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1. RSK3 switches cell fate: from stress-induced senescence to malignant progression

Author

Anda Huna, Jean-Michel Flaman, Catalina Lodillinsky, Kexin Zhu, Gabriela Makulyte, Victoria Pakulska, Yohann Coute, Clémence Ruisseaux, Pierre Saintigny, Hector Hernandez-Vargas, Pierre-Antoine Defossez, Mathieu Boissan, Nadine Martin, and David Bernard

Subjects
Cellular senescence, Epithelial-mesenchymal transition, TGFβ, Breast tumor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background TGFβ induces several cell phenotypes including senescence, a stable cell cycle arrest accompanied by a secretory program, and epithelial-mesenchymal transition (EMT) in normal epithelial cells. During carcinogenesis cells lose the ability to undergo senescence in response to TGFβ but they maintain an EMT, which can contribute to tumor progression. Our aim was to identify mechanisms promoting TGFβ-induced senescence escape. Methods In vitro experiments were performed with primary human mammary epithelial cells (HMEC) immortalized by hTert. For kinase library screen and modulation of gene expression retroviral transduction was used. To characterize gene expression, RNA microarray with GSEA analysis and RT-qPCR were used. For protein level and localization, Western blot and immunofluorescence were performed. For senescence characterization crystal violet assay, Senescence Associated-β-Galactosidase activity, EdU staining were conducted. To determine RSK3 partners FLAG-baited immunoprecipitation and mass spectrometry-based proteomic analyses were performed. Proteosome activity and proteasome enrichment assays were performed. To validate the role of RSK3 in human breast cancer, analysis of METABRIC database was performed. Murine intraductal xenografts using MCF10DCIS.com cells were carried out, with histological and immunofluorescence analysis of mouse tissue sections. Results A screen with active kinases in HMECs upon TGFβ treatment identified that the serine threonine kinase RSK3, or RPS6KA2, a kinase mainly known to regulate cancer cell death including in breast cancer, reverted TGFβ-induced senescence. Interestingly, RSK3 expression decreased in response to TGFβ in a SMAD3-dependent manner, and its constitutive expression rescued SMAD3-induced senescence, indicating that a decrease in RSK3 itself contributes to TGFβ-induced senescence. Using transcriptomic analyses and affinity purification coupled to mass spectrometry-based proteomics, we unveiled that RSK3 regulates senescence by inhibiting the NF-κΒ pathway through the decrease in proteasome-mediated IκBα degradation. Strikingly, senescent TGFβ-treated HMECs display features of epithelial to mesenchymal transition (EMT) and during RSK3-induced senescence escaped HMECs conserve EMT features. Importantly, RSK3 expression is correlated with EMT and invasion, and inversely correlated with senescence and NF-κΒ in human claudin-low breast tumors and its expression enhances the formation of breast invasive tumors in the mouse mammary gland. Conclusions We conclude that RSK3 switches cell fate from senescence to malignancy in response to TGFβ signaling.

Published
2023
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2. The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor

Author

Marie-Lise Lacombe, Frederic Lamarche, Olivier De Wever, Teresita Padilla-Benavides, Alyssa Carlson, Imran Khan, Anda Huna, Sophie Vacher, Claire Calmel, Céline Desbourdes, Cécile Cottet-Rousselle, Isabelle Hininger-Favier, Stéphane Attia, Béatrice Nawrocki-Raby, Joël Raingeaud, Christelle Machon, Jérôme Guitton, Morgane Le Gall, Guilhem Clary, Cedric Broussard, Philippe Chafey, Patrice Thérond, David Bernard, Eric Fontaine, Malgorzata Tokarska-Schlattner, Patricia Steeg, Ivan Bièche, Uwe Schlattner, and Mathieu Boissan

Subjects
Mitochondrial dynamics, Invasion, Metastasis, Nucleoside diphosphate kinase, NME4, Metabolic reprogramming, Biology (General), QH301-705.5
Abstract

Abstract Background Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. Results We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome. Conclusions These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.

Published
2021
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3. Surface tension of model tissues during malignant transformation and epithelial–mesenchymal transition

Author

Irène Nagle, Alain Richert, Michael Quinteros, Sébastien Janel, Edgar Buysschaert, Nathalie Luciani, Henry Debost, Véronique Thevenet, Claire Wilhelm, Céline Prunier, Frank Lafont, Teresita Padilla-Benavides, Mathieu Boissan, and Myriam Reffay

Subjects
mechanobiology, migration, invasion, adhesion, multicellular aggregates, breast tumor, Biology (General), QH301-705.5
Abstract

Epithelial–mesenchymal transition is associated with migration, invasion, and metastasis. The translation at the tissue scale of these changes has not yet been enlightened while being essential in the understanding of tumor progression. Thus, biophysical tools dedicated to measurements on model tumor systems are needed to reveal the impact of epithelial–mesenchymal transition at the collective cell scale. Herein, using an original biophysical approach based on magnetic nanoparticle insertion inside cells, we formed and flattened multicellular aggregates to explore the consequences of the loss of the metastasis suppressor NME1 on the mechanical properties at the tissue scale. Multicellular spheroids behave as viscoelastic fluids, and their equilibrium shape is driven by surface tension as measured by their deformation upon magnetic field application. In a model of breast tumor cells genetically modified for NME1, we correlated tumor invasion, migration, and adhesion modifications with shape maintenance properties by measuring surface tension and exploring both invasive and migratory potential as well as adhesion characteristics.

Published
2022
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4. Case report: Changes in the levels of stress hormones during Takotsubo syndrome

Author

Pablo Ruiz, Paul Gabarre, Camille Chenevier-Gobeaux, Hélène François, Mathieu Kerneis, John A. Cidlowski, Robert H. Oakley, Guillaume Lefèvre, and Mathieu Boissan

Subjects
cortisol, copeptin, cardiac biomarkers, Takotsubo syndrome, case report, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

BackgroundTakotsubo syndrome is an acute cardiac condition usually involving abnormal regional left ventricular wall motion and impaired left ventricular contractility. It is due mainly to hyper-stimulation of the sympathetic nerve system, inducing an excess of catecholamines, usually triggered by intense psychological or physiological stress. The relationship between Takotsubo syndrome and the circulating stress hormones cortisol and copeptin (a surrogate marker of arginine vasopressin) has not been well documented.Case summaryHere, we describe the dynamic changes in circulating cortisol and copeptin during an entire episode of Takotsubo syndrome in a post-partum woman after spontaneous vaginal delivery. The patient was diagnosed with inverted Takotsubo syndrome accompanied by HELLP syndrome. We found qualitative and quantitative changes in cortisol: a loss of circadian rhythm and a three-fold elevation in the plasma concentration of the hormone with a peak appearing several hours before circulating cardiac biomarkers began to rise. By contrast, levels of copeptin remained normal during the entire episode.DiscussionOur findings indicate that the levels of cortisol change during Takotsubo syndrome whereas those of copeptin do not. This association between elevated cortisol and Takotsubo syndrome suggests that aberrant levels of this stress hormone may contribute to the observed cardiac pathology. We conclude that biochemical assays of circulating cortisol and cardiac biomarkers may be a useful complement to the diagnosis of Takotsubo syndrome by non-invasive cardiac imaging.

Published
2022
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5. Inverted Takotsubo Syndrome With HELLP Syndrome: A Case Report

Author

Paul Gabarre, Pablo Ruiz, Camille Chenevier-Gobeaux, Etienne Charpentier, Laurie Soulat-Dufour, Ariel Cohen, Laurence Monnier-Cholley, Lotfi Chemali, Hélène François, Mathieu Kerneis, Guillaume Lefèvre, and Mathieu Boissan

Subjects
troponin T, troponin I, NT-proBNP, Takotsubo, HELLP syndrome, pregnancy, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

BackgroundTakotsubo syndrome is an acute cardiac condition involving sudden, transient apical ballooning of the left ventricle of the heart that may be triggered by emotional stress and some non-cardiac conditions. Its diagnosis is based on clinical presentation, electrocardiogram, cardiac imaging and biomarkers.Case SummaryHere, we present a novel and original case report of a patient presenting very soon in the post-partum period with an unusual form of Takotsubo syndrome without clinical symptoms of cardiac disease and accompanied by HELLP syndrome. The overall dynamics of the changes in troponin I, troponin T and NT-proBNP levels after delivery were generally similar, but the amount of troponin I was much greater than that of troponin T and troponin I was already elevated before delivery. NT-proBNP levels peaked around the same time as the troponins and the peak concentration was within the same range as that of troponin I.DiscussionOur findings indicate that assaying circulating cardiac biomarkers, especially troponin I and NT-proBNP, may be a useful complement to non-invasive cardiac imaging including transthoracic echocardiography and cardiovascular magnetic resonance imaging, in the diagnosis of Takotsubo syndrome. They illustrate the importance of cardiac biomarkers in assisting diagnosis of this disease.

