Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms8518
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Funding
- University of Copenhagen Faculty of Health and Medical Sciences
- Cancer Research UK
- NIH [R01 CA151564]
- Swedish Brain Foundation
- Aase og Ejnar Danielsens Fond
- Snedkermester Sophus Jacobsen og hustru Astrid Jacobsens Fond
- Fru Astrid Thaysens Legat for Laegevidenskabelig Grundforskning
- Kjaer Fonden
- Civilingenior Bent Bogh og hustru Inge Boghs Fond
- Frimodt-Heineke Fonden
- Horslev Fonden
- Laege Sophus Carl Emil Friis og hustru Olga Doris Friis' Legat
- Danish Cancer Society
- Cancer Research UK [15683] Funding Source: researchfish
- The Danish Cancer Society [R90-A5919] Funding Source: researchfish
- The Francis Crick Institute [10130, 10008] Funding Source: researchfish
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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.
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