Functional Characterization of Colon-Cancer-Associated Variants in <i>ADAM17</i> Affecting the Catalytic Domain
Although extensively investigated, cancer is still one of the most devastating and lethal diseases in the modern world. Among different types, colorectal cancer (CRC) is most prevalent and mortal, making it an important subject of research. The metalloprotease ADAM17 has been implicated in the devel...
| Main Authors: | , , , , , |
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| Format: | Article |
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MDPI AG
2020-10-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/8/11/463 |
| _version_ | 1827703100833529856 |
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| author | Jan Philipp Dobert Anne-Sophie Cabron Philipp Arnold Egor Pavlenko Stefan Rose-John Friederike Zunke |
| author_facet | Jan Philipp Dobert Anne-Sophie Cabron Philipp Arnold Egor Pavlenko Stefan Rose-John Friederike Zunke |
| author_sort | Jan Philipp Dobert |
| collection | DOAJ |
| description | Although extensively investigated, cancer is still one of the most devastating and lethal diseases in the modern world. Among different types, colorectal cancer (CRC) is most prevalent and mortal, making it an important subject of research. The metalloprotease ADAM17 has been implicated in the development of CRC due to its involvement in signaling pathways related to inflammation and cell proliferation. ADAM17 is capable of releasing membrane-bound proteins from the cell surface in a process called <i>shedding.</i> A deficiency of ADAM17 activity has been previously shown to have protective effects against CRC in mice, while an upregulation of ADAM17 activity is suspected to facilitate tumor development. In this study, we characterize ADAM17 variants found in tissue samples of cancer patients in overexpression studies. We here focus on point mutations identified within the catalytic domain of ADAM17 and could show a functional dysregulation of the CRC-associated variants. Since the catalytic domain of ADAM17 is the only region structurally determined by crystallography, we study the effect of each point mutation not only to learn more about the role of ADAM17 in cancer, but also to investigate the structure–function relationships of the metalloprotease. |
| first_indexed | 2024-03-10T15:11:39Z |
| format | Article |
| id | doaj.art-20a2e71ba50d48f78831e1d9b5fa94ac |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T15:11:39Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-20a2e71ba50d48f78831e1d9b5fa94ac2023-11-20T19:15:51ZengMDPI AGBiomedicines2227-90592020-10-0181146310.3390/biomedicines8110463Functional Characterization of Colon-Cancer-Associated Variants in <i>ADAM17</i> Affecting the Catalytic DomainJan Philipp Dobert0Anne-Sophie Cabron1Philipp Arnold2Egor Pavlenko3Stefan Rose-John4Friederike Zunke5Institute of Biochemistry Christian-Albrechts-Universität zu Kiel, 24118 Kiel, GermanyInstitute of Biochemistry Christian-Albrechts-Universität zu Kiel, 24118 Kiel, GermanyInstitute of Anatomy, Christian-Albrechts-Universität zu Kiel, 24118 Kiel, GermanyInstitute of Biochemistry Christian-Albrechts-Universität zu Kiel, 24118 Kiel, GermanyInstitute of Biochemistry Christian-Albrechts-Universität zu Kiel, 24118 Kiel, GermanyInstitute of Biochemistry Christian-Albrechts-Universität zu Kiel, 24118 Kiel, GermanyAlthough extensively investigated, cancer is still one of the most devastating and lethal diseases in the modern world. Among different types, colorectal cancer (CRC) is most prevalent and mortal, making it an important subject of research. The metalloprotease ADAM17 has been implicated in the development of CRC due to its involvement in signaling pathways related to inflammation and cell proliferation. ADAM17 is capable of releasing membrane-bound proteins from the cell surface in a process called <i>shedding.</i> A deficiency of ADAM17 activity has been previously shown to have protective effects against CRC in mice, while an upregulation of ADAM17 activity is suspected to facilitate tumor development. In this study, we characterize ADAM17 variants found in tissue samples of cancer patients in overexpression studies. We here focus on point mutations identified within the catalytic domain of ADAM17 and could show a functional dysregulation of the CRC-associated variants. Since the catalytic domain of ADAM17 is the only region structurally determined by crystallography, we study the effect of each point mutation not only to learn more about the role of ADAM17 in cancer, but also to investigate the structure–function relationships of the metalloprotease.https://www.mdpi.com/2227-9059/8/11/463ADAM17colorectal cancer (CRC)TNFαIL-6RAREGshedding |
| spellingShingle | Jan Philipp Dobert Anne-Sophie Cabron Philipp Arnold Egor Pavlenko Stefan Rose-John Friederike Zunke Functional Characterization of Colon-Cancer-Associated Variants in <i>ADAM17</i> Affecting the Catalytic Domain Biomedicines ADAM17 colorectal cancer (CRC) TNFα IL-6R AREG shedding |
| title | Functional Characterization of Colon-Cancer-Associated Variants in <i>ADAM17</i> Affecting the Catalytic Domain |
| title_full | Functional Characterization of Colon-Cancer-Associated Variants in <i>ADAM17</i> Affecting the Catalytic Domain |
| title_fullStr | Functional Characterization of Colon-Cancer-Associated Variants in <i>ADAM17</i> Affecting the Catalytic Domain |
| title_full_unstemmed | Functional Characterization of Colon-Cancer-Associated Variants in <i>ADAM17</i> Affecting the Catalytic Domain |
| title_short | Functional Characterization of Colon-Cancer-Associated Variants in <i>ADAM17</i> Affecting the Catalytic Domain |
| title_sort | functional characterization of colon cancer associated variants in i adam17 i affecting the catalytic domain |
| topic | ADAM17 colorectal cancer (CRC) TNFα IL-6R AREG shedding |
| url | https://www.mdpi.com/2227-9059/8/11/463 |
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