Published
2022
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6. Meningococcal purpura fulminans and severe myocarditis with clinical meningitis but no meningeal inflammation: a case report

Author

Mehdi Hage-Sleiman, Nicolas Derre, Charlotte Verdet, Gilles Pialoux, Olivier Gaudin, Patricia Senet, Muriel Fartoukh, Mathieu Boissan, and Marc Garnier

Subjects
Meningococcal disease, Purpura fulminans, Meningitis, Neisseria meningitidis, Myocarditis, Iloprost, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background During fulminant meningococcal septicaemia, meningococci are often observed in the cerebrospinal fluid (CSF) although the patients have frequently no meningeal symptoms. Meningococcal meningitis, by contrast, usually features clinical meningeal signs and biochemical markers of inflammation with elevated white blood cell count (pleiocytosis) in the CSF. Cases of typical symptomatic meningitis without these biochemical features are uncommon in adults. Case presentation A 21-year-old male presented with meningococcal purpura fulminans and disseminated intravascular coagulation (DIC) associated with multiple organ dysfunction syndrome requiring hospitalization in the Intensive Care Unit. Despite typical meningeal clinical signs, lumbar puncture showed no pleiocytosis, normal glycorachia and normal proteinorachia, whereas the lactate concentration in the CSF was high (5.8 mmol/L). CSF culture showed a high inoculum of serogroup C meningococci. On day 2, after initial improvement, a recurrence of hypotension led to the diagnosis of acute meningococcal myocarditis, which evolved favourably within a week. During the hospitalization, distal ischemic and necrotic lesions were observed, predominantly on the fingertips, which were treated with local and systemic vasodilators. Conclusions We report a rare case of adult meningococcal disease characterized by an intermediate form of meningitis between purulent meningitis and meningeal inoculation from fulminant meningococcal septicaemia, without classical signs of biological inflammation. It highlights the diagnostic value of CSF lactate, which may warrant administration of a meningeal dosing regimen of beta-lactam antibiotics. This case also demonstrates the potential severity of meningococcal myocarditis; we discuss its pathophysiology, which is distinct from other sepsis-related cardiomyopathies. Finally, the observed effects of vasodilators on the meningococcal skin ischemia in this case encourages future studies to assess their efficacy in DIC-associated necrosis.

Published
2019
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7. An updated evaluation of serum sHER2, CA15.3, and CEA levels as biomarkers for the response of patients with metastatic breast cancer to trastuzumab-based therapies.

Author

Alexandre Perrier, Pierre-Yves Boelle, Yves Chrétien, Joseph Gligorov, Jean-Pierre Lotz, Didier Brault, Eva Comperat, Guillaume Lefèvre, and Mathieu Boissan

Subjects
Medicine, Science
Abstract

BACKGROUND:The transmembrane receptor tyrosine kinase HER2 is overexpressed in approximately 15% of breast tumors and correlates with poor clinical prognosis. Several treatments that target HER2 are approved for treatment of HER2-positive metastatic breast cancer. The serum biomarkers most widely used to monitor anti-HER2 therapies in patients with HER2-positive metastatic breast cancer currently are CA15.3 and CEA. Nevertheless, their clinical utility in patients with breast cancer remains a subject of discussion and controversy; thus, additional markers may prove useful in monitoring the therapeutic responses of these patients. The extracellular domain of HER2 can be shed by proteolytic cleavage into the circulation and this shed form, sHER2, is reported to be augmented during metastasis of HER2-positive breast tumors. Here, we studied the clinical usefulness of sHER2, CA15.3, and CEA for monitoring treatment for breast cancer. METHODS:We measured prospectively pretreatment and post-treatment serum levels (day 1, 30, 60 and 90) of these three biomarkers in 47 HER2-positive, metastatic breast cancer patients treated with trastuzumab in combination with paclitaxel. Evaluation of the disease was performed according to the Response Evaluation Criteria in Solid Tumor (RECIST) at day 90. RESULTS:Patients with progressive disease at day 90 had smaller relative changes between day 1 and day 30 than those with complete, partial or stable responses at day 90: -9% versus -38% for sHER2 (P = 0.02), +23% versus -17% for CA15.3 (P = 0.005) and +29% versus -26% for CEA (P = 0.02). Patients with progressive disease at day 90 were less likely than the other patients to have a relative decrease of > 20% in their biomarker levels at day 30: 6% vs 33% for sHER2 (P = 0.03), 0% vs 27% for CA15.3 (P = 0.03), 4% vs 29% for CEA (P = 0.04). No patient with progressive disease at day 90 had > 20% reduction of the average combined biomarker levels at day 30 whereas 63% of the other patients had (P = 0.003). Moreover, when we analyzed a > 10% reduction of the average biomarker levels no patient with progressive disease at day 90 had a decrease > 10% at day 30 whereas 78% of other patients had (P 10% appears to be the best parameter to distinguish patients who go on to have progressive disease from those who will have a complete, partial or stable response.

Published
2020
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8. Force tuning through regulation of clathrin-dependent integrin endocytosis

Author

Alexander Kyumurkov, Anne-Pascale Bouin, Mathieu Boissan, Sandra Manet, Francesco Baschieri, Mathilde Proponnet-Guerault, Martial Balland, Olivier Destaing, Myriam Régent-Kloeckner, Claire Calmel, Alice Nicolas, François Waharte, Philippe Chavrier, Guillaume Montagnac, Emmanuelle Planus, Corinne Albiges-Rizo, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Dynamique des cellules tumorales (UMR1279), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Minatec, Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE13-0022,CODECIDE,Coincidence de detection dans l'identité cellulaire(2017), Chavrier, Philippe, Coincidence de detection dans l'identité cellulaire - - CODECIDE2017 - ANR-17-CE13-0022 - AAPG2017 - VALID, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Didactique André Revuz (LDAR (URP_4434)), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Paris Cité (UPCité)-CY Cergy Paris Université (CY), Laboratoire des technologies de la microélectronique (LTM ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Institut Curie [Paris], Centre de recherche de l'Institut Curie [Paris], Dynamique moléculaire de la transformation hématopoïétique (Dynamo), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Talin, [SDV] Life Sciences [q-bio], Focal Adhesions, Integrin beta1, [SDV]Life Sciences [q-bio], Integrin beta3, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mechanotransduction, Cellular, Clathrin, Endocytosis
Abstract

International audience; Integrin endocytosis is essential for many fundamental cellular processes. Whether and how the internalization impacts cellular mechanics remains elusive. Whereas previous studies reported the contribution of the integrin activator, talin, in force development, the involvement of inhibitors is less documented. We identified ICAP-1 as an integrin inhibitor involved in mechanotransduction by co-working with NME2 to control clathrin-mediated endocytosis of integrins at the edge of focal adhesions (FA). Loss of ICAP-1 enables β3-integrin-mediated force generation independently of β1 integrin. β3-integrin-mediated forces were associated with a decrease in β3 integrin dynamics stemming from their reduced diffusion within adhesion sites and slow turnover of FA. The decrease in β3 integrin dynamics correlated with a defect in integrin endocytosis. ICAP-1 acts as an adaptor for clathrin-dependent endocytosis of integrins. ICAP-1 controls integrin endocytosis by interacting with NME2, a key regulator of dynamin-dependent clathrin-coated pits fission. Control of clathrin-mediated integrin endocytosis by an inhibitor is an unprecedented mechanism to tune forces at FA.

Published
2023
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9. The advantage of channeling nucleotides for very processive functions [version 2; referees: 3 approved]

Author

Diana Zala, Uwe Schlattner, Thomas Desvignes, Julien Bobe, Aurélien Roux, Philippe Chavrier, and Mathieu Boissan

Subjects
Cell Signaling, Membranes & Sorting, Medicine, Science
Abstract

Nucleoside triphosphate (NTP)s, like ATP (adenosine 5’-triphosphate) and GTP (guanosine 5’-triphosphate), have long been considered sufficiently concentrated and diffusible to fuel all cellular ATPases (adenosine triphosphatases) and GTPases (guanosine triphosphatases) in an energetically healthy cell without becoming limiting for function. However, increasing evidence for the importance of local ATP and GTP pools, synthesised in close proximity to ATP- or GTP-consuming reactions, has fundamentally challenged our view of energy metabolism. It has become evident that cellular energy metabolism occurs in many specialised ‘microcompartments’, where energy in the form of NTPs is transferred preferentially from NTP-generating modules directly to NTP-consuming modules. Such energy channeling occurs when diffusion through the cytosol is limited, where these modules are physically close and, in particular, if the NTP-consuming reaction has a very high turnover, i.e. is very processive. Here, we summarise the evidence for these conclusions and describe new insights into the physiological importance and molecular mechanisms of energy channeling gained from recent studies. In particular, we describe the role of glycolytic enzymes for axonal vesicle transport and nucleoside diphosphate kinases for the functions of dynamins and dynamin-related GTPases.

