Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity

Katharina Bläsius, Lena Ludwig, Sarah Knapp, Charlotte Flaßhove, Friederike Sonnabend, Diandra Keller, Nikola Tacken, Xintong Gao, Selcan Kahveci-Türköz, Caroline Grannemann, Aaron Babendreyer, Colin Adrain, Sebastian Huth, Jens Malte Baron, Andreas Ludwig, Stefan Düsterhöft

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Abstract

The protease ADAM17 plays an important role in inflammation and cancer and is regulated by iRhom2. Mutations in the cytosolic N-terminus of human iRhom2 cause tylosis with oesophageal cancer (TOC). In mice, partial deletion of the N-terminus results in a curly hair phenotype (cub). These pathological consequences are consistent with our findings that iRhom2 is highly expressed in keratinocytes and in oesophageal cancer. Cub and TOC are associated with hyperactivation of ADAM17-dependent EGFR signalling. However, the underlying molecular mechanisms are not understood. We have identified a non-canonical, phosphorylation-independent 14-3-3 interaction site that encompasses all known TOC mutations. Disruption of this site dysregulates ADAM17 activity. The larger cub deletion also includes the TOC site and thus also dysregulated ADAM17 activity. The cub deletion, but not the TOC mutation, also causes severe reductions in stimulated shedding, binding, and stability of ADAM17, demonstrating the presence of additional regulatory sites in the N-terminus of iRhom2. Overall, this study contrasts the TOC and cub mutations, illustrates their different molecular consequences, and reveals important key functions of the iRhom2 N-terminus in regulating ADAM17.
Original languageEnglish
Article number102
JournalCellular and Molecular Life Sciences
Volume81
DOIs
Publication statusPublished - 27 Feb 2024

Keywords

  • Ectodomain Shedding
  • Adam17
  • 14-3-3 Proteins
  • Stratifin
  • Esophageal Squamous Cancer
  • Irhom2
  • Curly-bare (Cub) Mouse
  • Egfr Ligand Release
  • Howel–evans Syndrome
  • Tylosis With Oesophageal Cancer (Toc)
  • Animals
  • Humans
  • Mice
  • Esophageal Neoplasms
  • Keratoderma, Palmoplantar
  • Carrier Proteins
  • Signal Transduction
  • Phosphorylation
  • Mutation
  • ADAM17 Protein

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