WASH and Tsg101/ALIX-dependent diversion of stress-internalized EGFR from the canonical endocytic pathway.
WASH and Tsg101/ALIX-dependent diversion of stress-internalized EGFR from the canonical endocytic pathway.
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DOI：
10.1038/ncomms8324
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发表时间：
2015-06-12
影响因子：
16.6
通讯作者：
Futter, Clare E.
中科院分区：
文献类型：
--
作者：
Tomas, Alejandra;Vaughan, Simon O.;Burgoyne, Thomas;Sorkin, Alexander;Hartley, John A.;Hochhauser, Daniel;Futter, Clare E.
应激暴露触发配体非依赖性EGF受体（EGFR）的内吞作用，但其内吞后的命运及其在调节信号传导中的作用尚不清楚。我们发现，紫外线C （UVC）或癌症治疗顺铂诱导的p38 MAP激酶依赖性、EGFR酪氨酸激酶（TK）非依赖性EGFR内化，随后从典型的内吞途径转移。EGFR不是溶酶体降解或质膜再循环，而是在富含lbpa的核周多泡体（MVBs）中积累，与那些携带egf刺激的EGFR不同。在肌动蛋白聚合促进WASH复合体的早期内体分选之后，应激内化的EGFR与外源表达的黑素体前标记物OA1和纤维状PMEL共同分离。应激内化的EGFR通过持续的p38活性保留在细胞内，其机制涉及泛素不依赖、ESCRT/ alix依赖的结合到MVBs的腔内囊泡（ILVs）上。与内化无关的egf刺激激活相反，UVC/顺铂触发的EGFR激活依赖于EGFR内化和细胞内保留。来自MVB亚群的EGFR信号延迟细胞凋亡，并可能导致化疗耐药。应激诱导EGF受体（EGFR）的不依赖配体的内吞作用，但其命运和在信号传导中的作用尚不清楚。在这里，Tomas等人表明，应激内化的EGFR在不同的多泡体中积累并保留，并延迟应激诱导的细胞凋亡的发生。
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. Stress induces ligand-independent endocytosis of EGF receptor (EGFR), but its fate and role in signalling are not known. Here Tomas et al. show that stress-internalized EGFR accumulates and is retained in distinct multivesicular bodies, and delays the onset of stress-induced apoptosis.
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影响因子：
9.2
作者：
McGough, Ian J.;Steinberg, Florian;Jia, Da;Barbuti, Peter A.;McMillan, Kirsty J.;Heesom, Kate J.;Whone, Alan L.;Caldwell, Maeve A.;Billadeau, Daniel D.;Rosen, Michael K.;Cullen, Peter J.
通讯作者：
Cullen, Peter J.
DOI：
10.1111/j.1600-0854.2011.01305.x
发表时间：
2012-02
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Eden ER;Huang F;Sorkin A;Futter CE
通讯作者：
Futter CE
DOI：
10.1016/j.bbadis.2012.10.011
发表时间：
2013-01
影响因子：
6.2
作者：
Freeman, Caroline;Seaman, Matthew N. J.;Reid, Evan
通讯作者：
Reid, Evan
影响因子：
4
作者：
Burgoyne, Thomas;Jolly, Rushee;Futter, Clare E.
通讯作者：
Futter, Clare E.
DOI：
10.1073/pnas.0906541106
发表时间：
2009-10-20
影响因子：
11.1
作者：
Murphy, Jane E.;Padilla, Benjamin E.;Bunnett, Nigel W.
通讯作者：
Bunnett, Nigel W.