Published
2017
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10. The advantage of channeling nucleotides for very processive functions [version 1; referees: 3 approved]

Author

Diana Zala, Uwe Schlattner, Thomas Desvignes, Julien Bobe, Aurélien Roux, Philippe Chavrier, and Mathieu Boissan

Subjects
Cell Signaling, Membranes & Sorting, Medicine, Science
Abstract

Nucleoside triphosphate (NTP)s, like ATP (adenosine 5’-triphosphate) and GTP (guanosine 5’-triphosphate), have long been considered sufficiently concentrated and diffusible to fuel all cellular ATPases (adenosine triphosphatases) and GTPases (guanosine triphosphatases) in an energetically healthy cell without becoming limiting for function. However, increasing evidence for the importance of local ATP and GTP pools, synthesised in close proximity to ATP- or GTP-consuming reactions, has fundamentally challenged our view of energy metabolism. It has become evident that cellular energy metabolism occurs in many specialised ‘microcompartments’, where energy in the form of NTPs is transferred preferentially from NTP-generating modules directly to NTP-consuming modules. Such energy channeling occurs when diffusion through the cytosol is limited, where these modules are physically close and, in particular, if the NTP-consuming reaction has a very high turnover, i.e. is very processive. Here, we summarise the evidence for these conclusions and describe new insights into the physiological importance and molecular mechanisms of energy channeling gained from recent studies. In particular, we describe the role of glycolytic enzymes for axonal vesicle transport and nucleoside diphosphate kinases for the functions of dynamins and dynamin-related GTPases.

Published
2017
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11. The Function of NM23-H1/NME1 and Its Homologs in Major Processes Linked to Metastasis

Author

Zsolt Farkas, Anil Mehta, Anna Sebestyén, Krisztina Takács-Vellai, Barbara Mátyási, Mathieu Boissan, László Kopper, Embertani Tanszék, MTA-SE Molekuláris Pathológiai Kutatócsoport (2006 végéig működött), Biológia Doktori Iskola, Genetikai Tanszék, MTA-SE Molekuláris Onkológia Kutatócsoport, and I. Sz. Patológiai és Kísérleti Rákkutató Intézet

Subjects
0301 basic medicine, MAPK/ERK pathway, Cancer Research, Apoptosis, Review, Biology, Endocytosis, NDPK, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Phagocytosis, Cell Movement, Animals, Humans, Cell migration, Neoplasm Invasiveness, Neoplasm Metastasis, Dynamin, Cell Proliferation, Metastasis inhibitor, Kinase, Chemotaxis, General Medicine, NM23 Nucleoside Diphosphate Kinases, Nucleoside-diphosphate kinase, Cell biology, Metastasis Suppressor Gene, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Nucleoside-Diphosphate Kinase, Cftr, Phosphohistidine, NM23
Abstract

Metastasis suppressor genes (MSGs) inhibit different biological processes during metastatic progression without globally influencing development of the primary tumor. The first MSG, NM23 (non-metastatic clone 23, isoform H1) or now called NME1 (stands for non-metastatic) was identified some decades ago. Since then, ten human NM23 paralogs forming two groups have been discovered. Group I NM23 genes encode enzymes with evolutionarily highly conserved nucleoside diphosphate kinase (NDPK) activity. In this review we summarize how results from NDPKs in model organisms converged on human NM23 studies. Next, we examine the role of NM23-H1 and its homologs within the metastatic cascade, e.g. cell migration and invasion, proliferation and apoptosis. NM23-H1 homologs are well known inhibitors of cell migration. Drosophila studies revealed that AWD, the fly counterpart of NM23-H1 is a negative regulator of cell motility by modulating endocytosis of chemotactic receptors on the surface of migrating cells in cooperation with Shibire/Dynamin; this mechanism has been recently confirmed by human studies. NM23-H1 inhibits proliferation of tumor cells by phosphorylating the MAPK scaffold, kinase suppressor of Ras (KSR), resulting in suppression of MAPK signalling. This mechanism was also observed with the C. elegans homolog, NDK-1, albeit with an inverse effect on MAPK activation. Both NM23-H1 and NDK-1 promote apoptotic cell death. In addition, NDK-1, NM23-H1 and their mouse counterpart NM23-M1 were shown to promote phagocytosis in an evolutionarily conserved manner. In summary, inhibition of cell migration and proliferation, alongside actions in apoptosis and phagocytosis are all mechanisms through which NM23-H1 acts against metastatic progression.

Published
2020

12. Loss of the Metastasis Suppressor NME1, But Not of Its Highly Related Isoform NME2, Induces a Hybrid Epithelial–Mesenchymal State in Cancer Cells

Author

David Bernard, Sylvie Coscoy, Teresita Padilla-Benavides, Anda Huna, Julie Gavard, B. Nawrocki-Raby, Mathieu Boissan, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wesleyan University, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département d'Oncologie [Saint Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe labellisée Ligue contre le Cancer, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Bernardo, Elizabeth

Subjects
Epithelial-Mesenchymal Transition, MAP Kinase Signaling System, Cell, Mice, Nude, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, epithelial–mesenchymal transition, Catalysis, Article, Metastasis, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Cell Adhesion, Animals, Humans, cancer, metastasis, Metastasis suppressor, Epithelial–mesenchymal transition, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Protein kinase B, Spectroscopy, 030304 developmental biology, Gene Editing, 0303 health sciences, Chemistry, Organic Chemistry, Mesenchymal stem cell, Cancer, General Medicine, NM23 Nucleoside Diphosphate Kinases, medicine.disease, Cadherins, Computer Science Applications, medicine.anatomical_structure, lcsh:Biology (General), lcsh:QD1-999, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Female, epithelium
Abstract

International audience; Epithelial–mesenchymal transition (EMT) is important for the initial steps of metastasis. Although it is well accepted that the nucleoside diphosphate kinase NME1 is a metastasis suppressor, its effect on EMT remains poorly documented, as does that of its closely related isoform, NME2. Here, by using gene silencing, inactivation and overexpression strategies in a variety of cellular models of cancer, we show that NME1 is a powerful inhibitor of EMT. Genetic manipulation of NME2, by contrast, had no effect on the EMT phenotype of cancer cells, indicating a specific function of NME1 in EMT regulation. Loss of NME1 in epithelial cancer cells resulted in a hybrid phenotype intermediate between epithelial and mesenchymal cells, which is known to be associated with cells with a highly metastatic character. Conversely, overexpression of NME1 in mesenchymal cancer cells resulted in a more epithelial phenotype. We found that NME1 expression was negatively associated with EMT markers in many human cancers and was reduced in human breast tumor cell lines with the aggressive ‘triple-negative’ phenotype when compared to human breast tumor cell lines positive for estrogen receptor. We show that NME1, but not NME2, is an inhibitor of essential concerted intracellular signaling pathways involved in inducing EMT, including the AKT and MAPK (ERK, p38, and JNK) pathways. Additionally, NME1 depletion considerably altered the distribution of E-cadherin, a gatekeeper of the epithelial phenotype, shifting it from the plasma membrane to the cytosol and resulting in less E-cadherin on the cell surface than in control cells. Functional aggregation and dispersion assays demonstrated that inactivation of NME1 decreases E-cadherin-mediated cell–cell adhesion. We conclude that NME1, but not NME2, acts specifically to inhibit EMT and prevent the earliest stages of metastasis.

Published
2021
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13. Massive lactic acidosis and ketoacidosis with glucagon deficiency in a chronic alcoholic patient

Author

Patrick Gilon, Philippe Boudou, Fabrizio Andreelli, Michel Djibré, Pascal Ferré, Soraya Fellahi, Fidaa Ibrahim, Mathieu Boissan, and UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition

Subjects
2. Zero hunger, 0303 health sciences, medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Chronic alcoholic, 030209 endocrinology & metabolism, General Medicine, medicine.disease, Glucagon Deficiency, Gastroenterology, 3. Good health, Ketoacidosis, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, Lactic acidosis, Internal Medicine, medicine, business, 030304 developmental biology
Abstract

A non-diabetic chronic alcoholic and undernourished male patient [body mass index (BMI): 16.6 kg/m2] was admitted to our hospital emergency department. He had fasted for the previous 3 days. His blood lactate and ketone body concentrations were massively elevated (18 mmol/L and 14 mmol/L, respectively). Ethanolaemia was negative. Massive metabolic acidosis was noted with a pH of 7.04. Renal function remained normal, but there was mild hepatocellular deficiency and no acute pancreatitis. The patient was hypoglycaemic at admission with a blood glucose level of 3.0 mmol/L, and low concentrations of insulin, C-peptide and insulin-like growth factor (IGF)-1, as well as very low glucagon concentrations (5.2 ng/L; normal range: 8–74 ng/L) despite the prevailing glycaemia. In contrast, cortisol, sex hormone-binding globulin (SHBG) and growth hormone (GH) concentrations were elevated. [...]

