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

• DOI: 10.1038/ncomms8518
• Publication Date: 2015-06-25T10:27:03Z
• Authors: Sarah Louise Domb...; Jacob Samsøe-Pete...; Camilla Hansson P...; Rachael Instrell; Anne-Mette Bornha...; Laurel Thomas; Katelyn Mae Atkins; Sylvain Auclair; Reidar Albrechtsen; Kasper Johansen M...; Camilla Fröhlich; Michael Howell; Peter Parker; Gary Thomas; Marie Kveiborg
• Keywords: Enzymologic; ADAM Proteins/genetics; Vesicular Transport Proteins; 610; ADAM17 Protein; Article; Gene Expression Regulation, Enzymologic; Cell Line; Vesicular Transport Proteins/genetics; 12. Responsible consumption; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Oncogene Proteins v-erbB/genetics; 0303 health sciences; Tumor; Signal Transduction/physiology; Oncogene Proteins v-erbB; 540; ADAM Proteins; Gene Expression Regulation; Genome-Wide Association Study; Signal Transduction

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.