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

Autor: Dombernowsky SL; Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark., Samsøe-Petersen J; Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark., Petersen CH; Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark., Instrell R; High Throughput Screening Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK., Hedegaard AM; Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark., Thomas L; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, USA., Atkins KM; Department of Cell and Developmental Biology, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA., Auclair S; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, USA., Albrechtsen R; Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark., Mygind KJ; Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark., Fröhlich C; Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark., Howell M; High Throughput Screening Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK., Parker P; 1] Protein Phosphorylation Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK [2] Division of Cancer Studies, King's College London, New Hunts House, Guy's Campus, London SE1 1UL, UK., Thomas G; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, USA., Kveiborg M; Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2015 Jun 25; Vol. 6, pp. 7518. Date of Electronic Publication: 2015 Jun 25.
DOI: 10.1038/ncomms8518
Abstrakt: 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.
Databáze: MEDLINE
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