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

Sarah Louise Dombernowsky; Jacob Samsøe-Petersen; Camilla Hansson Petersen; Rachael Instrell; Anne-Mette Bornhardt Hedegaard; Laurel Thomas; Katelyn Mae Atkins; Sylvain Auclair; Reidar Albrechtsen; Kasper Johansen Mygind; Camilla Fröhlich; Michael Howell; Peter Parker; Gary Thomas; Marie Kveiborg

doi:10.1038/ncomms8518

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

Sarah Louise Dombernowsky, Jacob Samsøe-Petersen, Camilla Hansson Petersen, Rachael Instrell, Anne-Mette Bornhardt Hedegaard, Laurel Thomas, Katelyn Mae Atkins, Sylvain Auclair, Reidar Albrechtsen, Kasper Johansen Mygind, Camilla Fröhlich, Michael Howell, Peter Parker, Gary Thomas, Marie Kveiborg

Department of Biomedical Sciences

35 Citations (Scopus)

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.

Original language	English
Article number	7518
Journal	Nature Communications
Volume	6
Pages (from-to)	1-13
Number of pages	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms8518
Publication status	Published - 25 Jun 2015

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Dombernowsky, S. L., Samsøe-Petersen, J., Petersen, C. H., Instrell, R., Hedegaard, A-M. B., Thomas, L., Atkins, K. M., Auclair, S., Albrechtsen, R., Mygind, K. J., Fröhlich, C., Howell, M., Parker, P., Thomas, G., & Kveiborg, M. (2015). The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17. Nature Communications, 6, 1-13. [7518]. https://doi.org/10.1038/ncomms8518

Dombernowsky, SL, Samsøe-Petersen, J, Petersen, CH, Instrell, R, Hedegaard, A-MB, Thomas, L, Atkins, KM, Auclair, S, Albrechtsen, R, Mygind, KJ, Fröhlich, C, Howell, M, Parker, P, Thomas, G & Kveiborg, M 2015, 'The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17', Nature Communications, vol. 6, 7518, pp. 1-13. https://doi.org/10.1038/ncomms8518

@article{a3cf4600a8b2449c83d8d4aa5e211eac,

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.",

author = "Dombernowsky, {Sarah Louise} and Jacob Sams{\o}e-Petersen and Petersen, {Camilla Hansson} and Rachael Instrell and Hedegaard, {Anne-Mette Bornhardt} and Laurel Thomas and Atkins, {Katelyn Mae} and Sylvain Auclair and Reidar Albrechtsen and Mygind, {Kasper Johansen} and Camilla Fr{\"o}hlich and Michael Howell and Peter Parker and Gary Thomas and Marie Kveiborg",

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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 - 2015/6/25

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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

SN - 2041-1723

VL - 6

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

M1 - 7518

ER -

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

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