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

Comprehensive Cancer Centre

Department of Biomedical Sciences &Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, 2200 Copenhagen N, Denmark.
Francis Crick Institute
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 507 Bridgeside Point II, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, USA.
Oregon Health & Science University

Research output: Contribution to journal › Article › peer-review

45 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
Number of pages	13
Journal	Nature Communications
Volume	6
Issue number	1
Early online date	25 Jun 2015
DOIs	https://doi.org/10.1038/ncomms8518
Publication status	Published - 25 Jun 2015

Keywords

ADAM Proteins/genetics
ADAM17 Protein
Animals
Cell Line, Tumor
Gene Expression Regulation, Enzymologic
Genome-Wide Association Study
Humans
Mice
Oncogene Proteins v-erbB/genetics
Signal Transduction/physiology
Vesicular Transport Proteins/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms8518

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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), Article 7518. https://doi.org/10.1038/ncomms8518

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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. ",

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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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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, no. 1, 7518. https://doi.org/10.1038/ncomms8518

TY - JOUR

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 - 2015/6/25

Y1 - 2015/6/25

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.

KW - ADAM Proteins/genetics

KW - ADAM17 Protein

KW - Animals

KW - Cell Line, Tumor

KW - Gene Expression Regulation, Enzymologic

KW - Genome-Wide Association Study

KW - Humans

KW - Mice

KW - Oncogene Proteins v-erbB/genetics

KW - Signal Transduction/physiology

KW - Vesicular Transport Proteins/genetics

U2 - 10.1038/ncomms8518

DO - 10.1038/ncomms8518

M3 - Article

C2 - 26108729

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7518

ER -

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

Abstract

Keywords

UN SDGs

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