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DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur

Cleavage of Notch by furin is required to generate a mature, cell surface heterodimeric receptor that can be proteolytically activated to release its intracellular domain, which functions in signal transduction. Current models propose that ligand binding to heterodimeric Notch (hNotch) induces a dis...

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Autores principales: Nichols, James T., Miyamoto, Alison, Olsen, Samantha L., D'Souza, Brendan, Yao, Christine, Weinmaster, Gerry
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063980/
https://www.ncbi.nlm.nih.gov/pubmed/17296795
http://dx.doi.org/10.1083/jcb.200609014
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author Nichols, James T.
Miyamoto, Alison
Olsen, Samantha L.
D'Souza, Brendan
Yao, Christine
Weinmaster, Gerry
author_facet Nichols, James T.
Miyamoto, Alison
Olsen, Samantha L.
D'Souza, Brendan
Yao, Christine
Weinmaster, Gerry
author_sort Nichols, James T.
collection PubMed
description Cleavage of Notch by furin is required to generate a mature, cell surface heterodimeric receptor that can be proteolytically activated to release its intracellular domain, which functions in signal transduction. Current models propose that ligand binding to heterodimeric Notch (hNotch) induces a disintegrin and metalloprotease (ADAM) proteolytic release of the Notch extracellular domain (NECD), which is subsequently shed and/or endocytosed by DSL ligand cells. We provide evidence for NECD release and internalization by DSL ligand cells, which, surprisingly, did not require ADAM activity. However, losses in either hNotch formation or ligand endocytosis significantly decreased NECD transfer to DSL ligand cells, as well as signaling in Notch cells. Because endocytosis-defective ligands bind hNotch, but do not dissociate it, additional forces beyond those produced through ligand binding must function to disrupt the intramolecular interactions that keep hNotch intact and inactive. Based on our findings, we propose that mechanical forces generated during DSL ligand endocytosis function to physically dissociate hNotch, and that dissociation is a necessary step in Notch activation.
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spelling pubmed-20639802007-11-29 DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur Nichols, James T. Miyamoto, Alison Olsen, Samantha L. D'Souza, Brendan Yao, Christine Weinmaster, Gerry J Cell Biol Research Articles Cleavage of Notch by furin is required to generate a mature, cell surface heterodimeric receptor that can be proteolytically activated to release its intracellular domain, which functions in signal transduction. Current models propose that ligand binding to heterodimeric Notch (hNotch) induces a disintegrin and metalloprotease (ADAM) proteolytic release of the Notch extracellular domain (NECD), which is subsequently shed and/or endocytosed by DSL ligand cells. We provide evidence for NECD release and internalization by DSL ligand cells, which, surprisingly, did not require ADAM activity. However, losses in either hNotch formation or ligand endocytosis significantly decreased NECD transfer to DSL ligand cells, as well as signaling in Notch cells. Because endocytosis-defective ligands bind hNotch, but do not dissociate it, additional forces beyond those produced through ligand binding must function to disrupt the intramolecular interactions that keep hNotch intact and inactive. Based on our findings, we propose that mechanical forces generated during DSL ligand endocytosis function to physically dissociate hNotch, and that dissociation is a necessary step in Notch activation. The Rockefeller University Press 2007-02-12 /pmc/articles/PMC2063980/ /pubmed/17296795 http://dx.doi.org/10.1083/jcb.200609014 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Nichols, James T.
Miyamoto, Alison
Olsen, Samantha L.
D'Souza, Brendan
Yao, Christine
Weinmaster, Gerry
DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur
title DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur
title_full DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur
title_fullStr DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur
title_full_unstemmed DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur
title_short DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur
title_sort dsl ligand endocytosis physically dissociates notch1 heterodimers before activating proteolysis can occur
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063980/
https://www.ncbi.nlm.nih.gov/pubmed/17296795
http://dx.doi.org/10.1083/jcb.200609014
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