Article open access publication

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

Nature Communications, Springer Nature, ISSN 2041-1723

Volume 6, 1, 2015

DOI:10.1038/ncomms8518, Dimensions: pub.1031117663, PMC: PMC4481878, PMID: 26108729,

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  1. (1) University of Copenhagen, grid.5254.6, KU
  2. (2) The Francis Crick Institute, grid.451388.3
  3. (3) University of Pittsburgh, grid.21925.3d
  4. (4) Oregon Health & Science University, grid.5288.7
  5. (5) King's College London, grid.13097.3c

Description

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.

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University of Copenhagen

Danish Open Access Indicator

2015: Realized

Research area: Medicine

Danish Bibliometrics Indicator

2015: Level 1

Research area: Medicine

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Times Cited: 30

Field Citation Ratio (FCR): 4.35

Relative Citation ratio (RCR): 1.34

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