Published
2021

14. The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor

Author

David Bernard, Malgorzata Tokarska-Schlattner, Anda Huna, Patrice Thérond, Isabelle Hininger-Favier, Sophie Vacher, Patricia S. Steeg, Céline Desbourdes, Guilhem Clary, Philippe Chafey, Morgane Le Gall, Imran Khan, Jérôme Guitton, Olivier De Wever, Christelle Machon, Alyssa Carlson, Ivan Bièche, Teresita Padilla-Benavides, Cécile Cottet-Rousselle, Uwe Schlattner, Stéphane Attia, Béatrice Nawrocki-Raby, Cédric Broussard, Frédéric Lamarche, Mathieu Boissan, Joël Raingeaud, Marie-Lise Lacombe, Claire Calmel, Eric Fontaine, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Universiteit Gent = Ghent University [Belgium] (UGENT), Wesleyan University, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Institut Curie [Paris], Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique des cellules tumorales (UMR1279), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Biostatistique, traitement et modélisation des données biologiques (BioSDTM - URP_7537), Université de Paris (UP), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), raingeaud, joel, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Universiteit Gent = Ghent University (UGENT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
DYNAMICS, Physiology, MATRIX METALLOPROTEINASES, [SDV]Life Sciences [q-bio], PROMOTES METASTASIS, PROTEIN, Plant Science, Mitochondrion, Metastasis, Mice, 0302 clinical medicine, Invasion, Structural Biology, Neoplasms, Medicine and Health Sciences, Biology (General), Nucleoside Diphosphate Kinase D, 0303 health sciences, Ecology, Metabolic reprogramming, NM23 Nucleoside Diphosphate Kinases, Nucleoside-diphosphate kinase, Mitochondria, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, SYNUCLEIN-GAMMA, Intermembrane space, General Agricultural and Biological Sciences, Research Article, Biotechnology, QH301-705.5, Evolution, NM23-H4, Genetics and Molecular Biology, Nucleoside diphosphate kinase, Biology, Prognosis biomarker, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Behavior and Systematics, Animals, BREAST-CANCER, Metastasis suppressor, CELL, Kinase activity, Retrograde signaling, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, NME4, Intracellular Membranes, Cell Biology, GENE, Metastasis Suppressor Gene, Nucleoside-Diphosphate Kinase, Cancer cell, General Biochemistry, Mitochondrial dynamics, MEMBRANE, Developmental Biology
Abstract

Background Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. Results We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome. Conclusions These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.

Published
2021
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15. The nucleoside diphosphate kinase NDK-1/NME1 promotes phagocytosis in concert with DYN-1/Dynamin

Author

Floriane Herit, Tamás I. Orbán, Metka Petric, Florence Niedergang, Zsuzsa Bajtay, Anil Mehta, Xianghua Liu, Mathieu Boissan, Tibor Kovács, Zsófia Budai, Jun Qin, Zsolt Farkas, Muhammed Afaq Shakir, Zheng Zhou, Sára Sándor, Sung Yun Jung, Krisztina Takács-Vellai, Éva Rajnavölgyi, Zsuzsa Szondy, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Debrecen Egyetem [Debrecen], Biochemistry and Molecular Biology, Division of Medical Sciences, University of Dundee, University of Maryland [College Park], University of Maryland System, CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Dynamins, Phagocytosis, metastasis inhibitor, apoptotic clearance, Apoptosis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Phagosomes, Phagosome maturation, Genetics, Animals, Humans, Receptor, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Molecular Biology, Opsonin, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Dynamin, Chemistry, Research, Macrophages, phagosome maturation, NM23 Nucleoside Diphosphate Kinases, Nucleoside-diphosphate kinase, Actins, Cell biology, Mice, Inbred C57BL, Signaling network, 030104 developmental biology, Leukocytes, Mononuclear, phagosome formation, 030217 neurology & neurosurgery, Biotechnology, actin cup, Signal Transduction
Abstract

Phagocytosis of various targets, such as apoptotic cells or opsonized pathogens, by macrophages is coordinated by a complex signaling network initiated by distinct phagocytic receptors. Despite the different initial signaling pathways, each pathway ends up regulating the actin cytoskeletal network, phagosome formation and closure, and phagosome maturation leading to degradation of the engulfed particle. Herein, we describe a new phagocytic function for the nucleoside diphosphate kinase 1 (NDK-1), the nematode counterpart of the first identified metastasis inhibitor NM23-H1 (nonmetastatic clone number 23) nonmetastatic clone number 23 or nonmetastatic isoform 1 (NME1). We reveal by coimmunoprecipitation, Duolink proximity ligation assay, and mass spectrometry that NDK-1/NME1 works in a complex with DYN-1/Dynamin (Caenorhabditis elegans/human homolog proteins), which is essential for engulfment and phagosome maturation. Time-lapse microscopy shows that NDK-1 is expressed on phagosomal surfaces during cell corpse clearance in the same time window as DYN-1. Silencing of NM23-M1 in mouse bone marrow–derived macrophages resulted in decreased phagocytosis of apoptotic thymocytes. In human macrophages, NM23-H1 and Dynamin are corecruited at sites of phagosome formation in F-actin–rich cups. In addition, NM23-H1 was required for efficient phagocytosis. Together, our data demonstrate that NDK-1/NME1 is an evolutionarily conserved element of successful phagocytosis.—Farkas, Z., Petric, M., Liu, X., Herit, F., Rajnavölgyi, É., Szondy, Z., Budai, Z., Orbán, T. I., Sándor, S., Mehta, A., Bajtay, Z., Kovács, T., Jung, S. Y., Afaq Shakir, M., Qin, J., Zhou, Z., Niedergang, F., Boissan, M., Takács-Vellai, K. The nucleoside diphosphate kinase NDK-1/NME1 promotes phagocytosis in concert with DYN-1/dynamin.

Published
2019
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16. The mitochondrial nucleoside diphosphate kinase (NDPK-D/NME4), a moonlighting protein for cell homeostasis

Author

Mathieu Boissan, Malgorzata Tokarska-Schlattner, Marie-Lise Lacombe, Uwe Schlattner, Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Fondation pour la Recherche Médicale (FRM, DPM20121125557), Groupement des Entreprises Françaises contre le Cancer (GEFLUC), Cancéropôle IdF (n° 2015-1-EMERG-25-INSERM 6-1), and CMIRA Explo’ra - Région Rhone Alpes

Subjects
0301 basic medicine, Protein moonlighting, Cell, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Pathology and Forensic Medicine, 03 medical and health sciences, Neoplasms, Mitophagy, medicine, Animals, Homeostasis, Humans, Molecular Biology, Gene, Phospholipids, ComputingMilieux_MISCELLANEOUS, Chemistry, Kinase, Nucleoside Diphosphate Kinase D, Cell Biology, Nucleoside-diphosphate kinase, Cell biology, 030104 developmental biology, medicine.anatomical_structure
Abstract

Mitochondrial nucleoside diphosphate kinase (NDPK-D; synonyms: NME4, NM23-H4) represents the major mitochondrial NDP kinase. The homohexameric complex emerged as a protein with multiple functions in bioenergetics and phospholipid signaling. It occurs at different but precise mitochondrial locations and can affect among other mitochondrial shapes and dynamics, as well as the specific elimination of defective mitochondria or cells via mitophagy or apoptosis. With these various functions in cell homeostasis, NDPK-D/NME4 adds to the group of so-called moonlighting (or gene sharing) proteins.

Published
2018
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17. The NDPK/NME superfamily: state of the art

Author

Marie-Lise Lacombe, Uwe Schlattner, Mathieu Boissan, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Hamant, Sarah, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Protein family, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Neoplasms, Animals, Humans, Nucleotide, Neoplasm Metastasis, Molecular Biology, Gene, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Histidine, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Kinase, Tumor Suppressor Proteins, SUPERFAMILY, Cell Biology, Isoenzymes, 030104 developmental biology, Enzyme, chemistry, Biochemistry, Multigene Family, Nucleoside-Diphosphate Kinase, Phosphorylation
Abstract

Nucleoside diphosphate kinases (NDPK) are nucleotide metabolism enzymes encoded by NME genes (also called NM23). Given the fact that not all NME-encoded proteins are catalytically active NDPKs and that NM23 generally refers to clinical studies on metastasis, we use here NME/NDPK to denote the proteins. Since their discovery in the 1950's, NMEs/NDPKs have been shown to be involved in multiple physiological and pathological cellular processes, but the molecular mechanisms have not been fully determined. Recent progress in elucidating these underlying mechanisms has been presented by experts in the field at the 10th International Congress on the NDPK/NME/AWD protein family in October 2016 in Dubrovnik, Croatia, and is summarized in review articles or original research in this and an upcoming issue of Laboratory Investigation. Within this editorial, we discuss three major cellular processes that involve members of the multi-functional NME/NDPK family: (i) cancer and metastasis dissemination, (ii) membrane remodeling and nucleotide channeling, and iii) protein histidine phosphorylation.

