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...

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Autores principales:	Peter W Janes, Sabine H Wimmer-Kleikamp, Achilleas S Frangakis, Kane Treble, Bettina Griesshaber, Ola Sabet, Markus Grabenbauer, Alice Y Ting, Paul Saftig, Philippe I Bastiaens, Martin Lackmann
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/208a197eb2a04790bf321370e02d3201
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spelling	oai:doaj.org-article:208a197eb2a04790bf321370e02d32012021-11-25T05:34:32ZCytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10.1544-91731545-788510.1371/journal.pbio.1000215https://doaj.org/article/208a197eb2a04790bf321370e02d32012009-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19823572/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Release 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.Peter W JanesSabine H Wimmer-KleikampAchilleas S FrangakisKane TrebleBettina GriesshaberOla SabetMarkus GrabenbauerAlice Y TingPaul SaftigPhilippe I BastiaensMartin LackmannPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 7, Iss 10, p e1000215 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Peter W Janes Sabine H Wimmer-Kleikamp Achilleas S Frangakis Kane Treble Bettina Griesshaber Ola Sabet Markus Grabenbauer Alice Y Ting Paul Saftig Philippe I Bastiaens Martin Lackmann Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10.
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.
format	article
author	Peter W Janes Sabine H Wimmer-Kleikamp Achilleas S Frangakis Kane Treble Bettina Griesshaber Ola Sabet Markus Grabenbauer Alice Y Ting Paul Saftig Philippe I Bastiaens Martin Lackmann
author_facet	Peter W Janes Sabine H Wimmer-Kleikamp Achilleas S Frangakis Kane Treble Bettina Griesshaber Ola Sabet Markus Grabenbauer Alice Y Ting Paul Saftig Philippe I Bastiaens Martin Lackmann
author_sort	Peter W Janes
title	Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10.
title_short	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_sort	cytoplasmic relaxation of active eph controls ephrin shedding by adam10.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/208a197eb2a04790bf321370e02d3201
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Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10.

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