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Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1
Helicobacter pylori strains carrying the cagA gene are associated with severe disease outcomes, most notably gastric cancer. CagA protein is delivered into gastric epithelial cells by a type IV secretion system. The translocated CagA undergoes tyrosine phosphorylation at the C-terminal EPIYA motifs...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317943/ https://www.ncbi.nlm.nih.gov/pubmed/24354359 http://dx.doi.org/10.1111/cas.12342 |
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author | Hashi, Kana Murata-Kamiya, Naoko Varon, Christine Mégraud, Francis Dominguez-Bello, Maria Gloria Hatakeyama, Masanori |
author_facet | Hashi, Kana Murata-Kamiya, Naoko Varon, Christine Mégraud, Francis Dominguez-Bello, Maria Gloria Hatakeyama, Masanori |
author_sort | Hashi, Kana |
collection | PubMed |
description | Helicobacter pylori strains carrying the cagA gene are associated with severe disease outcomes, most notably gastric cancer. CagA protein is delivered into gastric epithelial cells by a type IV secretion system. The translocated CagA undergoes tyrosine phosphorylation at the C-terminal EPIYA motifs by host cell kinases. Tyrosine-phosphorylated CagA acquires the ability to interact with and activate SHP2, thereby activating mitogenic signaling and inducing cell morphological transformation (hummingbird phenotype). CagA also interacts with PAR1b via the CM sequence, resulting in induction of junctional and polarity defects. Furthermore, CagA-PAR1b interaction stabilizes the CagA-SHP2 complex. Because transgenic mice systemically expressing CagA develop gastrointestinal and hematological malignancies, CagA is recognized as a bacterium-derived oncoprotein. Interestingly, the C-terminal region of CagA displays a large diversity among H. pylori strains, which influences the ability of CagA to bind to SHP2 and PAR1b. In the present study, we investigated the biological activity of v225d CagA, an Amerindian CagA of H. pylori isolated from a Venezuelan Piaroa Amerindian subject, because the variant CagA does not possess a canonical CM sequence. We found that v225d CagA interacts with SHP2 but not PAR1b. Furthermore, SHP2-binding activity of v225d CagA was much lower than that of CagA of H. pylori isolated from Western countries (Western CagA). v225d CagA also displayed a reduced ability to induce the hummingbird phenotype than that of Western CagA. Given that perturbation of PAR1b and SHP2 by CagA underlies the oncogenic potential of CagA, the v225d strain is considered to be less oncogenic than other well-studied cagA-positive H. pylori strains. |
format | Online Article Text |
id | pubmed-4317943 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-43179432015-10-05 Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1 Hashi, Kana Murata-Kamiya, Naoko Varon, Christine Mégraud, Francis Dominguez-Bello, Maria Gloria Hatakeyama, Masanori Cancer Sci Original Articles Helicobacter pylori strains carrying the cagA gene are associated with severe disease outcomes, most notably gastric cancer. CagA protein is delivered into gastric epithelial cells by a type IV secretion system. The translocated CagA undergoes tyrosine phosphorylation at the C-terminal EPIYA motifs by host cell kinases. Tyrosine-phosphorylated CagA acquires the ability to interact with and activate SHP2, thereby activating mitogenic signaling and inducing cell morphological transformation (hummingbird phenotype). CagA also interacts with PAR1b via the CM sequence, resulting in induction of junctional and polarity defects. Furthermore, CagA-PAR1b interaction stabilizes the CagA-SHP2 complex. Because transgenic mice systemically expressing CagA develop gastrointestinal and hematological malignancies, CagA is recognized as a bacterium-derived oncoprotein. Interestingly, the C-terminal region of CagA displays a large diversity among H. pylori strains, which influences the ability of CagA to bind to SHP2 and PAR1b. In the present study, we investigated the biological activity of v225d CagA, an Amerindian CagA of H. pylori isolated from a Venezuelan Piaroa Amerindian subject, because the variant CagA does not possess a canonical CM sequence. We found that v225d CagA interacts with SHP2 but not PAR1b. Furthermore, SHP2-binding activity of v225d CagA was much lower than that of CagA of H. pylori isolated from Western countries (Western CagA). v225d CagA also displayed a reduced ability to induce the hummingbird phenotype than that of Western CagA. Given that perturbation of PAR1b and SHP2 by CagA underlies the oncogenic potential of CagA, the v225d strain is considered to be less oncogenic than other well-studied cagA-positive H. pylori strains. BlackWell Publishing Ltd 2014-03 2014-02-12 /pmc/articles/PMC4317943/ /pubmed/24354359 http://dx.doi.org/10.1111/cas.12342 Text en © 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Hashi, Kana Murata-Kamiya, Naoko Varon, Christine Mégraud, Francis Dominguez-Bello, Maria Gloria Hatakeyama, Masanori Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1 |
title | Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1 |
title_full | Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1 |
title_fullStr | Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1 |
title_full_unstemmed | Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1 |
title_short | Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1 |
title_sort | natural variant of the helicobacter pylori caga oncoprotein that lost the ability to interact with par1 |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317943/ https://www.ncbi.nlm.nih.gov/pubmed/24354359 http://dx.doi.org/10.1111/cas.12342 |
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