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

Tomas A, Vaughan SO, Burgoyne T, Sorkin A, Hartley JA, Hochhauser D, Futter CE - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Cell Biology, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK [2].

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.

No MeSH data available.


Related in: MedlinePlus

A working model for stress- versus EGF-induced EGFR trafficking.EGF stimulation triggers plasma membrane receptor activation and ubiquitination before internalization, whereas stress exposure induces p38-dependent EGFR-T669 phosphorylation and internalization into CCPs via interaction with AP2. EGF-bound and stress-internalized EGFR are then sorted from early endosomes onto separate MVB subsets, with stress-internalized EGFR undergoing WASH-dependent co-segregation with pre-melanosomal markers OA1 and fibrillar PMEL, whereas EGF-bound EGFR is retained in degradative MVBs by ubiquitin/ESCRT-dependent sorting onto ILVs and transported to lysosomes for degradation. Stress-exposed EGFR becomes activated post-internalization, and is largely retained in non-degradative MVBs from where it signals by the continued action of p38 in a mechanism that involves ALIX- and ESCRT-dependent receptor sorting onto ILVs, and may include cycles of internalization and back-fusion of ILVs with MVB-limiting membranes.
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f7: A working model for stress- versus EGF-induced EGFR trafficking.EGF stimulation triggers plasma membrane receptor activation and ubiquitination before internalization, whereas stress exposure induces p38-dependent EGFR-T669 phosphorylation and internalization into CCPs via interaction with AP2. EGF-bound and stress-internalized EGFR are then sorted from early endosomes onto separate MVB subsets, with stress-internalized EGFR undergoing WASH-dependent co-segregation with pre-melanosomal markers OA1 and fibrillar PMEL, whereas EGF-bound EGFR is retained in degradative MVBs by ubiquitin/ESCRT-dependent sorting onto ILVs and transported to lysosomes for degradation. Stress-exposed EGFR becomes activated post-internalization, and is largely retained in non-degradative MVBs from where it signals by the continued action of p38 in a mechanism that involves ALIX- and ESCRT-dependent receptor sorting onto ILVs, and may include cycles of internalization and back-fusion of ILVs with MVB-limiting membranes.

Mentions: This study has led to the elucidation of a novel mechanism of stress-induced EGFR activation linked to its intracellular sequestration in a specific subset of non-degradative MVBs (see Fig. 7 for a schematic diagram). P38- and AP2-dependent EGFR internalization is followed by WASH-dependent segregation into a subset of MVBs that are distinct from those harbouring ligand-stimulated EGFR, but related to those that mature into melanosomes in pigmented cells. Although multiple populations of MVBs and ILVs have previously been identified, the mechanisms that regulate sorting between MVBs and their cargo with different destinations remain obscure. This study suggests that WASH-dependent regulation of actin dynamics may play an important role in this sorting.


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

Tomas A, Vaughan SO, Burgoyne T, Sorkin A, Hartley JA, Hochhauser D, Futter CE - Nat Commun (2015)

A working model for stress- versus EGF-induced EGFR trafficking.EGF stimulation triggers plasma membrane receptor activation and ubiquitination before internalization, whereas stress exposure induces p38-dependent EGFR-T669 phosphorylation and internalization into CCPs via interaction with AP2. EGF-bound and stress-internalized EGFR are then sorted from early endosomes onto separate MVB subsets, with stress-internalized EGFR undergoing WASH-dependent co-segregation with pre-melanosomal markers OA1 and fibrillar PMEL, whereas EGF-bound EGFR is retained in degradative MVBs by ubiquitin/ESCRT-dependent sorting onto ILVs and transported to lysosomes for degradation. Stress-exposed EGFR becomes activated post-internalization, and is largely retained in non-degradative MVBs from where it signals by the continued action of p38 in a mechanism that involves ALIX- and ESCRT-dependent receptor sorting onto ILVs, and may include cycles of internalization and back-fusion of ILVs with MVB-limiting membranes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490399&req=5

f7: A working model for stress- versus EGF-induced EGFR trafficking.EGF stimulation triggers plasma membrane receptor activation and ubiquitination before internalization, whereas stress exposure induces p38-dependent EGFR-T669 phosphorylation and internalization into CCPs via interaction with AP2. EGF-bound and stress-internalized EGFR are then sorted from early endosomes onto separate MVB subsets, with stress-internalized EGFR undergoing WASH-dependent co-segregation with pre-melanosomal markers OA1 and fibrillar PMEL, whereas EGF-bound EGFR is retained in degradative MVBs by ubiquitin/ESCRT-dependent sorting onto ILVs and transported to lysosomes for degradation. Stress-exposed EGFR becomes activated post-internalization, and is largely retained in non-degradative MVBs from where it signals by the continued action of p38 in a mechanism that involves ALIX- and ESCRT-dependent receptor sorting onto ILVs, and may include cycles of internalization and back-fusion of ILVs with MVB-limiting membranes.
Mentions: This study has led to the elucidation of a novel mechanism of stress-induced EGFR activation linked to its intracellular sequestration in a specific subset of non-degradative MVBs (see Fig. 7 for a schematic diagram). P38- and AP2-dependent EGFR internalization is followed by WASH-dependent segregation into a subset of MVBs that are distinct from those harbouring ligand-stimulated EGFR, but related to those that mature into melanosomes in pigmented cells. Although multiple populations of MVBs and ILVs have previously been identified, the mechanisms that regulate sorting between MVBs and their cargo with different destinations remain obscure. This study suggests that WASH-dependent regulation of actin dynamics may play an important role in this sorting.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Cell Biology, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK [2].

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.

No MeSH data available.


Related in: MedlinePlus