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Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility

Release of cytokines, growth factors and other life-essential molecules from precursors by a-disintegrin-and-metalloproteases (ADAMs) is regulated with high substrate-specificity. We hypothesized that this is achieved by cleavage-regulatory intracellular-domain (ICD)-modifications of the precursors....

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Autores principales: Parra, Liseth M., Hartmann, Monika, Schubach, Salome, Ma, Junzhi, Herrlich, Peter, Herrlich, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120278/
https://www.ncbi.nlm.nih.gov/pubmed/27876763
http://dx.doi.org/10.1038/srep37464
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author Parra, Liseth M.
Hartmann, Monika
Schubach, Salome
Ma, Junzhi
Herrlich, Peter
Herrlich, Andreas
author_facet Parra, Liseth M.
Hartmann, Monika
Schubach, Salome
Ma, Junzhi
Herrlich, Peter
Herrlich, Andreas
author_sort Parra, Liseth M.
collection PubMed
description Release of cytokines, growth factors and other life-essential molecules from precursors by a-disintegrin-and-metalloproteases (ADAMs) is regulated with high substrate-specificity. We hypothesized that this is achieved by cleavage-regulatory intracellular-domain (ICD)-modifications of the precursors. We show here that cleavage-stimuli-induced specific ICD-modifications cause structural substrate changes that enhance ectodomain sensitivity of neuregulin-1 (NRG1; epidermal-growth-factor) or CD44 (receptor-tyrosine-kinase (RTK) co-receptor) to chymotrypsin/trypsin or soluble ADAM. This inside-out signal transfer required substrate homodimerization and was prevented by cleavage-inhibitory ICD-mutations. In chimeras, regulation could be conferred to a foreign ectodomain, suggesting a common higher-order structure. We predict that substrate-specific protease-accessibility-regulation controls release of numerous ADAM substrates.
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spelling pubmed-51202782016-11-28 Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility Parra, Liseth M. Hartmann, Monika Schubach, Salome Ma, Junzhi Herrlich, Peter Herrlich, Andreas Sci Rep Article Release of cytokines, growth factors and other life-essential molecules from precursors by a-disintegrin-and-metalloproteases (ADAMs) is regulated with high substrate-specificity. We hypothesized that this is achieved by cleavage-regulatory intracellular-domain (ICD)-modifications of the precursors. We show here that cleavage-stimuli-induced specific ICD-modifications cause structural substrate changes that enhance ectodomain sensitivity of neuregulin-1 (NRG1; epidermal-growth-factor) or CD44 (receptor-tyrosine-kinase (RTK) co-receptor) to chymotrypsin/trypsin or soluble ADAM. This inside-out signal transfer required substrate homodimerization and was prevented by cleavage-inhibitory ICD-mutations. In chimeras, regulation could be conferred to a foreign ectodomain, suggesting a common higher-order structure. We predict that substrate-specific protease-accessibility-regulation controls release of numerous ADAM substrates. Nature Publishing Group 2016-11-23 /pmc/articles/PMC5120278/ /pubmed/27876763 http://dx.doi.org/10.1038/srep37464 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
Parra, Liseth M.
Hartmann, Monika
Schubach, Salome
Ma, Junzhi
Herrlich, Peter
Herrlich, Andreas
Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility
title Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility
title_full Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility
title_fullStr Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility
title_full_unstemmed Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility
title_short Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility
title_sort growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120278/
https://www.ncbi.nlm.nih.gov/pubmed/27876763
http://dx.doi.org/10.1038/srep37464
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