Published
2018
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18. NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

Author

Marie-Lise Lacombe, Richard M. Epand, Uwe Schlattner, Valerian E. Kagan, Mathieu Boissan, Malgorzata Tokarska-Schlattner, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), McMaster University [Hamilton, Ontario], Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Fondation pour la Recherche Médicale (FRM, DPM20121125557), CMIRA Explo’ra doc - Région Rhône Alpes, NIH (HL114453, U19AI068021), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and HAL UPMC, Gestionnaire

Subjects
0301 basic medicine, Cardiolipins, [SDV]Life Sciences [q-bio], Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Pharmacology, Models, Biological, Pathology and Forensic Medicine, 03 medical and health sciences, chemistry.chemical_compound, Mitophagy, Cardiolipin, Animals, Humans, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Kinase activity, Inner mitochondrial membrane, Molecular Biology, Nucleoside Diphosphate Kinase D, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Intermembrane phospholipid transfer activity, 030102 biochemistry & molecular biology, Cell Biology, Cell biology, 030104 developmental biology, chemistry, Mitochondrial Membranes, Signal transduction, Protein Binding, Signal Transduction
Abstract

International audience; Mitophagy is an emerging paradigm for mitochondrial quality control and cell homeostasis. Dysregulation of mitophagy can lead to human pathologies such as neurodegenerative disorders and contributes to the aging process. Complex protein signaling cascades have been described that regulate mitophagy. We have identified a novel lipid signaling pathway that involves the phospholipid cardiolipin (CL). CL is synthesized and normally confined at the inner mitochondrial membrane. However, upon a mitophagic trigger, ie, collapse of the inner membrane potential, CL is rapidly externalized to the mitochondrial surface with the assistance of the hexameric nucleoside diphosphate kinase D (NME4, NDPK-D, or NM23-H4). In addition to its NDP kinase activity, NME4/NDPK-D shows intermembrane phospholipid transfer activity in vitro and in cellular systems, which relies on NME4/NDPK-D interaction with CL, CL-dependent crosslinking of inner and outer mitochondrial membranes by symmetrical, hexameric NME4/NDPK-D, and a putative NME4/NDPK-D-based CL-transfer pathway. CL exposed at the mitochondrial surface then serves as an 'eat me' signal for the mitophagic machinery; it is recognized by the LC3 receptor of autophagosomes, targeting the dysfunctional mitochondrion to lysosomal degradation. Similar NME4-supported CL externalization is likely also involved in apoptosis and inflammatory reactions.

Published
2017
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19. Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity

Author

Michel Lepoivre, Isabelle Moranvillier, Evelyne Peuchant, François Moreau-Gaudry, Sandrine Dabernat, Jérôme Guitton, Mathieu Boissan, Dominique Wendum, Marie-Lise Bats, Marie-Lise Lacombe, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire Bioénergétique Membranaire et Stress (LBMS), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, MAPK/ERK pathway, Keratinocytes, Male, Paraquat, MAP Kinase Signaling System, [SDV]Life Sciences [q-bio], keratinocyte, medicine.disease_cause, NDPK, Biochemistry, Cell Line, 03 medical and health sciences, Mice, Genetics, medicine, hepatocyte, Animals, Humans, ASK1, Metastasis suppressor, Molecular Biology, Cells, Cultured, Kinase, Chemistry, Article RECHERCHE, Fibroblasts, NM23 Nucleoside Diphosphate Kinases, Molecular biology, MAPK, Nucleoside-diphosphate kinase, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, Liver, Cell culture, Hepatocytes, Nucleoside, Oxidative stress, Gene Deletion, Biotechnology
Abstract

NME1 (nonmetastatic expressed 1) gene, which encodes nucleoside diphosphate kinase (NDPK) A [also known as nonmetastatic clone 23 (NM23)-H1 in humans and NM23-M1 in mice], is a suppressor of metastasis, but several lines of evidence-mostly from plants-also implicate it in the regulation of the oxidative stress response. Here, our aim was to investigate the physiologic relevance of NDPK A with respect to the oxidative stress response in mammals and to study its molecular basis. NME1-knockout mice died sooner, suffered greater hepatocyte injury, and had lower superoxide dismutase activity than did wild-type (WT) mice in response to paraquat-induced acute oxidative stress. Deletion of NME1 reduced total NDPK activity and exacerbated activation of the stress-related MAPK, JNK, in the liver in response to paraquat. In a mouse transformed hepatocyte cell line and in primary cultures of normal human keratinocytes, MAPK activation in response to H2O2 and UVB, respectively, was dampened by expression of NM23-M1/NM23-H1, dependent on its NDPK catalytic activity. Furthermore, excess or depletion of NM23-M1/NM23-H1 NDPK activity did not affect the intracellular bulk concentration of nucleoside di- and triphosphates. NME1-deficient mouse embryo fibroblasts grew poorly in culture, were more sensitive to stress than WT fibroblasts, and did not immortalize, which suggested that they senesce earlier than do WT fibroblasts. Collectively, these results indicate that the NDPK activity of NM23-M1/NM23-H1 protects cells from acute oxidative stress by inhibiting activation of JNK in mammal models.-Peuchant, E., Bats, M.-L., Moranvillier, I., Lepoivre, M., Guitton, J., Wendum, D., Lacombe, M.-L., Moreau-Gaudry, F., Boissan, M., Dabernat, S. Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity.

Published
2017
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20. The advantage of channeling nucleotides for very processive functions

Author

Philippe Chavrier, Diana Zala, Mathieu Boissan, Thomas Desvignes, Julien Bobe, Aurélien Roux, Uwe Schlattner, Laboratoire Plasticité du Cerveau (PdC), ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-Paris Sciences et Lettres (PSL), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Laboratoire de Physiologie et Génomique des Poissons (LPGP), Institut National de la Recherche Agronomique (INRA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Curie, Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Fondation pour la Recherche Médicale (FRM DPM20121125557), Groupement des Entreprises Françaises contre le Cancer (GEFLUC R16170DD/RAK16044DDA), Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris ( ESPCI ParisTech ), Laboratoire de bioénergétique fondamentale et appliquée ( LBFA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Grenoble Alpes ( UGA ), Station commune de Recherches en Ichtyophysiologie, Biodiversité et Environnement ( SCRIBE ), Institut National de la Recherche Agronomique ( INRA ) -IFR140, Laboratoire de Physiologie et Génomique des Poissons ( LPGP ), Institut National de la Recherche Agronomique ( INRA ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire d'acoustique de l'université du Mans ( LAUM ), Le Mans Université ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), UMRS 938 : Saint-Antoine Research Center, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), University of Oregon [Eugene], Université de Genève = University of Geneva (UNIGE), Swiss National Centre for Competence in Research Programme Chemical Biology (NCCR-Chemical Biology), Institut Curie [Paris], Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Chavrier, Philippe, Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, GTP', ATPase, [SDV]Life Sciences [q-bio], Review, GTPase, bioenergetics, mécanisme moléculaire, chemistry.chemical_compound, atp, 0302 clinical medicine, Cell Signaling, canalisation, General Pharmacology, Toxicology and Pharmaceutics, glycolyse, ComputingMilieux_MISCELLANEOUS, gtp, Kinase, nucleoside diphosphate kinase, Articles, General Medicine, glycolysis, Nucleoside-diphosphate kinase, [SDV] Life Sciences [q-bio], pipe, ddc:540, Nucleoside triphosphate, Glycolysis, bioénergétique, medicine.drug, métabolisme énergétique, oxidative phosphorylation, Guanosine, Nucleoside diphosphate kinase, Bioenergetics, Biology, atpase, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, dynamin, medicine, creatine kinase, Oxidative phosphorylation, Creatine kinase, General Immunology and Microbiology, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, cell, Adenosine, ATP, Dynamin, 030104 developmental biology, chemistry, biology.protein, Biophysics, enzyme glycolytique, cellule, Neuroscience, GTP, 030217 neurology & neurosurgery, nucléoside triphosphatase, Membranes & Sorting
Abstract

[version 2]; International audience; Nucleoside triphosphate (NTP)s, like ATP (adenosine 5'-triphosphate) and GTP (guanosine 5'-triphosphate), have long been considered sufficiently concentrated and diffusible to fuel all cellular ATPases (adenosine triphosphatases) and GTPases (guanosine triphosphatases) in an energetically healthy cell without becoming limiting for function. However, increasing evidence for the importance of local ATP and GTP pools, synthesised in close proximity to ATP-or GTP-consuming reactions, has fundamentally challenged our view of energy metabolism. It has become evident that cellular energy metabolism occurs in many specialised 'microcompartments', where energy in the form of NTPs is transferred preferentially from NTP-generating modules directly to NTP-consuming modules. Such energy channeling occurs when diffusion through the cytosol is limited, where these modules are physically close and, in particular, if the NTP-consuming reaction has a very high turnover,. is i.e very processive. Here, we summarise the evidence for these conclusions and describe new insights into the physiological importance and molecular mechanisms of energy channeling gained from recent studies. In particular, we describe the role of glycolytic enzymes for axonal vesicle transport and nucleoside diphosphate kinases for the functions of dynamins and dynamin-related GTPases. Keywords

