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@ARTICLE{Tretter:140001,
      author       = {Tretter, Jana Ylva and Schorpp, Kenji and Luxenburger, Elke
                      and Trambauer, Johannes and Steiner, Harald and Hadian,
                      Kamyar and Gires, Olivier and Niessing, Dierk},
      title        = {{A} high-content screen for small-molecule regulators of
                      epithelial cell-adhesion molecule ({E}p{CAM}) cleavage
                      yields a robust inhibitor.},
      journal      = {The journal of biological chemistry},
      volume       = {293},
      number       = {23},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.60645},
      reportid     = {DZNE-2020-06323},
      pages        = {8994-9005},
      year         = {2018},
      abstract     = {Epithelial cell-adhesion molecule (EpCAM) is a
                      transmembrane protein that regulates cell cycle progression
                      and differentiation and is overexpressed in many carcinomas.
                      The EpCAM-induced mitogenic cascade is activated via
                      regulated intramembrane proteolysis (RIP) of EpCAM by ADAM
                      and γ-secretases, generating the signaling-active
                      intracellular domain EpICD. Because of its expression
                      pattern and molecular function, EpCAM is a valuable target
                      in prognostic and therapeutic approaches for various
                      carcinomas. So far, several immunotherapeutic strategies
                      have targeted the extracellular domain of EpCAM. However,
                      targeting the intracellular signaling cascade of EpCAM holds
                      promise for specifically interfering with EpCAM's
                      proliferation-stimulating signaling cascade. Here, using a
                      yellow fluorescence protein-tagged version of the C-terminal
                      fragment of EpCAM, we established a high-content screening
                      (HCS) of a small-molecule compound library (n = 27,280) and
                      characterized validated hits that target EpCAM signaling. In
                      total, 128 potential inhibitors were initially identified,
                      of which one compound with robust inhibitory effects on RIP
                      of EpCAM was analyzed in greater detail. In summary, our
                      study demonstrates that the development of an HCS for
                      small-molecule inhibitors of the EpCAM signaling pathway is
                      feasible. We propose that this approach may also be useful
                      for identifying chemical compounds targeting other disorders
                      involving membrane cleavage-dependent signaling pathways.},
      keywords     = {Cell Proliferation: drug effects / Drug Evaluation,
                      Preclinical: methods / Epithelial Cell Adhesion Molecule:
                      antagonists $\&$ inhibitors / Epithelial Cell Adhesion
                      Molecule: metabolism / HEK293 Cells / High-Throughput
                      Screening Assays: methods / Humans / Signal Transduction:
                      drug effects / Small Molecule Libraries: chemistry / Small
                      Molecule Libraries: pharmacology / Transcription, Genetic:
                      drug effects / Epithelial Cell Adhesion Molecule (NLM
                      Chemicals) / Small Molecule Libraries (NLM Chemicals)},
      cin          = {AG Steiner},
      ddc          = {540},
      cid          = {I:(DE-2719)1110000-1},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29700109},
      pmc          = {pmc:PMC5995519},
      doi          = {10.1074/jbc.RA118.002776},
      url          = {https://pub.dzne.de/record/140001},
}