Open AccessFGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization
Author(s) -
Pozniak Marta,
SokolowskaWedzina Aleksandra,
Jastrzebski Kamil,
Szymczyk Jakub,
Porebska Natalia,
Krzyscik Mateusz Adam,
Zakrzewska Malgorzata,
Miaczynska Marta,
Otlewski Jacek,
Opalinski Lukasz
Publication year - 2020
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12740
Subject(s) - internalization , endocytosis , endocytic cycle , fibroblast growth factor receptor 1 , microbiology and biotechnology , clathrin , receptor , cancer cell , biology , receptor mediated endocytosis , chemistry , cancer research , cancer , biochemistry , fibroblast growth factor , genetics
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.