Published
2017
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21. NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

Author

Vladimir A. Tyurin, Yiran Li, Cécile Cottet-Rousselle, Jianfei Jiang, Charleen T. Chu, Zhentai Huang, Amin Cheikhi, Marie-Lise Lacombe, Malgorzata Tokarska-Schlattner, Y.Y. Tyurina, C. St. Croix, Alexander A. Kapralov, Simon C. Watkins, Valerian E. Kagan, Zheni Shen, Manish Verma, Mathieu Boissan, Donna B. Stolz, Gaowei Mao, Miriam L. Greenberg, Céline Desbourdes, Haider H. Dar, Rama K. Mallampalli, Uwe Schlattner, Hülya Bayır, Richard M. Epand, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, Programmed cell death, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Cardiolipins, [SDV]Life Sciences [q-bio], Mitochondrial Degradation, Proximity ligation assay, Biology, Mitochondrion, Cell Line, GTP Phosphohydrolases, 03 medical and health sciences, chemistry.chemical_compound, Mice, Rotenone, Mitophagy, Cardiolipin, Autophagy, Animals, Humans, Inner mitochondrial membrane, Oxidopamine, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Original Paper, 030102 biochemistry & molecular biology, Nucleoside Diphosphate Kinase D, Cell Biology, Cell biology, Mitochondria, 030104 developmental biology, chemistry, Mitochondrial Membranes, Mutagenesis, Site-Directed, RNA Interference, Intermembrane space, Lysosomes, Microtubule-Associated Proteins, HeLa Cells, Protein Binding
Abstract

Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified as a mitophageal signal recognized by the microtubule-associated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission-fusion dynamics in mitophagy regulation.

Published
2016
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22. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling

Author

Ioan Lascu, Graça Raposo, Céline Desbourdes, Philippe Chavrier, Nathalie Sauvonnet, Thibault Lagache, Guillaume Montagnac, Jérôme Guitton, Qinfang Shen, Aurélien Roux, Marie-Lise Lacombe, Maryse Romao, Uwe Schlattner, Lorena Griparic, AlexanderM van der Bliek, Mathieu Boissan, Simona Polo, Institut Curie [Paris], Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dynamique de la membrane et du cytosquelette, Compartimentation et dynamique cellulaires (CDC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Hospices Civils de Lyon (HCL), Université de Lyon, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biologie des Interactions Cellulaires (BIC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Università degli Studi di Milano [Milano] (UNIMI), University of Geneva [Switzerland], This work was supported by Institut Curie, CNRS, Fondation ARC pour la Recherche sur le Cancer, Groupement des Entreprises Françaises contre le Cancer, Fondation pour la Recherche Médicale, the Human Frontier Science Program, the Swiss National Fund for Research Grant, and the European Research Council., Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of California (UC)-University of California (UC), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano = University of Milan (UNIMI), and Université de Genève = University of Geneva (UNIGE)

Subjects
endocrine system, MESH: GTP Phosphohydrolases, GTP', MESH: Mitochondria, [SDV]Life Sciences [q-bio], MESH: Guanosine Diphosphate, Biology, Guanosine triphosphate, MESH: Membrane Fusion, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MESH: Adenosine Triphosphate, MESH: Animals, Nucleoside Diphosphate Kinase D, 030304 developmental biology, Dynamin, 0303 health sciences, Multidisciplinary, MESH: Guanosine Triphosphate, MESH: Humans, Kinase, Cell biology, MESH: Cell Line, MESH: Dynamins, MESH: Intracellular Membranes, chemistry, Guanosine diphosphate, 030220 oncology & carcinogenesis, ddc:540, MESH: Endocytosis, MESH: Coated Pits, Cell-Membrane, GTP Phosphohydrolases, MESH: NM23 Nucleoside Diphosphate Kinases, MESH: Nucleoside Diphosphate Kinase D, Adenosine triphosphate, MESH: Cell Membrane
Abstract

Supplying power: Right time, right place Cell membranes are very flexible and easily molded to shape; however, to physically pinch off a membrane vesicle from a membrane tube still requires power. A type of molecular machine known as dynamin is involved in this sort of membrane remodeling. Dynamins use guanosine triphosphate (GTP) rather than the more commonly used cellular energy source adenosine triphosphate to work. Boissan et al. now show that two separate dynamins found in the cytoplasm or the mitochondria both use the same sort of enzyme—nucleoside diphosphate kinases—to provide GTP at just the right time and the right place to power membrane fission. Science , this issue p. 1510

Published
2014
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23. Mitochondrial cardiolipin/phospholipid trafficking: The role of membrane contact site complexes and lipid transfer proteins

Author

Denis Rousseau, Malgorzata Tokarska-Schlattner, Mathieu Boissan, Uwe Schlattner, Richard M. Epand, Marie-Lise Lacombe, Carmen A. Mannella, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Biochemistry and Biomedical Sciences, McMaster University [Hamilton, Ontario], Centre de Recherche Saint-Antoine (UMRS893), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Membrane junction complexes, Cardiolipins, [SDV]Life Sciences [q-bio], Nucleoside diphosphate kinase, Lipid trafficking, Mitochondrion, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Lipid translocation, Cardiolipin, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Creatine kinase, Inner mitochondrial membrane, Molecular Biology, Lipid Transport, Nm23, 030304 developmental biology, 0303 health sciences, Membrane contact sites, Endoplasmic reticulum, 030302 biochemistry & molecular biology, Organic Chemistry, Biological Transport, Cell Biology, Intracellular Membranes, Membrane contact site, Cell biology, Mitochondria, chemistry, Mitochondrial Membranes, lipids (amino acids, peptides, and proteins), Lipid transfer proteins, Bacterial outer membrane, Carrier Proteins
Abstract

International audience; Historically, cellular trafficking of lipids has received much less attention than protein trafficking, mostly because its biological importance was underestimated, involved sorting and translocation mechanisms were not known, and analytical tools were limiting. This has changed during the last decade, and we discuss here some progress made in respect to mitochondria and the trafficking of phospholipids, in particular cardiolipin. Different membrane contact site or junction complexes and putative lipid transfer proteins for intra- and intermembrane lipid translocation have been described, involving mitochondrial inner and outer membrane, and the adjacent membranes of the endoplasmic reticulum. An image emerges how cardiolipin precursors, remodeling intermediates, mature cardiolipin and its oxidation products could migrate between membranes, and how this trafficking is involved in cardiolipin biosynthesis and cell signaling events. Particular emphasis in this review is given to mitochondrial nucleoside diphosphate kinase D and mitochondrial creatine kinases, which emerge to have roles in both, membrane junction formation and lipid transfer.

Published
2014
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24. Mitochondrial Nm23-H4/NDPK-D is Multifunctional: Intermembrane Cardiolipin Transfer Linked to Apoptosis

Author

Richard M. Epand, Malgorzata Tokarska-Schlattner, Sacnicte Ramirez, Yulia Y. Tyurina, Marie-Lise Lacombe, Mathieu Boissan, Uwe Schlattner, Andrew A. Amoscato, Dariush Mohammadsanyi, Judith Klein-Seetharaman, Raquel F. Epand, Zhentai Huang, Jianfei Jiang, Valerian E. Kagan, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Department of Biochemistry and Biomedical Sciences, McMaster University [Hamilton, Ontario], University of Warwick [Coventry], Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0303 health sciences, biology, Mitochondrial intermembrane space, Cytochrome c, [SDV]Life Sciences [q-bio], Biophysics, Intermembrane lipid transfer, Nucleoside-diphosphate kinase, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, Cytosol, 0302 clinical medicine, chemistry, Biochemistry, Cardiolipin, biology.protein, lipids (amino acids, peptides, and proteins), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Intermembrane space, Inner mitochondrial membrane, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

International audience; Nm23-H4/NDPK-D forms symmetrical homohexameric complexes in the mitochondrial intermembrane space. The well established function of the enzyme is phosphotransfer activity as a nucleoside diphosphate kinase (NDPK), using mitochondrial ATP to regenerate nucleoside triphosphates. Nm23-H4 is further known to strongly bind in vitro to anionic phospholipids, mainly cardiolipin, and in vivo to inner mitochondrial membranes. We show here that such protein/lipid complexes inhibit NDPK activity but are necessary for Nm23-H4 to function in selective intermembrane lipid transfer. Nm23-H4-deficient HeLa cells expressing either wild-type Nm23-H4 or a membrane-binding deficient mutant were analyzed by membrane fractionation and LC-ESI-MS. Data revealed that wild-type Nm24-H4 increased cardiolipin content in the outer mitochondrial membrane as compared to mutant enzyme. This correlated with higher susceptibility of wild-type enzyme expressing cells to rotenone-induced apoptosis as seen by increased annexin V binding, elevated caspase 3/7 activity and stimulated release of cytochrome c into the cytosol. Molecular modeling of Nm23-H4 binding with cardiolipin reveals potential intermembrane transfer mechanisms. We propose that Nm23-H4 acts as a lipid-dependent mitochondrial switch with dual function, allowing either for phosphotransfer or for cardiolipin transfer, with a role in apoptotic signaling.

