title: The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17.
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.
authors.affiliation: Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Sarah Louise
authors.initials: SL
authors.lastname: Dombernowsky
authors.affiliation: Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Samsøe-Petersen
authors.affiliation: Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Camilla Hansson
authors.initials: CH
authors.lastname: Petersen
authors.affiliation: High Throughput Screening Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Instrell
authors.affiliation: Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Anne-Mette Bornhardt
authors.initials: AM
authors.lastname: Hedegaard
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Laurel
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Katelyn Mae
authors.initials: KM
authors.lastname: Atkins
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Auclair
authors.affiliation: Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Reidar
authors.initials: R
authors.lastname: Albrechtsen
authors.affiliation: Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Kasper Johansen
authors.initials: KJ
authors.lastname: Mygind
authors.affiliation: Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Fröhlich
authors.affiliation: High Throughput Screening Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Parker
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Marie
authors.initials: M
authors.lastname: Kveiborg
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D018739:Oncogene Proteins v-erbB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018739:Oncogene Proteins v-erbB; C499638:PACS2 protein, human; C529570:Pacs2 protein, mouse; D033921:Vesicular Transport Proteins; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse