HYAL-2–WWOX–SMAD4 signaling in cell death and anticancer response
Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hem...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-12-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fcell.2016.00141/full |
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| author | Li-Jin Hsu Ming-Fu Chiang Chun-I Sze Wan-Pei Su Ye Vone Yap I-Ting Lee Hsiang-Ling Kuo Nan-Shan Chang |
| author_facet | Li-Jin Hsu Ming-Fu Chiang Chun-I Sze Wan-Pei Su Ye Vone Yap I-Ting Lee Hsiang-Ling Kuo Nan-Shan Chang |
| author_sort | Li-Jin Hsu |
| collection | DOAJ |
| description | Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3- CD19- Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response. |
| first_indexed | 2024-04-12T10:38:23Z |
| format | Article |
| id | doaj.art-bd7d93a771c04d61bf73fdf89bc61fae |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-12T10:38:23Z |
| publishDate | 2016-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-bd7d93a771c04d61bf73fdf89bc61fae2022-12-22T03:36:40ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2016-12-01410.3389/fcell.2016.00141229322HYAL-2–WWOX–SMAD4 signaling in cell death and anticancer responseLi-Jin Hsu0Ming-Fu Chiang1Chun-I Sze2Wan-Pei Su3Ye Vone Yap4I-Ting Lee5Hsiang-Ling Kuo6Nan-Shan Chang7National Cheng Kung UniversityMackay Memorial Hospital, Mackay Medicine, Nursing and Management College, and Graduate Institute of Injury Prevention and Control, Taipei Medical UniversityNational Cheng Kung UniversityNational Cheng Kung UniversityNational Cheng Kung UniversityNational Cheng Kung UniversityNational Cheng Kung UniversityNational Cheng Kung UniversityHyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3- CD19- Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.http://journal.frontiersin.org/Journal/10.3389/fcell.2016.00141/fullPeptidesPolymerizationCancerTreatmentpreventionHyaluronidase |
| spellingShingle | Li-Jin Hsu Ming-Fu Chiang Chun-I Sze Wan-Pei Su Ye Vone Yap I-Ting Lee Hsiang-Ling Kuo Nan-Shan Chang HYAL-2–WWOX–SMAD4 signaling in cell death and anticancer response Frontiers in Cell and Developmental Biology Peptides Polymerization Cancer Treatment prevention Hyaluronidase |
| title | HYAL-2–WWOX–SMAD4 signaling in cell death and anticancer response |
| title_full | HYAL-2–WWOX–SMAD4 signaling in cell death and anticancer response |
| title_fullStr | HYAL-2–WWOX–SMAD4 signaling in cell death and anticancer response |
| title_full_unstemmed | HYAL-2–WWOX–SMAD4 signaling in cell death and anticancer response |
| title_short | HYAL-2–WWOX–SMAD4 signaling in cell death and anticancer response |
| title_sort | hyal 2 wwox smad4 signaling in cell death and anticancer response |
| topic | Peptides Polymerization Cancer Treatment prevention Hyaluronidase |
| url | http://journal.frontiersin.org/Journal/10.3389/fcell.2016.00141/full |
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