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@ARTICLE{Gner:165254,
      author       = {Güner, Gökhan and Assfalg, Marlene and Zhao, Kai and
                      Dreyer, Tobias and Lahiri, Shibojyoti and Lo, Yun and
                      Slivinschi, Bianca and Imhof, Axel and Jocher, Georg and
                      Strohm, Laura and Behrends, Christian and Langosch, Dieter
                      and Bronger, Holger and Nimsky, Christopher and Bartsch,
                      Jörg W and Riddell, Stanley R and Steiner, Harald and
                      Lichtenthaler, Stefan},
      title        = {{P}roteolytically generated soluble {T}weak {R}eceptor
                      {F}n14 is a blood biomarker for γ-secretase activity.},
      journal      = {EMBO molecular medicine},
      volume       = {14},
      number       = {10},
      issn         = {1715-4684},
      address      = {Heidelberg},
      publisher    = {EMBO Press},
      reportid     = {DZNE-2022-01547},
      pages        = {e16084},
      year         = {2022},
      note         = {CC BY: https://creativecommons.org/licenses/by/4.0/},
      abstract     = {Fn14 is a cell surface receptor with key functions in
                      tissue homeostasis and injury but is also linked to chronic
                      diseases. Despite its physiological and medical importance,
                      the regulation of Fn14 signaling and turnover is only partly
                      understood. Here, we demonstrate that Fn14 is cleaved within
                      its transmembrane domain by the protease γ-secretase,
                      resulting in secretion of the soluble Fn14 ectodomain
                      (sFn14). Inhibition of γ-secretase in tumor cells reduced
                      sFn14 secretion, increased full-length Fn14 at the cell
                      surface, and enhanced TWEAK ligand-stimulated Fn14 signaling
                      through the NFκB pathway, which led to enhanced release of
                      the cytokine tumor necrosis factor. γ-Secretase-dependent
                      sFn14 release was also detected ex vivo in primary tumor
                      cells from glioblastoma patients, in mouse and human plasma
                      and was strongly reduced in blood from human cancer patients
                      dosed with a γ-secretase inhibitor prior to chimeric
                      antigen receptor (CAR)-T-cell treatment. Taken together, our
                      study demonstrates a novel function for γ-secretase in
                      attenuating TWEAK/Fn14 signaling and suggests the use of
                      sFn14 as an easily measurable pharmacodynamic biomarker to
                      monitor γ-secretase activity in vivo.},
      keywords     = {Amyloid Precursor Protein Secretases / Animals / Biomarkers
                      / Cytokine TWEAK / Humans / Ligands / Mice / Receptors, Cell
                      Surface: metabolism / Receptors, Chimeric Antigen /
                      Receptors, Tumor Necrosis Factor: metabolism / TWEAK
                      Receptor / Tumor Necrosis Factor-alpha / Alzheimer's disease
                      (Other) / TNR12 (Other) / ectodomain shedding (Other) /
                      glioblastoma (Other) / intramembrane proteolysis (Other)},
      cin          = {AG Lichtenthaler / AG Steiner},
      ddc          = {610},
      cid          = {I:(DE-2719)1110006 / I:(DE-2719)1110000-1},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC9549706},
      pubmed       = {pmid:36069059},
      doi          = {10.15252/emmm.202216084},
      url          = {https://pub.dzne.de/record/165254},
}