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

Alejandra Tomas, Simon O. Vaughan, Thomas Burgoyne, Alexander Sorkin, John A. Hartley, Daniel Hochhauser and Clare E. Futter ()
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Alejandra Tomas: UCL Institute of Ophthalmology, University College London
Simon O. Vaughan: UCL Institute of Ophthalmology, University College London
Thomas Burgoyne: UCL Institute of Ophthalmology, University College London
Alexander Sorkin: University of Pittsburgh School of Medicine
John A. Hartley: Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, University College London
Daniel Hochhauser: Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, University College London
Clare E. Futter: UCL Institute of Ophthalmology, University College London

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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 internalization 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-internalized EGFR co-segregates with exogenously expressed pre-melanosomal markers OA1 and fibrillar PMEL, following early endosomal sorting by the actin polymerization-promoting WASH complex. Stress-internalized 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 internalization-independent EGF-stimulated activation, UVC/cisplatin-triggered EGFR activation depends on EGFR internalization and intracellular retention. EGFR signalling from this MVB subpopulation delays apoptosis and might contribute to chemoresistance.

Date: 2015
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DOI: 10.1038/ncomms8324

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