Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10
Release of cell surface-bound ligands by A-Disintegrin-And-Metalloprotease (ADAM) transmembrane metalloproteases is essential for signalling by cytokine, cell adhesion, and tyrosine kinase receptors. For Eph receptor ligands, it provides the switch between cell-cell adhesion and repulsion. Ligand sh...
| Main Authors: | , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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Public Library of Science
2010
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| Online Access: | http://hdl.handle.net/1721.1/52586 https://orcid.org/0000-0002-8277-5226 |
| _version_ | 1811072185728499712 |
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| author | Janes, Peter W. Wimmer-Kleikamp, Sabine H. Frangakis, Achilleas S. Treble, Kane Griensshaber, Bettina Sabet, Ola Grabenbauer, Markus Ting, Alice Y. Saftig, Paul Bastiaens, Philippe I. Lackmann, Martin |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Janes, Peter W. Wimmer-Kleikamp, Sabine H. Frangakis, Achilleas S. Treble, Kane Griensshaber, Bettina Sabet, Ola Grabenbauer, Markus Ting, Alice Y. Saftig, Paul Bastiaens, Philippe I. Lackmann, Martin |
| author_sort | Janes, Peter W. |
| collection | MIT |
| description | Release of cell surface-bound ligands by A-Disintegrin-And-Metalloprotease (ADAM) transmembrane metalloproteases is essential for signalling by cytokine, cell adhesion, and tyrosine kinase receptors. For Eph receptor ligands, it provides the switch between cell-cell adhesion and repulsion. Ligand shedding is tightly controlled by intrinsic tyrosine kinase activity, which for Eph receptors relies on the release of an inhibitory interaction of the cytoplasmic juxtamembrane segment with the kinase domain. However, a mechanism linking kinase and sheddase activities had remained elusive. We demonstrate that it is a membrane-proximal localisation of the latent kinase domain that prevents ephrin ligand shedding in trans. Fluorescence lifetime imaging microscopy and electron tomography reveal that activation extends the Eph receptor tyrosine kinase intracellular domain away from the cell membrane into a conformation that facilitates productive association with ADAM10. Accordingly, EphA3 mutants with constitutively-released kinase domains efficiently support shedding, even when their kinase is disabled. Our data suggest that this phosphorylation-activated conformational switch of EphA3 directly controls ADAM-mediated shedding. |
| first_indexed | 2024-09-23T09:01:58Z |
| format | Article |
| id | mit-1721.1/52586 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:01:58Z |
| publishDate | 2010 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/525862022-09-26T09:58:30Z Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10 Janes, Peter W. Wimmer-Kleikamp, Sabine H. Frangakis, Achilleas S. Treble, Kane Griensshaber, Bettina Sabet, Ola Grabenbauer, Markus Ting, Alice Y. Saftig, Paul Bastiaens, Philippe I. Lackmann, Martin Massachusetts Institute of Technology. Department of Chemistry Ting, Alice Y. Ting, Alice Y. Release of cell surface-bound ligands by A-Disintegrin-And-Metalloprotease (ADAM) transmembrane metalloproteases is essential for signalling by cytokine, cell adhesion, and tyrosine kinase receptors. For Eph receptor ligands, it provides the switch between cell-cell adhesion and repulsion. Ligand shedding is tightly controlled by intrinsic tyrosine kinase activity, which for Eph receptors relies on the release of an inhibitory interaction of the cytoplasmic juxtamembrane segment with the kinase domain. However, a mechanism linking kinase and sheddase activities had remained elusive. We demonstrate that it is a membrane-proximal localisation of the latent kinase domain that prevents ephrin ligand shedding in trans. Fluorescence lifetime imaging microscopy and electron tomography reveal that activation extends the Eph receptor tyrosine kinase intracellular domain away from the cell membrane into a conformation that facilitates productive association with ADAM10. Accordingly, EphA3 mutants with constitutively-released kinase domains efficiently support shedding, even when their kinase is disabled. Our data suggest that this phosphorylation-activated conformational switch of EphA3 directly controls ADAM-mediated shedding. National Health and Medical Research Council (grants 234707 and 384242) 2010-03-15T18:02:10Z 2010-03-15T18:02:10Z 2009-10 2009-03 Article http://purl.org/eprint/type/JournalArticle 1544-9173 http://hdl.handle.net/1721.1/52586 Janes, Peter W. et al. “Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10.” PLoS Biol 7.10 (2009): e1000215. 19823572 https://orcid.org/0000-0002-8277-5226 en_US http://dx.doi.org/10.1371/journal.pbio.1000215 PLoS Biology Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Janes, Peter W. Wimmer-Kleikamp, Sabine H. Frangakis, Achilleas S. Treble, Kane Griensshaber, Bettina Sabet, Ola Grabenbauer, Markus Ting, Alice Y. Saftig, Paul Bastiaens, Philippe I. Lackmann, Martin Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10 |
| title | Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10 |
| title_full | Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10 |
| title_fullStr | Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10 |
| title_full_unstemmed | Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10 |
| title_short | Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10 |
| title_sort | cytoplasmic relaxation of active eph controls ephrin shedding by adam10 |
| url | http://hdl.handle.net/1721.1/52586 https://orcid.org/0000-0002-8277-5226 |
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