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    MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis

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    Type
    Article
    Authors
    Kotelnikova, Ekaterina
    Kiani, Narsis A.
    Messinis, Dimitris
    Pertsovskaya, Inna
    Pliaka, Vicky
    Bernardo-Faura, Marti
    Rinas, Melanie
    Vila, Gemma
    Zubizarreta, Irati
    Pulido-Valdeolivas, Irene
    Sakellaropoulos, Theodore
    Faigle, Wolfgang
    Silberberg, Gilad
    Masso, Mar
    Stridh, Pernilla
    Behrens, Janina
    Olsson, Tomas
    Martin, Roland
    Paul, Friedemann
    Alexopoulos, Leonidas G.
    Saez-Rodriguez, Julio
    Tegner, Jesper cc
    Villoslada, Pablo
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Date
    2019-04-19
    Embargo End Date
    2019-10-19
    Permanent link to this record
    http://hdl.handle.net/10754/656425
    
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    Abstract
    Dysregulation of signaling pathways in multiple sclerosis (MS) can be analyzed by phosphoproteomics in peripheral blood mono-nuclear cells (PBMCs). We performed in vitro kinetic assays on PBMCs in 195 MS patients and 60 matched controls and quantified the phosphorylation of 17 kinases using xMAP assays. Phosphopro-tein levels were tested for association with genetic susceptibility by typing 112 single-nucleotide polymorphisms (SNPs) associated with MS susceptibility. We found increased phosphorylation of MP2K1 in MS patients relative to the controls. Moreover, we identified one SNP located in the PHDGH gene and another on IRF8 gene that were associated with MP2K1 phosphorylation levels, providing a first clue on how this MS risk gene may act. The analyses in patients treated with disease-modifying drugs identified the phosphorylation of each receptor’s downstream kinases. Finally, using flow cytometry, we detected in MS patients increased STAT1, STAT3, TF65, and HSPB1 phosphorylation in CD19+ cells. These findings indicate the activation of cell survival and proliferation (MAPK), and proinflammatory (STAT) pathways in the immune cells of MS patients, primarily in B cells. The changes in the activation of these kinases suggest that these pathways may represent therapeutic targets for modulation by kinase inhibitors.
    Citation
    Kotelnikova, E., Kiani, N. A., Messinis, D., Pertsovskaya, I., Pliaka, V., Bernardo-Faura, M., … Villoslada, P. (2019). MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis. Proceedings of the National Academy of Sciences, 201818347. doi:10.1073/pnas.1818347116
    Sponsors
    We thank Mark Sefton for editorial assistance. This study was supported by the European Commission (CombiMS project) under Grant Agreement 305397 (FP7/2007-2013); Sys4MS project (Horizon2020: Eracosysmed: ID-43); the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional funds “Otra forma de hacer Europa” Grant AC15-00052); and Centres de Recerca de Catalunya Programme/Generalitat de Catalunya.
    Publisher
    National Academy of Sciences
    Journal
    Proceedings of the National Academy of Sciences of the United States of America
    DOI
    10.1073/pnas.1818347116
    Additional Links
    http://www.pnas.org/lookup/doi/10.1073/pnas.1818347116
    Relations
    Is Supplemented By:
    • [Software]
      Title: saezlab/combiMS: combiMS code for Prediction of combination therapy based on perturbation modeling of the multiple sclerosis signaling network. Code started by Marti at EBI on Feb 2013. Publication Date: 2016-10-26. github: saezlab/combiMS Handle: 10754/666983
    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.1818347116
    Scopus Count
    Collections
    Articles; Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program

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