Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells
Abstract Glypican-3 (GPC3) is a cell surface heparan sulfate proteoglycan that is being evaluated as an emerging therapeutic target in hepatocellular carcinoma (HCC). GPC3 has been shown to interact with several extracellular signaling molecules, including Wnt, HGF, and Hedgehog. Here, we reported a...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-79524-3 |
| _version_ | 1819202212912431104 |
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| author | Panpan Meng Yi-Fan Zhang Wangli Zhang Xin Chen Tong Xu Sheng Hu Xinjun Liang Mingqian Feng Xiaoqing Yang Mitchell Ho |
| author_facet | Panpan Meng Yi-Fan Zhang Wangli Zhang Xin Chen Tong Xu Sheng Hu Xinjun Liang Mingqian Feng Xiaoqing Yang Mitchell Ho |
| author_sort | Panpan Meng |
| collection | DOAJ |
| description | Abstract Glypican-3 (GPC3) is a cell surface heparan sulfate proteoglycan that is being evaluated as an emerging therapeutic target in hepatocellular carcinoma (HCC). GPC3 has been shown to interact with several extracellular signaling molecules, including Wnt, HGF, and Hedgehog. Here, we reported a cell surface transmembrane protein (FAT1) as a new GPC3 interacting protein. The GPC3 binding region on FAT1 was initially mapped to the C-terminal region (Q14517, residues 3662-4181), which covered a putative receptor tyrosine phosphatase (RTP)-like domain, a Laminin G-like domain, and five EGF-like domains. Fine mapping by ELISA and flow cytometry showed that the last four EGF-like domains (residues 4013-4181) contained a specific GPC3 binding site, whereas the RTP domain (residues 3662-3788) and the downstream Laminin G-2nd EGF-like region (residues 3829-4050) had non-specific GPC3 binding. In support of their interaction, GPC3 and FAT1 behaved concomitantly or at a similar pattern, e.g. having elevated expression in HCC cells, being up-regulated under hypoxia conditions, and being able to regulate the expression of EMT-related genes Snail, Vimentin, and E-Cadherin and promoting HCC cell migration. Taken together, our study provides the initial evidence for the novel mechanism of GPC3 and FAT1 in promoting HCC cell migration. |
| first_indexed | 2024-12-23T04:00:26Z |
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| id | doaj.art-329ef05cc3ff4f34a6454608732c6a4c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-23T04:00:26Z |
| publishDate | 2021-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-329ef05cc3ff4f34a6454608732c6a4c2022-12-21T18:00:44ZengNature PortfolioScientific Reports2045-23222021-01-0111111210.1038/s41598-020-79524-3Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cellsPanpan Meng0Yi-Fan Zhang1Wangli Zhang2Xin Chen3Tong Xu4Sheng Hu5Xinjun Liang6Mingqian Feng7Xiaoqing Yang8Mitchell Ho9College of Life Science and Technology, Huazhong Agricultural UniversityLaboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthCollege of Life Science and Technology, Huazhong Agricultural UniversityCollege of Life Science and Technology, Huazhong Agricultural UniversityCollege of Life Science and Technology, Huazhong Agricultural UniversityHubei Cancer HospitalHubei Cancer HospitalCollege of Biomedicine and Health, Huazhong Agricultural UniversityHospital of Huazhong Agricultural UniversityLaboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthAbstract Glypican-3 (GPC3) is a cell surface heparan sulfate proteoglycan that is being evaluated as an emerging therapeutic target in hepatocellular carcinoma (HCC). GPC3 has been shown to interact with several extracellular signaling molecules, including Wnt, HGF, and Hedgehog. Here, we reported a cell surface transmembrane protein (FAT1) as a new GPC3 interacting protein. The GPC3 binding region on FAT1 was initially mapped to the C-terminal region (Q14517, residues 3662-4181), which covered a putative receptor tyrosine phosphatase (RTP)-like domain, a Laminin G-like domain, and five EGF-like domains. Fine mapping by ELISA and flow cytometry showed that the last four EGF-like domains (residues 4013-4181) contained a specific GPC3 binding site, whereas the RTP domain (residues 3662-3788) and the downstream Laminin G-2nd EGF-like region (residues 3829-4050) had non-specific GPC3 binding. In support of their interaction, GPC3 and FAT1 behaved concomitantly or at a similar pattern, e.g. having elevated expression in HCC cells, being up-regulated under hypoxia conditions, and being able to regulate the expression of EMT-related genes Snail, Vimentin, and E-Cadherin and promoting HCC cell migration. Taken together, our study provides the initial evidence for the novel mechanism of GPC3 and FAT1 in promoting HCC cell migration.https://doi.org/10.1038/s41598-020-79524-3 |
| spellingShingle | Panpan Meng Yi-Fan Zhang Wangli Zhang Xin Chen Tong Xu Sheng Hu Xinjun Liang Mingqian Feng Xiaoqing Yang Mitchell Ho Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells Scientific Reports |
| title | Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells |
| title_full | Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells |
| title_fullStr | Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells |
| title_full_unstemmed | Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells |
| title_short | Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells |
| title_sort | identification of the atypical cadherin fat1 as a novel glypican 3 interacting protein in liver cancer cells |
| url | https://doi.org/10.1038/s41598-020-79524-3 |
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