FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization
Fibroblast growth factor receptor 1 (FGFR1) transmits signals through the plasma membrane regulating essential cellular processes like division, motility, metabolism, and death. Overexpression of FGFR1 is observed in numerous tumors and thus constitutes an attractive molecular target for selective c...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-09-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12740 |
| _version_ | 1818275139446374400 |
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| author | Marta Pozniak Aleksandra Sokolowska‐Wedzina Kamil Jastrzebski Jakub Szymczyk Natalia Porebska Mateusz Adam Krzyscik Malgorzata Zakrzewska Marta Miaczynska Jacek Otlewski Lukasz Opalinski |
| author_facet | Marta Pozniak Aleksandra Sokolowska‐Wedzina Kamil Jastrzebski Jakub Szymczyk Natalia Porebska Mateusz Adam Krzyscik Malgorzata Zakrzewska Marta Miaczynska Jacek Otlewski Lukasz Opalinski |
| author_sort | Marta Pozniak |
| collection | DOAJ |
| description | Fibroblast growth factor receptor 1 (FGFR1) transmits signals through the plasma membrane regulating essential cellular processes like division, motility, metabolism, and death. Overexpression of FGFR1 is observed in numerous tumors and thus constitutes an attractive molecular target for selective cancer treatment. Targeted anti‐cancer therapies aim for the precise delivery of drugs into cancer cells, sparing the healthy ones and thus limiting unwanted side effects. One of the key steps in targeted drug delivery is receptor‐mediated endocytosis. Here, we show that the efficiency and the mechanism of FGFR1 internalization are governed by the spatial distribution of the receptor in the plasma membrane. Using engineered antibodies of different valency, we demonstrate that dimerization of FGFR1 with bivalent antibody triggers clathrin‐mediated endocytosis (CME) of the receptor. Clustering of FGFR1 into larger oligomers with tetravalent antibody stimulates fast and highly efficient uptake of the receptor that occurs via two distinct mechanisms: CME and dynamin‐dependent clathrin‐independent endocytic routes. Furthermore, we show that all endocytic pathways engaged in FGFR1 internalization do not require receptor activation. Our data provide novel insights into the mechanisms of intracellular trafficking of FGFR1 and constitute guidelines for development of highly internalizing antibody‐based drug carriers for targeted therapy of FGFR1‐overproducing cancers. |
| first_indexed | 2024-12-12T22:25:00Z |
| format | Article |
| id | doaj.art-41add822f32c4099b544103cf1062b2c |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-12T22:25:00Z |
| publishDate | 2020-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-41add822f32c4099b544103cf1062b2c2022-12-22T00:09:47ZengWileyMolecular Oncology1574-78911878-02612020-09-011491998202110.1002/1878-0261.12740FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalizationMarta Pozniak0Aleksandra Sokolowska‐Wedzina1Kamil Jastrzebski2Jakub Szymczyk3Natalia Porebska4Mateusz Adam Krzyscik5Malgorzata Zakrzewska6Marta Miaczynska7Jacek Otlewski8Lukasz Opalinski9Faculty of Biotechnology Department of Protein Engineering University of Wroclaw PolandFaculty of Biotechnology Department of Protein Engineering University of Wroclaw PolandLaboratory of Cell Biology International Institute of Molecular and Cell Biology PolandFaculty of Biotechnology Department of Protein Engineering University of Wroclaw PolandFaculty of Biotechnology Department of Protein Engineering University of Wroclaw PolandFaculty of Biotechnology Department of Protein Engineering University of Wroclaw PolandFaculty of Biotechnology Department of Protein Engineering University of Wroclaw PolandLaboratory of Cell Biology International Institute of Molecular and Cell Biology PolandFaculty of Biotechnology Department of Protein Engineering University of Wroclaw PolandFaculty of Biotechnology Department of Protein Engineering University of Wroclaw PolandFibroblast growth factor receptor 1 (FGFR1) transmits signals through the plasma membrane regulating essential cellular processes like division, motility, metabolism, and death. Overexpression of FGFR1 is observed in numerous tumors and thus constitutes an attractive molecular target for selective cancer treatment. Targeted anti‐cancer therapies aim for the precise delivery of drugs into cancer cells, sparing the healthy ones and thus limiting unwanted side effects. One of the key steps in targeted drug delivery is receptor‐mediated endocytosis. Here, we show that the efficiency and the mechanism of FGFR1 internalization are governed by the spatial distribution of the receptor in the plasma membrane. Using engineered antibodies of different valency, we demonstrate that dimerization of FGFR1 with bivalent antibody triggers clathrin‐mediated endocytosis (CME) of the receptor. Clustering of FGFR1 into larger oligomers with tetravalent antibody stimulates fast and highly efficient uptake of the receptor that occurs via two distinct mechanisms: CME and dynamin‐dependent clathrin‐independent endocytic routes. Furthermore, we show that all endocytic pathways engaged in FGFR1 internalization do not require receptor activation. Our data provide novel insights into the mechanisms of intracellular trafficking of FGFR1 and constitute guidelines for development of highly internalizing antibody‐based drug carriers for targeted therapy of FGFR1‐overproducing cancers.https://doi.org/10.1002/1878-0261.12740CIECMEendocytosisFGFRprotein transportsignaling |
| spellingShingle | Marta Pozniak Aleksandra Sokolowska‐Wedzina Kamil Jastrzebski Jakub Szymczyk Natalia Porebska Mateusz Adam Krzyscik Malgorzata Zakrzewska Marta Miaczynska Jacek Otlewski Lukasz Opalinski FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization Molecular Oncology CIE CME endocytosis FGFR protein transport signaling |
| title | FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization |
| title_full | FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization |
| title_fullStr | FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization |
| title_full_unstemmed | FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization |
| title_short | FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization |
| title_sort | fgfr1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization |
| topic | CIE CME endocytosis FGFR protein transport signaling |
| url | https://doi.org/10.1002/1878-0261.12740 |
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