Published
2013
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25. Dual Function of Mitochondrial Nm23-H4 Protein in Phosphotransfer and Intermembrane Lipid Transfer

Author

Malgorzata Tokarska-Schlattner, Jianfei Jiang, Amal Seffouh, Valerian E. Kagan, Uwe Schlattner, Marie-Lise Lacombe, Dariush Mohammadyani, Zhentai Huang, Naveena Yanamala, Andrew A. Amoscato, Judith Klein-Seetharaman, Richard M. Epand, Mathieu Boissan, Raquel F. Epand, Yulia Y. Tyurina, Sacnicte Ramirez, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Biochemistry and Biomedical Sciences, McMaster University [Hamilton, Ontario], University of Warwick [Coventry], Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pittsburgh (PITT), and Pennsylvania Commonwealth System of Higher Education (PCSHE)

Subjects
0303 health sciences, Mitochondrial intermembrane space, [SDV]Life Sciences [q-bio], 030302 biochemistry & molecular biology, Cell Biology, Biology, Mitochondrial carrier, Biochemistry, Mitochondrial apoptosis-induced channel, Intermembrane lipid transfer, Cell biology, 03 medical and health sciences, chemistry.chemical_compound, chemistry, Translocase of the inner membrane, Cardiolipin, Cardiolipin binding, Inner mitochondrial membrane, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

The nucleoside diphosphate kinase Nm23-H4/NDPK-D forms symmetrical hexameric complexes in the mitochondrial intermembrane space with phosphotransfer activity using mitochondrial ATP to regenerate nucleoside triphosphates. We demonstrate the complex formation between Nm23-H4 and mitochondrial GTPase OPA1 in rat liver, suggesting its involvement in local and direct GTP delivery. Similar to OPA1, Nm23-H4 is further known to strongly bind in vitro to anionic phospholipids, mainly cardiolipin, and in vivo to the inner mitochondrial membrane. We show here that such protein-lipid complexes inhibit nucleoside diphosphate kinase activity but are necessary for another function of Nm23-H4, selective intermembrane lipid transfer. Mitochondrial lipid distribution was analyzed by liquid chromatography-mass spectrometry using HeLa cells expressing either wild-type Nm23-H4 or a membrane binding-deficient mutant at a site predicted based on molecular modeling to be crucial for cardiolipin binding and transfer mechanism. We found that wild type, but not the mutant enzyme, selectively increased the content of cardiolipin in the outer mitochondrial membrane, but the distribution of other more abundant phospholipids (e.g. phosphatidylcholine) remained unchanged. HeLa cells expressing the wild-type enzyme showed increased accumulation of Bax in mitochondria and were sensitized to rotenone-induced apoptosis as revealed by stimulated release of cytochrome c into the cytosol, elevated caspase 3/7 activity, and increased annexin V binding. Based on these data and molecular modeling, we propose that Nm23-H4 acts as a lipid-dependent mitochondrial switch with dual function in phosphotransfer serving local GTP supply and cardiolipin transfer for apoptotic signaling and putative other functions.

Published
2013
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26. KIF20A mRNA and Its Product MKlp2 Are Increased During Hepatocyte Proliferation and Hepatocarcinogenesis

Author

Florence Bourgain-Guglielmetti, Dominique Wendum, Mathieu Boissan, Jessica Zucman-Rossi, Gabrielle Couchy, Marie-Lise Lacombe, Joëlle Sobczak-Thépot, Chantal Desdouets, Germain Margall-Ducos, Isabelle Gasnereau, Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5), University Paris, CNRS, INSERM, La Ligue Comite de Paris [RS06/75-57], Ligue Nationale Contre le Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Male, Carcinoma, Hepatocellular, Kinesins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Tumor Cells, Cultured, medicine, Animals, Humans, Mitosis, Aged, 030304 developmental biology, 0303 health sciences, Gene knockdown, Cell growth, Endoplasmic reticulum, Cell Cycle, Liver Neoplasms, Middle Aged, Cell cycle, Liver regeneration, Liver Regeneration, Cell biology, Mice, Inbred C57BL, Cell Transformation, Neoplastic, Ki-67 Antigen, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hepatocyte, Hepatocytes, Cancer research, Female, Mitogens, Precancerous Conditions, Cytokinesis
Abstract

International audience; Mitotic kinesin-like protein 2 (MKlp2), a microtubule-associated motor, is required during mitosis exit for the final step of cytokine;is. It also contributes to retrograde vesicular trafficking from the Golgi apparatus to the endoplasmic reticulum in interphase. The KIF20A gene encoding MKlp2 is controlled by the E2F-retinoblastoma protein-p16 pathway, and its widely expressed mRNA is found in fetal and proliferating adult tissues. The expression pattern and function of MKlp2 in the adult liver, however, have not been investigated. We report herein that MKlp2 transiently accumulates in vivo during mouse liver regeneration after partial hepatectomy and is strongly overexpressed in preneoplastic and neoplastic mouse liver. In vitro in mitogen-stimulated primary hepatocytes, MKlp2 accumulated in the nucleus during the G2 phase of the cell cycle coincident with the mitotic kinase Aurora B. Human hepatoma cell lines exhibited high levels of MKlp2; however, it was undetectable in normal human hepatocytes. RNAi-mediated MKlp2 knockdown in hepatoma cells induced polyploidization consistent with its essential function in promoting cytokinesis and inhibited cell proliferation without inducing apoptosis. KIF20A mRNA was strongly accumulated in a large series of human hepatocellular carcinomas, with the highest expression observed in tumors with genomic instability. Accumulation of MKlp2 in normal proliferating, preneoplastic, and transformed hepatocytes suggests that MKlp2 contributes to both normal and pathologic hepatocyte proliferation and is linked to tumor aggressiveness in human hepatocellular carcinomas.

Published
2012
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27. Proteomic analysis of NME1/NDPK A null mouse liver: evidence for a post-translational regulation of annexin IV and EF-1Bα

Author

Bruno Baudin, Joëlle Vinh, Mathieu Boissan, Arnaud Bruneel, Marie-Lise Lacombe, Valérie Labas, Odile Mulner-Lorillon, Chantal Housset, Dominique Wendum, Sandrine Dabernat, Eric Ballot, Nelly Bosselut, Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Mer et santé (MS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Spectrométrie de Masse Biologique et Protéomique (USR3149 / FRE2032) (SMBP), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Centre de Gestion Scientifique i3 (CGS i3), Centre National de la Recherche Scientifique (CNRS)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut interdisciplinaire de l’innovation (I3), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CNRS/ESPCI ParisTech USR 3149, Centre National de la Recherche Scientifique (CNRS), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [APHP], and Centre de Recherche Saint-Antoine (CR Saint-Antoine)

Subjects
Genetically modified mouse, Male, Proteomics, Blotting, Western, Biology, Endoplasmic Reticulum, Real-Time Polymerase Chain Reaction, 03 medical and health sciences, Mice, 0302 clinical medicine, Cytosol, Peptide Elongation Factor 1, Tandem Mass Spectrometry, Cell Line, Tumor, Animals, Humans, Post-translational regulation, Metastasis suppressor, Electrophoresis, Gel, Two-Dimensional, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Annexin A4, 030304 developmental biology, Pharmacology, Mice, Knockout, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Endoplasmic reticulum, Wild type, General Medicine, NM23 Nucleoside Diphosphate Kinases, Molecular biology, Eukaryotic translation elongation factor 1 alpha 1, Cell biology, Protein Transport, Liver, 030220 oncology & carcinogenesis, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Proteome, Protein Processing, Post-Translational, Annexin A2
Abstract

International audience; NME/NDPK family proteins are involved in the control of intracellular nucleotide homeostasis as well as in both physiological and pathological cellular processes, such as proliferation, differentiation, development, apoptosis, and metastasis dissemination, through mechanisms still largely unknown. One family member, NME1/NDPK-A, is a metastasis suppressor, yet the primary physiological functions of this protein are still missing. The purpose of this study was to identify new NME1/NDPK-A-dependent biological functions and pathways regulated by this gene in the liver. We analyzed the proteomes of wild-type and transgenic NME1-null mouse livers by combining two-dimensional gel electrophoresis and mass spectrometry (matrix-assisted laser desorption/ionization time of flight and liquid chromatography-tandem mass spectrometry). We found that the levels of three proteins, namely, phenylalanine hydroxylase, annexin IV, and elongation factor 1 Bα (EF-1Bα), were strongly reduced in the cytosolic fraction of NME1(-/-) mouse livers when compared to the wild type. This was confirmed by immunoblotting analysis. No concomitant reduction in the corresponding messenger RNAs or of total protein level was observed, however, suggesting that NME1 controls annexin IV and EF-1Bα amounts by post-translational mechanisms. NME1 deletion induced a change in the subcellular location of annexin IV in hepatocytes resulting in enrichment of this protein at the plasma membrane. We also observed a redistribution of EF-1Bα in NME1(-/-) hepatocytes to an intracytoplasmic compartment that colocalized with a marker of the reticulum endoplasmic. Finally, we found reduced expression of annexin IV coincident with decreased NME1 expression in a panel of different carcinoma cell lines. Taken together, our data suggest for the first time that NME1 might regulate the subcellular trafficking of annexin IV and EF-1Bα. The potential role of these proteins in metastatic dissemination is discussed.

