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

2015; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/ncomms8518

2041-1723

Sarah Louise Dombernowsky, Jacob Samsøe‐Petersen, Camilla Hansson Petersen, Rachael Instrell, Anne-Mette Bornhardt Hedegaard, Laurel Thomas, Katelyn M. Atkins, Sylvain Auclair, Reidar Albrechtsen, Kasper J. Mygind, Camilla Fröhlich, Michael Howell, Peter J. Parker, Gary Thomas, Marie Kveiborg,

Monoclonal and Polyclonal Antibodies Research

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. ErbB signalling is stimulated by the release of its ligands from the cell surface through metalloproteinase-dependent cleavage. Dombernowsky et al. show that this process is controlled by the sorting protein PACS-2, which enhances ErbB ligand release by regulating trafficking of the metalloprotease ADAM17.