Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations

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  • Stephan Wilmes
    Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany.
  • Maximillian Hafer
    Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany.
  • Joni Vuorio
    Department of Physics, University of Helsinki, Helsinki, Finland.
  • Julie A. Tucker
    York Biomedical Research Institute and Department of Biology, University of York, Heslington, York YO10 5DD, UK.
  • Hauke Winkelmann
    Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany.
  • Sara Löchte
    Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany.
  • Tess A. Stanly
    York Biomedical Research Institute and Department of Biology, University of York, Heslington, York YO10 5DD, UK.
  • Katiuska D. Pulgar Prieto
    York Biomedical Research Institute and Department of Biology, University of York, Heslington, York YO10 5DD, UK.
  • Chetan Poojari
    Department of Physics, University of Helsinki, Helsinki, Finland.
  • Vivek Sharma
    Department of Physics, University of Helsinki, Helsinki, Finland.
  • Christian P. Richter
    Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany.
  • Rainer Kurre
    Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany.
  • Stevan R. Hubbard
    Skirball Institute and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
  • K. Christopher Garcia
    Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Ignacio Moraga
    Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
  • Ilpo Vattulainen
    Department of Physics, University of Helsinki, Helsinki, Finland.
  • Ian S. Hitchcock
    York Biomedical Research Institute and Department of Biology, University of York, Heslington, York YO10 5DD, UK.
  • Jacob Piehler
    Department of Biology and Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany.

Description

<jats:title>Activated by interaction</jats:title> <jats:p> Cytokines trigger immune responses when they bind to their cognate receptors. Class I cytokine receptors rely on the associated Janus kinase 2 (JAK2) to initiate signal transduction. There has been debate over whether activation involves ligand-induced dimerization of these receptors or ligand-induced conformational change of preformed dimers. Wilmes <jats:italic>et al.</jats:italic> imaged cytokine receptors in the plasma membranes of live human cells by single-molecule fluorescence microscopy and observed ligand-induced dimerization. They found that the JAK2 pseudokinase domains contribute to dimerization and that hyperactive JAK2 mutants promote dimerization, consistent with the model that dimerization triggers activation. </jats:p> <jats:p> <jats:italic>Science</jats:italic> , this issue p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6478" page="643" related-article-type="in-this-issue" vol="367" xlink:href="10.1126/science.aaw3242">643</jats:related-article> </jats:p>

Journal

  • Science

    Science 367 (6478), 643-652, 2020-02-07

    American Association for the Advancement of Science (AAAS)

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