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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

AUTHORS

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

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. More... »

PAGES

7518

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ncomms8518

DOI

http://dx.doi.org/10.1038/ncomms8518

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1031117663

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26108729


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