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Endocytosis of ABCG2 drug transporter caused by binding of 5D3 antibody: trafficking mechanisms and intracellular fate.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2015 Aug; Vol. 1853 (8), pp. 1759-71. Date of Electronic Publication: 2015 Apr 24. - Publication Year :
- 2015
-
Abstract
- ABCG2, a metabolite and xenobiotic transporter located at the plasma membrane (predominantly in barrier tissues and progenitor cells), undergoes a direct progressive endocytosis process from plasma membrane to intracellular compartments upon binding of 5D3 monoclonal antibody. This antibody is specific to an external epitope on the protein molecule and locks it in a discrete conformation within its activity cycle, presumably providing a structural trigger for the observed internalization phenomenon. Using routine and novel assays, we show that ABCG2 is endocytosed by a mixed mechanism: partially via a rapid, clathrin-dependent pathway and partially in a cholesterol-dependent, caveolin-independent manner. While the internalization process is entirely dynamin-dependent and converges initially at the early endosome, subsequent intracellular fate of ABCG2 is again twofold: endocytosis leads to only partial lysosomal degradation, while a significant fraction of the protein is retained in a post-endosomal compartment with the possibility of at least partial recycling back to the cell surface. This externally triggered, conformation-related trafficking pathway may serve as a general regulatory paradigm for membrane transporters, and its discovery was made possible thanks to consistent application of quantitative methods.<br /> (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Subjects :
- ATP Binding Cassette Transporter, Subfamily G, Member 2
Animals
Caveolin 1 metabolism
Cells, Cultured
Cholesterol pharmacology
Clathrin metabolism
Dogs
HEK293 Cells
HT29 Cells
Humans
MCF-7 Cells
Metabolic Networks and Pathways drug effects
Protein Binding
Protein Transport drug effects
Transport Vesicles drug effects
Transport Vesicles metabolism
ATP-Binding Cassette Transporters metabolism
Antibodies, Monoclonal metabolism
Endocytosis drug effects
Endocytosis physiology
Neoplasm Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1853
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 25918011
- Full Text :
- https://doi.org/10.1016/j.bbamcr.2015.04.011