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
