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The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17

Author

Listed:
  • Sarah Louise Dombernowsky

    (University of Copenhagen)

  • Jacob Samsøe-Petersen

    (University of Copenhagen)

  • Camilla Hansson Petersen

    (University of Copenhagen)

  • Rachael Instrell

    (High Throughput Screening Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory)

  • Anne-Mette Bornhardt Hedegaard

    (University of Copenhagen)

  • Laurel Thomas

    (University of Pittsburgh School of Medicine)

  • Katelyn Mae Atkins

    (Oregon Health & Science University)

  • Sylvain Auclair

    (University of Pittsburgh School of Medicine)

  • Reidar Albrechtsen

    (University of Copenhagen)

  • Kasper Johansen Mygind

    (University of Copenhagen)

  • Camilla Fröhlich

    (University of Copenhagen)

  • Michael Howell

    (High Throughput Screening Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory)

  • Peter Parker

    (Protein Phosphorylation Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory
    King’s College London, New Hunts House, Guy’s Campus)

  • Gary Thomas

    (University of Pittsburgh School of Medicine)

  • Marie Kveiborg

    (University of Copenhagen)

Abstract

The metalloproteinase ADAM17 activates ErbB signalling by releasing ligands from the cell surface, a key step underlying epithelial development, growth and tumour progression. However, mechanisms acutely controlling ADAM17 cell-surface availability to modulate the extent of ErbB ligand release are poorly understood. Here, through a functional genome-wide siRNA screen, we identify the sorting protein PACS-2 as a regulator of ADAM17 trafficking and ErbB signalling. PACS-2 loss reduces ADAM17 cell-surface levels and ADAM17-dependent ErbB ligand shedding, without apparent effects on related proteases. PACS-2 co-localizes with ADAM17 on early endosomes and PACS-2 knockdown decreases the recycling and stability of internalized ADAM17. Hence, PACS-2 sustains ADAM17 cell-surface activity by diverting ADAM17 away from degradative pathways. Interestingly, Pacs2-deficient mice display significantly reduced levels of phosphorylated EGFR and intestinal proliferation. We suggest that this mechanism controlling ADAM17 cell-surface availability and EGFR signalling may play a role in intestinal homeostasis, with potential implications for cancer biology.

Suggested Citation

  • Sarah Louise Dombernowsky & Jacob Samsøe-Petersen & Camilla Hansson Petersen & Rachael Instrell & Anne-Mette Bornhardt Hedegaard & Laurel Thomas & Katelyn Mae Atkins & Sylvain Auclair & Reidar Albrech, 2015. "The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8518
    DOI: 10.1038/ncomms8518
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