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Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies

BACKGROUND: Short in-frame deletions in the second extracellular domain of the cytokine receptor gp130 are the leading cause of inflammatory hepatocellular adenomas (IHCAs). The deletions render gp130 constitutively active. In this study we investigate the intracellular signaling potential of one of...

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Autores principales: Rinis, Natalie, Küster, Andrea, Schmitz-Van de Leur, Hildegard, Mohr, Anne, Müller-Newen, Gerhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007646/
https://www.ncbi.nlm.nih.gov/pubmed/24612692
http://dx.doi.org/10.1186/1478-811X-12-14
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author Rinis, Natalie
Küster, Andrea
Schmitz-Van de Leur, Hildegard
Mohr, Anne
Müller-Newen, Gerhard
author_facet Rinis, Natalie
Küster, Andrea
Schmitz-Van de Leur, Hildegard
Mohr, Anne
Müller-Newen, Gerhard
author_sort Rinis, Natalie
collection PubMed
description BACKGROUND: Short in-frame deletions in the second extracellular domain of the cytokine receptor gp130 are the leading cause of inflammatory hepatocellular adenomas (IHCAs). The deletions render gp130 constitutively active. In this study we investigate the intracellular signaling potential of one of the most potent constitutively active gp130 mutants (CAgp130) found in IHCAs. RESULTS: Trafficking and signaling of CAgp130 were studied in stably transfected cell lines that allowed the inducible expression of CAgp130 fused to fluorescent proteins such as YFP and mCherry. In contrast to the predominantly highly glycosylated gp130 wild type (WTgp130), CAgp130 is preferentially found in the less glycosylated high-mannose form. Accordingly, the mutated receptor is retained intracellularly and therefore less prominently expressed at the cell surface. CAgp130 persistently activates Stat3 despite the presence of the feedback inhibitor SOCS3 but fails to activate Erk1/2. De novo synthesized CAgp130 signals already from the ER-Golgi compartment before having reached the plasma membrane. Cell surface expressed and endocytosed CAgp130 do not significantly contribute to signaling. As a consequence, Stat3 activation through CAgp130 cannot be inhibited by neutralizing gp130 antibodies but through overexpression of a dominant-negative Stat3 mutant. CONCLUSION: CAgp130 and WTgp130 differ significantly with respect to glycosylation, trafficking and signaling. As a consequence of intracellular signaling pharmacological inhibition of CAgp130 will not be achieved by targeting the receptor extracellularly but by compounds that act from within the cell.
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spelling pubmed-40076462014-05-03 Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies Rinis, Natalie Küster, Andrea Schmitz-Van de Leur, Hildegard Mohr, Anne Müller-Newen, Gerhard Cell Commun Signal Research BACKGROUND: Short in-frame deletions in the second extracellular domain of the cytokine receptor gp130 are the leading cause of inflammatory hepatocellular adenomas (IHCAs). The deletions render gp130 constitutively active. In this study we investigate the intracellular signaling potential of one of the most potent constitutively active gp130 mutants (CAgp130) found in IHCAs. RESULTS: Trafficking and signaling of CAgp130 were studied in stably transfected cell lines that allowed the inducible expression of CAgp130 fused to fluorescent proteins such as YFP and mCherry. In contrast to the predominantly highly glycosylated gp130 wild type (WTgp130), CAgp130 is preferentially found in the less glycosylated high-mannose form. Accordingly, the mutated receptor is retained intracellularly and therefore less prominently expressed at the cell surface. CAgp130 persistently activates Stat3 despite the presence of the feedback inhibitor SOCS3 but fails to activate Erk1/2. De novo synthesized CAgp130 signals already from the ER-Golgi compartment before having reached the plasma membrane. Cell surface expressed and endocytosed CAgp130 do not significantly contribute to signaling. As a consequence, Stat3 activation through CAgp130 cannot be inhibited by neutralizing gp130 antibodies but through overexpression of a dominant-negative Stat3 mutant. CONCLUSION: CAgp130 and WTgp130 differ significantly with respect to glycosylation, trafficking and signaling. As a consequence of intracellular signaling pharmacological inhibition of CAgp130 will not be achieved by targeting the receptor extracellularly but by compounds that act from within the cell. BioMed Central 2014-03-10 /pmc/articles/PMC4007646/ /pubmed/24612692 http://dx.doi.org/10.1186/1478-811X-12-14 Text en Copyright © 2014 Rinis et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Rinis, Natalie
Küster, Andrea
Schmitz-Van de Leur, Hildegard
Mohr, Anne
Müller-Newen, Gerhard
Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies
title Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies
title_full Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies
title_fullStr Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies
title_full_unstemmed Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies
title_short Intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies
title_sort intracellular signaling prevents effective blockade of oncogenic gp130 mutants by neutralizing antibodies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007646/
https://www.ncbi.nlm.nih.gov/pubmed/24612692
http://dx.doi.org/10.1186/1478-811X-12-14
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