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WASH and Tsg101/ALIX-dependent diversion of stress-internalised EGFR from the canonical endocytic pathway

Futter, CE; Tomas, A; Vaughan, SO; Burgoyne, T; Sorkin, A; Hochhauser, D; (2015) WASH and Tsg101/ALIX-dependent diversion of stress-internalised EGFR from the canonical endocytic pathway. Nature Communications , 6 , Article 7324. 10.1038/ncomms8324. Green open access

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Abstract

Stress exposure triggers ligand-independent EGF receptor (EGFR) endocytosis, but its post-endocytic fate and role in regulating signalling are unclear. We show that the p38 MAP kinase-dependent, EGFR tyrosine kinase (TK)-independent EGFR internalisation induced by ultraviolet light C (UVC) or the cancer therapeutic cisplatin, is followed by diversion from the canonical endocytic pathway. Instead of lysosomal degradation or plasma membrane recycling, EGFR accumulates in a subset of LBPA-rich perinuclear multivesicular bodies (MVBs) distinct from those carrying EGF-stimulated EGFR. Stress-internalised EGFR co-segregates with exogenously-expressed pre-melanosomal markers OA1 and fibrillar PMEL, following early endosomal sorting by the actin polymerisation-promoting WASH complex. Stress-internalised EGFR is retained intracellularly by continued p38 activity in a mechanism involving ubiquitin-independent, ESCRT/ALIX-dependent incorporation onto intraluminal vesicles (ILVs) of MVBs. In contrast to the internalisation-independent EGF-stimulated activation, UVC/cisplatin-triggered EGFR activation depends on EGFR internalisation and intracellular retention. EGFR signalling from this MVB subpopulation delays apoptosis and might contribute to chemoresistance.

Type: Article
Title: WASH and Tsg101/ALIX-dependent diversion of stress-internalised EGFR from the canonical endocytic pathway
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ncomms8324
Publisher version: http://dx.doi.org/10.1038/ncomms8324
Additional information: © 2015. Macmillan Publishers Limited. his work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/1468844
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