Published
2011
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28. The mammalian Nm23/NDPK family: from metastasis control to cilia movement

Author

Uwe Schlattner, Evelyne Peuchant, Marie-Lise Lacombe, Sandrine Dabernat, Mathieu Boissan, Ioan Lascu, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), U876, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biochimie et Génétique Cellulaires, Université Bordeaux Segalen - Bordeaux 2, Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Grellety, Marie-Lise

Subjects
Lineage (genetic), [SDV]Life Sciences [q-bio], Clinical Biochemistry, Biology, Mitochondrion, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Animals, Humans, Nucleotide, Cilia, Neoplasm Metastasis, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Gene, Phylogeny, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mammals, chemistry.chemical_classification, 0303 health sciences, Kinase, Cilium, Cell Biology, General Medicine, NM23 Nucleoside Diphosphate Kinases, Nucleoside-diphosphate kinase, Mitochondria, Isoenzymes, chemistry, Biochemistry, Nucleoside-Diphosphate Kinase, 030220 oncology & carcinogenesis, Nucleoside, Protein Binding, Signal Transduction
Abstract

Nucleoside diphosphate kinases (NDPK) are encoded by the NME genes, also called NM23. They catalyze the transfer of gamma-phosphate from nucleoside triphosphates to nucleoside diphosphates by a ping-pong mechanism involving the formation of a high energy phospho-histidine intermediate [1, 2]. Besides their known functions in the control of intracellular nucleotide homeostasis, they are involved in multiple physiological and pathological cellular processes such as differentiation, development, metastastic dissemination or cilia functions. Over the past 15 years, ten human genes have been discovered encoding partial, full length, and/or tandemly repeated Nm23/NDPK domains, with or without N-or C-terminal extensions and/or additional domains. These genes encode proteins exhibiting different functions at various tissular and subcellular localizations. Most of these genes appear late in evolution with the emergence of the vertebrate lineage. This review summarizes the present knowledge on these multitalented proteins.

Published
2009
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29. Interaction of NDPK-D with cardiolipin-containing membranes: Structural basis and implications for mitochondrial physiology

Author

Malgorzata Tokarska-Schlattner, Raquel F. Epand, Marie-Lise Lacombe, Uwe Schlattner, Richard M. Epand, Mathieu Boissan, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry and Biomedical Sciences, McMaster University [Hamilton, Ontario], and Hamant, Sarah

Subjects
Models, Molecular, Cardiolipins, Protein Conformation, Translocase of the outer membrane, 7. Clean energy, Biochemistry, 03 medical and health sciences, Mitochondrial membrane transport protein, chemistry.chemical_compound, 0302 clinical medicine, Cardiolipin, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Inner mitochondrial membrane, 030304 developmental biology, 0303 health sciences, biology, Nucleoside Diphosphate Kinase D, Membrane Proteins, General Medicine, Intracellular Membranes, NM23 Nucleoside Diphosphate Kinases, Surface Plasmon Resonance, Mitochondrial carrier, Cell biology, Mitochondria, chemistry, Translocase of the inner membrane, biology.protein, DNAJA3, ATP–ADP translocase, 030217 neurology & neurosurgery, Protein Binding
Abstract

International audience; Nucleoside diphosphate kinases (NDPKs/Nm23), responsible for intracellular di- and tri-phosphonucleoside homeostasis, play multi-faceted roles in cellular energetic, signaling, proliferation, differentiation and tumor invasion. The mitochondrial NDPK-D, the NME4 gene product, is a peripheral protein of the inner membrane. Several new aspects of the interaction of NDPK-D with the inner mitochondrial membrane have been recently characterized. Surface plasmon resonance analysis using recombinant NDPK-D and different phospholipid liposomes showed that NDPK-D interacts electrostatically with anionic phospholipids, with highest affinity observed for cardiolipin, a phospholipid located mostly in the mitochondrial inner membrane. Mutation of the central arginine (R90) in a surface exposed cationic RRK motif unique to NDPK-D strongly reduced phospholipid interaction in vitro and in vivo. Stable expression of NDPK-D proteins in HeLa cells naturally almost devoid of this isoform revealed a tight functional coupling of NDPK-D with oxidative phosphorylation that depends on the membrane-bound state of the enzyme. Owing to its symmetrical hexameric structure exposing membrane binding motifs on two opposite sides, NDPK-D could bridge liposomes containing anionic phospholipids and promote lipid transfer between them. In vivo, NDPK-D could induce intermembrane contacts and facilitate lipid movements between mitochondrial membranes. Most of these properties are reminiscent to those of the mitochondrial creatine kinase. We review here the common properties of both kinases and we discuss their potential roles in mitochondrial functions such as energy production, apoptosis and mitochondrial dynamics.

Published
2009
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30. Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice

Author

Colette Rey, Chantal Housset, Elisabeth Lasnier, Axelle Cadoret, Dominique Wendum, Thomas Braescu, Silvia Zúñiga, Nicolas Chignard, Thomas Falguières, Mathieu Boissan, Dominique Rainteau, Delphine Firrincieli, Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC), Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de la Recherche Agronomique (INRA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
medicine.medical_specialty, Molecular Sequence Data, Calcitriol receptor, Cell junction, digestive system, 03 medical and health sciences, Mice, 0302 clinical medicine, Cholestasis, Internal medicine, medicine, Animals, Amino Acid Sequence, Receptor, Biliary Tract, Ligation, 030304 developmental biology, Liver injury, Mice, Knockout, 0303 health sciences, Hepatology, biology, Bile duct, Calpain, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Epithelial Cells, medicine.disease, Cadherins, ErbB Receptors, Disease Models, Animal, Endocrinology, medicine.anatomical_structure, Intercellular Junctions, Autoimmune, Cholestatic and Biliary Disease, Liver, Biliary tract, biology.protein, Receptors, Calcitriol, 030211 gastroenterology & hepatology, Bile Ducts
Abstract

Alterations in apical junctional complexes (AJCs) have been reported in genetic or acquired biliary diseases. The vitamin D nuclear receptor (VDR), predominantly expressed in biliary epithelial cells in the liver, has been shown to regulate AJCs. The aim of our study was thus to investigate the role of VDR in the maintenance of bile duct integrity in mice challenged with biliary-type liver injury. Vdr−/− mice subjected to bile duct ligation (BDL) displayed increased liver damage compared to wildtype BDL mice. Adaptation to cholestasis, ascertained by expression of genes involved in bile acid metabolism and tissue repair, was limited in Vdr−/− BDL mice. Furthermore, evaluation of Vdr−/− BDL mouse liver tissue sections indicated altered E-cadherin staining associated with increased bile duct rupture. Total liver protein analysis revealed that a truncated form of E-cadherin was present in higher amounts in Vdr−/− mice subjected to BDL compared to wildtype BDL mice. Truncated E-cadherin was also associated with loss of cell adhesion in biliary epithelial cells silenced for VDR. In these cells, E-cadherin cleavage occurred together with calpain 1 activation and was prevented by the silencing of calpain 1. Furthermore, VDR deficiency led to the activation of the epidermal growth factor receptor (EGFR) pathway, while EGFR activation by EGF induced both calpain 1 activation and E-cadherin cleavage in these cells. Finally, truncation of E-cadherin was blunted when EGFR signaling was inhibited in VDR-silenced cells. Conclusion: Biliary-type liver injury is exacerbated in Vdr−/− mice by limited adaptive response and increased bile duct rupture. These results indicate that loss of VDR restricts the adaptation to cholestasis and diminishes bile duct integrity in the setting of biliary-type liver injury. (Hepatology 2013;58:1401–1412)

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