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TNFR1 membrane reorganization promotes distinct modes of TNFα signaling.
Morton, Penny E; Perrin, Camille; Levitt, James; Matthews, Daniel R; Marsh, Richard J; Pike, Rosemary; McMillan, David; Maloney, Alison; Poland, Simon; Ameer-Beg, Simon; Parsons, Maddy.
Affiliation
  • Morton PE; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
  • Perrin C; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
  • Levitt J; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
  • Matthews DR; Nikon Imaging Centre, King's College London, Hodgkin Building, Guy's Campus, London SE1 1UL, UK.
  • Marsh RJ; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
  • Pike R; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
  • McMillan D; UCB Celltech, 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
  • Maloney A; UCB Celltech, 208 Bath Road, Slough, Berkshire SL1 3WE, UK.
  • Poland S; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
  • Ameer-Beg S; School of Cancer and Pharmaceutical Sciences, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
  • Parsons M; Randall Centre for Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
Sci Signal ; 12(592)2019 07 30.
Article in En | MEDLINE | ID: mdl-31363067
Signaling by the ubiquitously expressed tumor necrosis factor receptor 1 (TNFR1) after ligand binding plays an essential role in determining whether cells exhibit survival or death. TNFR1 forms distinct signaling complexes that initiate gene expression programs downstream of the transcriptional regulators NFκB and AP-1 and promote different functional outcomes, such as inflammation, apoptosis, and necroptosis. Here, we investigated the ways in which TNFR1 was organized at the plasma membrane at the nanoscale level to elicit different signaling outcomes. We confirmed that TNFR1 forms preassembled clusters at the plasma membrane of adherent cells in the absence of ligand. After trimeric TNFα binding, TNFR1 clusters underwent a conformational change, which promoted lateral mobility, their association with the kinase MEKK1, and activation of the JNK/p38/NFκB pathway. These phenotypes required a minimum of two TNFR1-TNFα contact sites; fewer binding sites resulted in activation of NFκB but not JNK and p38. These data suggest that distinct modes of TNFR1 signaling depend on nanoscale changes in receptor organization.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tumor Necrosis Factor-alpha / MAP Kinase Signaling System / Receptors, Tumor Necrosis Factor, Type I Limits: Humans Language: En Journal: Sci Signal Journal subject: CIENCIA / FISIOLOGIA Year: 2019 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tumor Necrosis Factor-alpha / MAP Kinase Signaling System / Receptors, Tumor Necrosis Factor, Type I Limits: Humans Language: En Journal: Sci Signal Journal subject: CIENCIA / FISIOLOGIA Year: 2019 Document type: Article Country of publication: United States