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Control of ADAM17 activity by regulation of its cellular localisation
An important, irreversible step in many signalling pathways is the shedding of membrane-anchored proteins. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059621/ https://www.ncbi.nlm.nih.gov/pubmed/27731361 http://dx.doi.org/10.1038/srep35067 |
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author | Lorenzen, Inken Lokau, Juliane Korpys, Yvonne Oldefest, Mirja Flynn, Charlotte M. Künzel, Ulrike Garbers, Christoph Freeman, Matthew Grötzinger, Joachim Düsterhöft, Stefan |
author_facet | Lorenzen, Inken Lokau, Juliane Korpys, Yvonne Oldefest, Mirja Flynn, Charlotte M. Künzel, Ulrike Garbers, Christoph Freeman, Matthew Grötzinger, Joachim Düsterhöft, Stefan |
author_sort | Lorenzen, Inken |
collection | PubMed |
description | An important, irreversible step in many signalling pathways is the shedding of membrane-anchored proteins. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. This central role in signalling implies that ADAM17 activity has to be tightly regulated, including at the level of localisation. Most mature ADAM17 is localised intracellularly, with only a small amount at the cell surface. We found that ADAM17 is constitutively internalised by clathrin-coated pits and that physiological stimulators such as GPCR ligands induce ADAM17-mediated shedding, but do not alter the cell-surface abundance of the protease. In contrast, the PKC-activating phorbol ester PMA, often used as a strong inducer of ADAM17, causes not only proteolysis by ADAM17 but also a rapid increase of the mature protease at the cell surface. This is followed by internalisation and subsequent degradation of the protease. Eventually, this leads to a substantial downregulation of mature ADAM17. Our results therefore imply that physiological activation of ADAM17 does not rely on its relocalisation, but that PMA-induced PKC activity drastically dysregulates the localisation of ADAM17. |
format | Online Article Text |
id | pubmed-5059621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50596212016-10-24 Control of ADAM17 activity by regulation of its cellular localisation Lorenzen, Inken Lokau, Juliane Korpys, Yvonne Oldefest, Mirja Flynn, Charlotte M. Künzel, Ulrike Garbers, Christoph Freeman, Matthew Grötzinger, Joachim Düsterhöft, Stefan Sci Rep Article An important, irreversible step in many signalling pathways is the shedding of membrane-anchored proteins. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. This central role in signalling implies that ADAM17 activity has to be tightly regulated, including at the level of localisation. Most mature ADAM17 is localised intracellularly, with only a small amount at the cell surface. We found that ADAM17 is constitutively internalised by clathrin-coated pits and that physiological stimulators such as GPCR ligands induce ADAM17-mediated shedding, but do not alter the cell-surface abundance of the protease. In contrast, the PKC-activating phorbol ester PMA, often used as a strong inducer of ADAM17, causes not only proteolysis by ADAM17 but also a rapid increase of the mature protease at the cell surface. This is followed by internalisation and subsequent degradation of the protease. Eventually, this leads to a substantial downregulation of mature ADAM17. Our results therefore imply that physiological activation of ADAM17 does not rely on its relocalisation, but that PMA-induced PKC activity drastically dysregulates the localisation of ADAM17. Nature Publishing Group 2016-10-12 /pmc/articles/PMC5059621/ /pubmed/27731361 http://dx.doi.org/10.1038/srep35067 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Lorenzen, Inken Lokau, Juliane Korpys, Yvonne Oldefest, Mirja Flynn, Charlotte M. Künzel, Ulrike Garbers, Christoph Freeman, Matthew Grötzinger, Joachim Düsterhöft, Stefan Control of ADAM17 activity by regulation of its cellular localisation |
title | Control of ADAM17 activity by regulation of its cellular localisation |
title_full | Control of ADAM17 activity by regulation of its cellular localisation |
title_fullStr | Control of ADAM17 activity by regulation of its cellular localisation |
title_full_unstemmed | Control of ADAM17 activity by regulation of its cellular localisation |
title_short | Control of ADAM17 activity by regulation of its cellular localisation |
title_sort | control of adam17 activity by regulation of its cellular localisation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059621/ https://www.ncbi.nlm.nih.gov/pubmed/27731361 http://dx.doi.org/10.1038/srep35067 |
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