Journal
DEVELOPMENTAL CELL
Volume 37, Issue 5, Pages 473-483Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2016.05.005
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Funding
- Medical Research Council [G0801878, M010767]
- Wellcome Trust [093445]
- MRC [G0801878, MR/M010767/1] Funding Source: UKRI
- Medical Research Council [MR/M010767/1, G0801878] Funding Source: researchfish
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Membrane contact sites between the ER and multivesicular endosomes/bodies (MVBs) play important roles in endosome positioning and fission and in neurite outgrowth. ER-MVB contacts additionally function in epidermal growth factor receptor (EGFR) tyrosine kinase downregulation by providing sites where the ER-localized phosphatase, PTP1B, interacts with endocytosed EGFR before the receptor is sorted onto intraluminal vesicles (ILVs). Here we show that these contacts are tethered by annexin A1 and its Ca2+-dependent ligand, S100A11, and form a subpopulation of differentially regulated contact sites between the ER and endocytic organelles. Annexin A1-regulated contacts function in the transfer of ER-derived cholesterol to the MVB when low-density lipoprotein-cholesterol in endosomes is low. This sterol traffic depends on interaction between ER-localized VAP and endosomal oxysterol-binding protein ORP1L, and is required for the formation of ILVs within the MVB and thus for the spatial regulation of EGFR signaling.
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