The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17
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The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17. / Dombernowsky, Sarah Louise; Samsøe-Petersen, Jacob; Petersen, Camilla Hansson; Instrell, Rachael; Hedegaard, Anne-Mette Bornhardt; Thomas, Laurel; Atkins, Katelyn Mae; Auclair, Sylvain; Albrechtsen, Reidar; Mygind, Kasper Johansen; Fröhlich, Camilla; Howell, Michael; Parker, Peter; Thomas, Gary; Kveiborg, Marie.
In: Nature Communications, Vol. 6, 7518, 2015, p. 1-13.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17
AU - Dombernowsky, Sarah Louise
AU - Samsøe-Petersen, Jacob
AU - Petersen, Camilla Hansson
AU - Instrell, Rachael
AU - Hedegaard, Anne-Mette Bornhardt
AU - Thomas, Laurel
AU - Atkins, Katelyn Mae
AU - Auclair, Sylvain
AU - Albrechtsen, Reidar
AU - Mygind, Kasper Johansen
AU - Fröhlich, Camilla
AU - Howell, Michael
AU - Parker, Peter
AU - Thomas, Gary
AU - Kveiborg, Marie
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms8518
DO - 10.1038/ncomms8518
M3 - Journal article
C2 - 26108729
VL - 6
SP - 1
EP - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 7518
ER -
ID: 141030965