Tobys, David, Kowalski, Lisa Maria, Cziudaj, Eva, Mueller, Stefan, Zentis, Peter, Pach, Elke, Zigrino, Paola, Blaeske, Tobias and Hoening, Stefan . Inhibition of clathrin-mediated endocytosis by knockdown of AP-2 leads to alterations in the plasma membrane proteome. Traffic. HOBOKEN: WILEY. ISSN 1600-0854

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Abstract

In eukaryotic cells, clathrin-mediated endocytosis (CME) is a central pathway for the internalization of proteins from the cell surface, thereby contributing to the maintenance of the plasma membrane protein composition. A key component for the formation of endocytic clathrin-coated vesicles (CCVs) is AP-2, as it sequesters cargo membrane proteins, recruits a multitude of other endocytic factors and initiates clathrin polymerization. Here, we inhibited CME by depletion of AP-2 and explored the consequences for the plasma membrane proteome. Quantitative analysis revealed accumulation of major constituents of the endosomal-lysosomal system reflecting a block in retrieval by compensatory CME. The noticeable enrichment of integrins and blockage of their turnover resulted in severely impaired cell migration. Rare proteins such as the anti-cancer drug target CA9 and tumor markers (CD73, CD164, CD302) were significantly enriched. The AP-2 knockdown attenuated the global endocytic capacity, but clathrin-independent entry pathways were still operating, as indicated by persistent internalization of specific membrane-spanning and GPI-anchored receptors (PVR, IGF1R, CD55, TNAP). We hypothesize that blocking AP-2 function and thus inhibiting CME may be a novel approach to identify new druggable targets, or to increase their residence time at the plasma membrane, thereby increasing the probability for efficient therapeutic intervention.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Tobys, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kowalski, Lisa MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cziudaj, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zentis, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pach, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zigrino, PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blaeske, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoening, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-307777
DOI: 10.1111/tra.12770
Journal or Publication Title: Traffic
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1600-0854
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CARBONIC-ANHYDRASE IX; MHC CLASS-II; CRYSTAL-STRUCTURE; MOLECULAR-BASIS; CARGO PROTEINS; TRAFFICKING; RECEPTOR; ALPHA; IDENTIFICATION; COMPLEXMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/30777

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