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Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis
Podoplanin/Aggrus is a sialoglycoprotein expressed in various cancers. We previously identified podoplanin as a key factor in tumor-induced platelet aggregation. Podoplanin-mediated platelet aggregation enhances tumor growth and metastasis by secreting growth factors and by forming tumor emboli in t...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826181/ https://www.ncbi.nlm.nih.gov/pubmed/26684030 http://dx.doi.org/10.18632/oncotarget.6598 |
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author | Sekiguchi, Takaya Takemoto, Ai Takagi, Satoshi Takatori, Kazuki Sato, Shigeo Takami, Miho Fujita, Naoya |
author_facet | Sekiguchi, Takaya Takemoto, Ai Takagi, Satoshi Takatori, Kazuki Sato, Shigeo Takami, Miho Fujita, Naoya |
author_sort | Sekiguchi, Takaya |
collection | PubMed |
description | Podoplanin/Aggrus is a sialoglycoprotein expressed in various cancers. We previously identified podoplanin as a key factor in tumor-induced platelet aggregation. Podoplanin-mediated platelet aggregation enhances tumor growth and metastasis by secreting growth factors and by forming tumor emboli in the microvasculature. Thus, precise analysis of the mechanisms of podoplanin-mediated platelet aggregation is critical for developing anti-tumor therapies. Here we report the discovery of a novel platelet aggregation-inducing domain, PLAG4 (81-EDLPT-85). PLAG4 has high homology to the previously reported PLAG3 and contributes to the binding of its platelet receptor CLEC-2. Mutant analyses indicated that PLAG4 exhibits a predominant platelet-aggregating function relative to PLAG3 and that conserved Glu(81)/Asp(82)/Thr(85) residues in PLAG4 are indispensable for CLEC-2 binding. By establishing anti-PLAG4-neutralizing monoclonal antibodies, we confirmed its role in CLEC-2 binding, platelet aggregation, and tumor emboli formation. Our results suggest the requirement of simultaneous inhibition of PLAG3/4 for complete suppression of podoplanin-mediated tumor growth and metastasis. |
format | Online Article Text |
id | pubmed-4826181 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-48261812016-05-09 Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis Sekiguchi, Takaya Takemoto, Ai Takagi, Satoshi Takatori, Kazuki Sato, Shigeo Takami, Miho Fujita, Naoya Oncotarget Research Paper Podoplanin/Aggrus is a sialoglycoprotein expressed in various cancers. We previously identified podoplanin as a key factor in tumor-induced platelet aggregation. Podoplanin-mediated platelet aggregation enhances tumor growth and metastasis by secreting growth factors and by forming tumor emboli in the microvasculature. Thus, precise analysis of the mechanisms of podoplanin-mediated platelet aggregation is critical for developing anti-tumor therapies. Here we report the discovery of a novel platelet aggregation-inducing domain, PLAG4 (81-EDLPT-85). PLAG4 has high homology to the previously reported PLAG3 and contributes to the binding of its platelet receptor CLEC-2. Mutant analyses indicated that PLAG4 exhibits a predominant platelet-aggregating function relative to PLAG3 and that conserved Glu(81)/Asp(82)/Thr(85) residues in PLAG4 are indispensable for CLEC-2 binding. By establishing anti-PLAG4-neutralizing monoclonal antibodies, we confirmed its role in CLEC-2 binding, platelet aggregation, and tumor emboli formation. Our results suggest the requirement of simultaneous inhibition of PLAG3/4 for complete suppression of podoplanin-mediated tumor growth and metastasis. Impact Journals LLC 2015-12-14 /pmc/articles/PMC4826181/ /pubmed/26684030 http://dx.doi.org/10.18632/oncotarget.6598 Text en Copyright: © 2016 Sekiguchi et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Sekiguchi, Takaya Takemoto, Ai Takagi, Satoshi Takatori, Kazuki Sato, Shigeo Takami, Miho Fujita, Naoya Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis |
title | Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis |
title_full | Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis |
title_fullStr | Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis |
title_full_unstemmed | Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis |
title_short | Targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis |
title_sort | targeting a novel domain in podoplanin for inhibiting platelet-mediated tumor metastasis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826181/ https://www.ncbi.nlm.nih.gov/pubmed/26684030 http://dx.doi.org/10.18632/oncotarget.6598 |
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