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Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed
Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386674/ https://www.ncbi.nlm.nih.gov/pubmed/27845895 http://dx.doi.org/10.18632/oncotarget.13268 |
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author | Hsu, Li-Jin Hong, Qunying Chen, Shur-Tzu Kuo, Hsiang-Lin Schultz, Lori Heath, John Lin, Sing-Ru Lee, Ming-Hui Li, Dong-Zhang Li, Zih-Ling Cheng, Hui-Ching Armand, Gerard Chang, Nan-Shan |
author_facet | Hsu, Li-Jin Hong, Qunying Chen, Shur-Tzu Kuo, Hsiang-Lin Schultz, Lori Heath, John Lin, Sing-Ru Lee, Ming-Hui Li, Dong-Zhang Li, Zih-Ling Cheng, Hui-Ching Armand, Gerard Chang, Nan-Shan |
author_sort | Hsu, Li-Jin |
collection | PubMed |
description | Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed. |
format | Online Article Text |
id | pubmed-5386674 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53866742017-04-26 Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed Hsu, Li-Jin Hong, Qunying Chen, Shur-Tzu Kuo, Hsiang-Lin Schultz, Lori Heath, John Lin, Sing-Ru Lee, Ming-Hui Li, Dong-Zhang Li, Zih-Ling Cheng, Hui-Ching Armand, Gerard Chang, Nan-Shan Oncotarget Research Paper Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed. Impact Journals LLC 2016-11-10 /pmc/articles/PMC5386674/ /pubmed/27845895 http://dx.doi.org/10.18632/oncotarget.13268 Text en Copyright: © 2017 Hsu et al. http://creativecommons.org/licenses/by/3.0/ 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 Hsu, Li-Jin Hong, Qunying Chen, Shur-Tzu Kuo, Hsiang-Lin Schultz, Lori Heath, John Lin, Sing-Ru Lee, Ming-Hui Li, Dong-Zhang Li, Zih-Ling Cheng, Hui-Ching Armand, Gerard Chang, Nan-Shan Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed |
title | Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed |
title_full | Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed |
title_fullStr | Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed |
title_full_unstemmed | Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed |
title_short | Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed |
title_sort | hyaluronan activates hyal-2/wwox/smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386674/ https://www.ncbi.nlm.nih.gov/pubmed/27845895 http://dx.doi.org/10.18632/oncotarget.13268 |
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