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.
Preview |
Text (Article)
ncomms8324.pdf Download (6MB) | Preview |
Preview |
Text (Supplementary Figures 1-6, Supplementary Tables 1-2)
ncomms8324-s1.pdf Download (1MB) | Preview |
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 |
Archive Staff Only
 |
View Item |
