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Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IR(A) axis in malignant mesothelioma

Malignant mesothelioma is a deadly disease with limited therapeutic options. EphB4 is an oncogenic tyrosine kinase receptor expressed in malignant mesothelioma as well as in a variety of cancers. It is involved in tumor microenvironment mediating angiogenesis and invasive cellular effects via both E...

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Autores principales: Scalia, Pierluigi, Pandini, Giuseppe, Carnevale, Vincenzo, Giordano, Antonio, Williams, Stephen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075896/
https://www.ncbi.nlm.nih.gov/pubmed/31270394
http://dx.doi.org/10.1038/s41388-019-0854-y
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author Scalia, Pierluigi
Pandini, Giuseppe
Carnevale, Vincenzo
Giordano, Antonio
Williams, Stephen J.
author_facet Scalia, Pierluigi
Pandini, Giuseppe
Carnevale, Vincenzo
Giordano, Antonio
Williams, Stephen J.
author_sort Scalia, Pierluigi
collection PubMed
description Malignant mesothelioma is a deadly disease with limited therapeutic options. EphB4 is an oncogenic tyrosine kinase receptor expressed in malignant mesothelioma as well as in a variety of cancers. It is involved in tumor microenvironment mediating angiogenesis and invasive cellular effects via both EphrinB2 ligand-dependent and independent mechanisms. The molecular network underlying EphB4 oncogenic effects is still unclear. Here we show that EphB4 expression in malignant mesothelioma cells is markedly decreased upon neutralization of cancer-secreted IGF-II. In particular, we demonstrate that EphB4 protein expression in malignant mesothelioma cells depend upon a degradation rescue mechanism controlled by the autocrine IGF-II-insulin receptor-A specific signaling axis. We show that the regulation of EphB4 expression is linked to a competing post-translational modification of its carboxy-terminal tail via phosphorylation of its tyrosine 987 by the Insulin receptor isoform-A kinase-associated activity in response to the autocrine IGF-II stimuli. Neutralization of this autocrine-induced EphB4-phosphorylation by IGF-II associates with the increased ubiquitination of EphB4 carboxy-terminal tail and with its rapid degradation. We also describe a novel Ubiquitin binding motif in the targeted region as part of the identified EphB4 phosphodegron and provide 3D modeling data supporting a possible model for the acute EphB4 PTM-driven regulation by IGF-II. Altogether, these findings disclose a novel molecular mechanism for the maintenance of EphB4-expression in malignant mesothelioma cells and other IGF-II-secreting cancers (IGF2omas).
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spelling pubmed-80758962021-05-06 Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IR(A) axis in malignant mesothelioma Scalia, Pierluigi Pandini, Giuseppe Carnevale, Vincenzo Giordano, Antonio Williams, Stephen J. Oncogene Article Malignant mesothelioma is a deadly disease with limited therapeutic options. EphB4 is an oncogenic tyrosine kinase receptor expressed in malignant mesothelioma as well as in a variety of cancers. It is involved in tumor microenvironment mediating angiogenesis and invasive cellular effects via both EphrinB2 ligand-dependent and independent mechanisms. The molecular network underlying EphB4 oncogenic effects is still unclear. Here we show that EphB4 expression in malignant mesothelioma cells is markedly decreased upon neutralization of cancer-secreted IGF-II. In particular, we demonstrate that EphB4 protein expression in malignant mesothelioma cells depend upon a degradation rescue mechanism controlled by the autocrine IGF-II-insulin receptor-A specific signaling axis. We show that the regulation of EphB4 expression is linked to a competing post-translational modification of its carboxy-terminal tail via phosphorylation of its tyrosine 987 by the Insulin receptor isoform-A kinase-associated activity in response to the autocrine IGF-II stimuli. Neutralization of this autocrine-induced EphB4-phosphorylation by IGF-II associates with the increased ubiquitination of EphB4 carboxy-terminal tail and with its rapid degradation. We also describe a novel Ubiquitin binding motif in the targeted region as part of the identified EphB4 phosphodegron and provide 3D modeling data supporting a possible model for the acute EphB4 PTM-driven regulation by IGF-II. Altogether, these findings disclose a novel molecular mechanism for the maintenance of EphB4-expression in malignant mesothelioma cells and other IGF-II-secreting cancers (IGF2omas). Nature Publishing Group UK 2019-07-03 2019 /pmc/articles/PMC8075896/ /pubmed/31270394 http://dx.doi.org/10.1038/s41388-019-0854-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Scalia, Pierluigi
Pandini, Giuseppe
Carnevale, Vincenzo
Giordano, Antonio
Williams, Stephen J.
Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IR(A) axis in malignant mesothelioma
title Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IR(A) axis in malignant mesothelioma
title_full Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IR(A) axis in malignant mesothelioma
title_fullStr Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IR(A) axis in malignant mesothelioma
title_full_unstemmed Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IR(A) axis in malignant mesothelioma
title_short Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IR(A) axis in malignant mesothelioma
title_sort identification of a novel ephb4 phosphodegron regulated by the autocrine igfii/ir(a) axis in malignant mesothelioma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075896/
https://www.ncbi.nlm.nih.gov/pubmed/31270394
http://dx.doi.org/10.1038/s41388-019-0854-y
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