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The structural network of Interleukin-10 and its implications in inflammation and cancer
BACKGROUND: Inflammation has significant roles in all phases of tumor development, including initiation, progression and metastasis. Interleukin-10 (IL-10) is a well-known immuno-modulatory cytokine with an anti-inflammatory activity. Lack of IL-10 allows induction of pro-inflammatory cytokines and...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083408/ https://www.ncbi.nlm.nih.gov/pubmed/25056661 http://dx.doi.org/10.1186/1471-2164-15-S4-S2 |
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author | Acuner-Ozbabacan, Ece Saliha Engin, Billur Hatice Guven-Maiorov, Emine Kuzu, Guray Muratcioglu, Serena Baspinar, Alper Chen, Zhong Van Waes, Carter Gursoy, Attila Keskin, Ozlem Nussinov, Ruth |
author_facet | Acuner-Ozbabacan, Ece Saliha Engin, Billur Hatice Guven-Maiorov, Emine Kuzu, Guray Muratcioglu, Serena Baspinar, Alper Chen, Zhong Van Waes, Carter Gursoy, Attila Keskin, Ozlem Nussinov, Ruth |
author_sort | Acuner-Ozbabacan, Ece Saliha |
collection | PubMed |
description | BACKGROUND: Inflammation has significant roles in all phases of tumor development, including initiation, progression and metastasis. Interleukin-10 (IL-10) is a well-known immuno-modulatory cytokine with an anti-inflammatory activity. Lack of IL-10 allows induction of pro-inflammatory cytokines and hinders anti-tumor immunity, thereby favoring tumor growth. The IL-10 network is among the most important paths linking cancer and inflammation. The simple node-and-edge network representation is useful, but limited, hampering the understanding of the mechanistic details of signaling pathways. Structural networks complete the missing parts, and provide details. The IL-10 structural network may shed light on the mechanisms through which disease-related mutations work and the pathogenesis of malignancies. RESULTS: Using PRISM (a PRotein Interactions by Structural Matching tool), we constructed the structural network of IL-10, which includes its first and second degree protein neighbor interactions. We predicted the structures of complexes involved in these interactions, thereby enriching the available structural data. In order to reveal the significance of the interactions, we exploited mutations identified in cancer patients, mapping them onto key proteins of this network. We analyzed the effect of these mutations on the interactions, and demonstrated a relation between these and inflammation and cancer. Our results suggest that mutations that disrupt the interactions of IL-10 with its receptors (IL-10RA and IL-10RB) and α2-macroglobulin (A2M) may enhance inflammation and modulate anti-tumor immunity. Likewise, mutations that weaken the A2M-APP (amyloid precursor protein) association may increase the proliferative effect of APP through preventing β-amyloid degradation by the A2M receptor, and mutations that abolish the A2M-Kallikrein-13 (KLK13) interaction may lead to cell proliferation and metastasis through the destructive effect of KLK13 on the extracellular matrix. CONCLUSIONS: Prediction of protein-protein interactions through structural matching can enrich the available cellular pathways. In addition, the structural data of protein complexes suggest how oncogenic mutations influence the interactions and explain their potential impact on IL-10 signaling in cancer and inflammation. |
format | Online Article Text |
id | pubmed-4083408 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-40834082014-07-18 The structural network of Interleukin-10 and its implications in inflammation and cancer Acuner-Ozbabacan, Ece Saliha Engin, Billur Hatice Guven-Maiorov, Emine Kuzu, Guray Muratcioglu, Serena Baspinar, Alper Chen, Zhong Van Waes, Carter Gursoy, Attila Keskin, Ozlem Nussinov, Ruth BMC Genomics Research BACKGROUND: Inflammation has significant roles in all phases of tumor development, including initiation, progression and metastasis. Interleukin-10 (IL-10) is a well-known immuno-modulatory cytokine with an anti-inflammatory activity. Lack of IL-10 allows induction of pro-inflammatory cytokines and hinders anti-tumor immunity, thereby favoring tumor growth. The IL-10 network is among the most important paths linking cancer and inflammation. The simple node-and-edge network representation is useful, but limited, hampering the understanding of the mechanistic details of signaling pathways. Structural networks complete the missing parts, and provide details. The IL-10 structural network may shed light on the mechanisms through which disease-related mutations work and the pathogenesis of malignancies. RESULTS: Using PRISM (a PRotein Interactions by Structural Matching tool), we constructed the structural network of IL-10, which includes its first and second degree protein neighbor interactions. We predicted the structures of complexes involved in these interactions, thereby enriching the available structural data. In order to reveal the significance of the interactions, we exploited mutations identified in cancer patients, mapping them onto key proteins of this network. We analyzed the effect of these mutations on the interactions, and demonstrated a relation between these and inflammation and cancer. Our results suggest that mutations that disrupt the interactions of IL-10 with its receptors (IL-10RA and IL-10RB) and α2-macroglobulin (A2M) may enhance inflammation and modulate anti-tumor immunity. Likewise, mutations that weaken the A2M-APP (amyloid precursor protein) association may increase the proliferative effect of APP through preventing β-amyloid degradation by the A2M receptor, and mutations that abolish the A2M-Kallikrein-13 (KLK13) interaction may lead to cell proliferation and metastasis through the destructive effect of KLK13 on the extracellular matrix. CONCLUSIONS: Prediction of protein-protein interactions through structural matching can enrich the available cellular pathways. In addition, the structural data of protein complexes suggest how oncogenic mutations influence the interactions and explain their potential impact on IL-10 signaling in cancer and inflammation. BioMed Central 2014-05-20 /pmc/articles/PMC4083408/ /pubmed/25056661 http://dx.doi.org/10.1186/1471-2164-15-S4-S2 Text en Copyright © 2014 Acuner-Ozbabacan 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 cited. 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 Acuner-Ozbabacan, Ece Saliha Engin, Billur Hatice Guven-Maiorov, Emine Kuzu, Guray Muratcioglu, Serena Baspinar, Alper Chen, Zhong Van Waes, Carter Gursoy, Attila Keskin, Ozlem Nussinov, Ruth The structural network of Interleukin-10 and its implications in inflammation and cancer |
title | The structural network of Interleukin-10 and its implications in inflammation and cancer |
title_full | The structural network of Interleukin-10 and its implications in inflammation and cancer |
title_fullStr | The structural network of Interleukin-10 and its implications in inflammation and cancer |
title_full_unstemmed | The structural network of Interleukin-10 and its implications in inflammation and cancer |
title_short | The structural network of Interleukin-10 and its implications in inflammation and cancer |
title_sort | structural network of interleukin-10 and its implications in inflammation and cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083408/ https://www.ncbi.nlm.nih.gov/pubmed/25056661 http://dx.doi.org/10.1186/1471-2164-15-S4-S2 |
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