FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization.

Published on Sep 1, 2020in Molecular Oncology6.574
· DOI :10.1002/1878-0261.12740
Marta Pozniak1
Estimated H-index: 1
(UWr: University of Wrocław),
Aleksandra Sokolowska-Wedzina7
Estimated H-index: 7
(UWr: University of Wrocław)
+ 7 AuthorsLukasz Opalinski3
Estimated H-index: 3
(UWr: University of Wrocław)
Sources
Abstract
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.
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