 phosphorylation. The pharmacologic activation of Epac and GPCR ligands slightly stimulated Akt, a likely concomitant process of VM modulation. Collectively, these data show that forskolin strongly inhibits VM through PKA-independent activation of Epac/Rap1, PKA-, and Epac-independent inactivation of ERK1/2 and inhibition of PI3K/Akt. The data also show that VM inhibition by GPCR ligands involves mainly the Epac/Rap1-activated signal. Thus cyclic AMP inhibits VM through multiple signaling pathways.
- Published
- 2009
- Full Text
- View/download PDF
22. alpha1beta1-integrin engagement to distinct laminin-1 domains orchestrates spreading, migration and survival of neural crest cells through independent signaling pathways.
- Author
-
Desban N, Lissitzky JC, Rousselle P, and Duband JL
- Subjects
- Animals, Cell Adhesion physiology, Cell Shape, Cells, Cultured, Enzyme Activation, Enzyme Inhibitors metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Focal Adhesion Protein-Tyrosine Kinases metabolism, Laminin chemistry, Pancreatic Elastase metabolism, Peptide Fragments metabolism, Protein Isoforms chemistry, Protein Isoforms metabolism, Protein Structure, Tertiary, Cell Movement physiology, Cell Survival, Integrin alpha1beta1 metabolism, Laminin metabolism, Neural Crest cytology, Signal Transduction physiology
- Abstract
Integrin engagement regulates cell adhesion, shape, migration, growth, and differentiation, but molecular mechanisms coordinating these functions in cells remain unclear. Because of their migratory and differentiation potential, neural crest cells constitute a powerful paradigm to address this question. Here, we describe that laminin-1, a major component of their migration routes, promotes crest cell spreading, migration and survival through two distinct integrin-binding domains that are situated on both sides of its alpha1 subunit and can be separated in the LN-1 elastase proteolytic fragments E1' and E8. Interaction with either domain was mediated by the same integrin alpha1beta1 but produced distinct, complementary responses through specific signaling cascades. FAK activation upon E8 binding induced spreading, formation of actin bundles and focal adhesions, stimulated oriented migration, but failed to support survival. Conversely, Erk activation upon E1' binding promoted long-term survival and random migration without actin reorganization. Consistent with this, interaction with laminin-5 or laminin-10/11, which do not harbor integrin-binding domains in the N-terminal side of their alpha chains, failed to support survival. Thus, the signaling activity and function of integrins might depend on binding domains in their ligands, thereby revealing ligand control of integrin function as a possible mechanism for the modulation and coordination of cell response to adhesive signals.
- Published
- 2006
- Full Text
- View/download PDF
23. Down-regulation of alpha v/beta 3 integrin via misrouting to lysosomes by overexpression of a beta 3Lamp1 fusion protein.
- Author
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Conesa M, Prat A, Mort JS, Marvaldi J, Lissitzky JC, and Seidah NG
- Subjects
- Down-Regulation physiology, Golgi Apparatus metabolism, Humans, Integrin alphaV, Lysosomal-Associated Membrane Protein 1, Lysosomal Membrane Proteins, Antigens, CD genetics, Integrin alphaVbeta3 metabolism, Integrin beta3 genetics, Lysosomes metabolism, Recombinant Fusion Proteins genetics
- Abstract
We present a general strategy for the dominant negative reduction in the levels of type-1 membrane-bound heterodimeric proteins within the secretory pathway through fusion of the soluble ectodomain of one of the partners to the transmembrane-cytosolic tail of the lysosomal protein Lamp1. Thus, in human embryonic kidney (HEK)-293 cells, overexpression of an integrin beta 3Lamp1 chimera resulted in a drastic reduction of its endogenous partner, the integrin alpha v subunit. The mechanism involves the formation in the endoplasmic reticulum of a alpha v/beta 3Lamp1 complex that is subsequently sorted towards a lysosomal/endosomal degradation pathway. The specificity of this approach is afforded by the invariance in the levels of the endogenous integrins alpha 5 and beta1 as compared with control cells. Conversely overexpression of integrin beta 3 in HEK-293 cells led to an increased level of alpha v beta 3 at the cell surface. Functionally beta 3Lamp1 and beta 3 overexpressors exhibit decreased and increased adhesion to vitronectin, respectively, as well as diminished cellular aggregation. The application of this technology should enable the analysis of the functional importance of homodimers or heterodimers in the cell types of choice and the identification of novel partner proteins by proteomic approaches.
- Published
- 2003
- Full Text
- View/download PDF
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