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

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 () and Marie Kveiborg ()
Additional contact information
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
Gary Thomas: University of Pittsburgh School of Medicine
Marie Kveiborg: University of Copenhagen

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms8518 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8518

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms8518

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().