Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner
Abstract Background Sushi domain-containing protein 4 (SUSD4) is a recently discovered protein with unknown cellular functions. We previously revealed that SUSD4 can act as complement inhibitor and as a potential tumor suppressor. Methods In a syngeneic mouse model of breast cancer, tumors expressin...
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02565-1 |
| _version_ | 1797973464942903296 |
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| author | Konstantinos S. Papadakos Alexander Ekström Piotr Slipek Eleni Skourti Steven Reid Kristian Pietras Anna M. Blom |
| author_facet | Konstantinos S. Papadakos Alexander Ekström Piotr Slipek Eleni Skourti Steven Reid Kristian Pietras Anna M. Blom |
| author_sort | Konstantinos S. Papadakos |
| collection | DOAJ |
| description | Abstract Background Sushi domain-containing protein 4 (SUSD4) is a recently discovered protein with unknown cellular functions. We previously revealed that SUSD4 can act as complement inhibitor and as a potential tumor suppressor. Methods In a syngeneic mouse model of breast cancer, tumors expressing SUSD4 had a smaller volume compared with the corresponding mock control tumors. Additionally, data from three different expression databases and online analysis tools confirm that for breast cancer patients, high mRNA expression of SUSD4 in the tumor tissue correlates with a better prognosis. In vitro experiments utilized triple-negative breast cancer cell lines (BT-20 and MDA-MB-468) stably expressing SUSD4. Moreover, we established a cell line based on BT-20 in which the gene for EGFR was knocked out with the CRISPR-Cas9 method. Results We discovered that the Epithelial Growth Factor Receptor (EGFR) interacts with SUSD4. Furthermore, triple-negative breast cancer cell lines stably expressing SUSD4 had higher autophagic flux. The initiation of autophagy required the expression of EGFR but not phosphorylation of the receptor. Expression of SUSD4 in the breast cancer cells led to activation of the tumor suppressor LKB1 and consequently to the activation of AMPKα1. Finally, autophagy was initiated after stimulation of the ULK1, Atg14 and Beclin-1 axis in SUSD4 expressing cells. Conclusions In this study we provide novel insight into the molecular mechanism of action whereby SUSD4 acts as an EGFR inhibitor without affecting the phosphorylation of the receptor and may potentially influence the recycling of EGFR to the plasma membrane. |
| first_indexed | 2024-04-11T04:04:44Z |
| format | Article |
| id | doaj.art-ffa37e609d214cb0acb3b113686e5eb0 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-11T04:04:44Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-ffa37e609d214cb0acb3b113686e5eb02023-01-01T12:30:18ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-12-0141111910.1186/s13046-022-02565-1Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent mannerKonstantinos S. Papadakos0Alexander Ekström1Piotr Slipek2Eleni Skourti3Steven Reid4Kristian Pietras5Anna M. Blom6Division of Medical Protein Chemistry, Department of Translational Medicine, Lund UniversityDivision of Medical Protein Chemistry, Department of Translational Medicine, Lund UniversityDivision of Medical Protein Chemistry, Department of Translational Medicine, Lund UniversityDivision of Medical Protein Chemistry, Department of Translational Medicine, Lund UniversityDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityDivision of Medical Protein Chemistry, Department of Translational Medicine, Lund UniversityAbstract Background Sushi domain-containing protein 4 (SUSD4) is a recently discovered protein with unknown cellular functions. We previously revealed that SUSD4 can act as complement inhibitor and as a potential tumor suppressor. Methods In a syngeneic mouse model of breast cancer, tumors expressing SUSD4 had a smaller volume compared with the corresponding mock control tumors. Additionally, data from three different expression databases and online analysis tools confirm that for breast cancer patients, high mRNA expression of SUSD4 in the tumor tissue correlates with a better prognosis. In vitro experiments utilized triple-negative breast cancer cell lines (BT-20 and MDA-MB-468) stably expressing SUSD4. Moreover, we established a cell line based on BT-20 in which the gene for EGFR was knocked out with the CRISPR-Cas9 method. Results We discovered that the Epithelial Growth Factor Receptor (EGFR) interacts with SUSD4. Furthermore, triple-negative breast cancer cell lines stably expressing SUSD4 had higher autophagic flux. The initiation of autophagy required the expression of EGFR but not phosphorylation of the receptor. Expression of SUSD4 in the breast cancer cells led to activation of the tumor suppressor LKB1 and consequently to the activation of AMPKα1. Finally, autophagy was initiated after stimulation of the ULK1, Atg14 and Beclin-1 axis in SUSD4 expressing cells. Conclusions In this study we provide novel insight into the molecular mechanism of action whereby SUSD4 acts as an EGFR inhibitor without affecting the phosphorylation of the receptor and may potentially influence the recycling of EGFR to the plasma membrane.https://doi.org/10.1186/s13046-022-02565-1SUSD4EGFRAMPKα1Autophagy |
| spellingShingle | Konstantinos S. Papadakos Alexander Ekström Piotr Slipek Eleni Skourti Steven Reid Kristian Pietras Anna M. Blom Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner Journal of Experimental & Clinical Cancer Research SUSD4 EGFR AMPKα1 Autophagy |
| title | Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner |
| title_full | Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner |
| title_fullStr | Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner |
| title_full_unstemmed | Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner |
| title_short | Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner |
| title_sort | sushi domain containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an egfr phosphorylation independent manner |
| topic | SUSD4 EGFR AMPKα1 Autophagy |
| url | https://doi.org/10.1186/s13046-022-02565-1 |
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