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.
Highlights
Stress exposure triggers ligand-independent EGF receptor (EGFR) endocytosis, but its postendocytic fate and role in regulating signalling are unclear
We analyse the post-endocytic fate of the EGFR following exposure to ultraviolet light C (UVC) and the chemotherapeutic drug, cisplatin, and show that EGFR undergoes p38-dependent accumulation in a subpopulation of perinuclear multivesicular bodies (MVBs) that are distinct from those that traffic ligand-stimulated EGFR to the lysosome but contain exogenously expressed markers of melanosome biogenesis
Intracellular retention of stressinduced EGFR in MVBs is independent of EGFR ubiquitination but depends on the endosomal sorting complex required for transport (ESCRT) machinery and ALG-2-interacting Protein X (ALIX) and is required for stress-induced EGFR signalling and protection from apoptosis
Summary
Stress exposure triggers ligand-independent EGF receptor (EGFR) endocytosis, but its postendocytic 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. We analyse the post-endocytic fate of the EGFR following exposure to ultraviolet light C (UVC) and the chemotherapeutic drug, cisplatin, and show that EGFR undergoes p38-dependent accumulation in a subpopulation of perinuclear multivesicular bodies (MVBs) that are distinct from those that traffic ligand-stimulated EGFR to the lysosome but contain exogenously expressed markers of melanosome biogenesis. Intracellular retention of stressinduced EGFR in MVBs is independent of EGFR ubiquitination but depends on the endosomal sorting complex required for transport (ESCRT) machinery and ALG-2-interacting Protein X (ALIX) and is required for stress-induced EGFR signalling and protection from apoptosis
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