1. An Endosomal NAADP-Sensitive Two-Pore Ca 2+ Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling.
- Author
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Kilpatrick BS, Eden ER, Hockey LN, Yates E, Futter CE, and Patel S
- Subjects
- Calcium Signaling physiology, Cell Line, Tumor, Cells, Cultured, HeLa Cells, Humans, Lysosomes metabolism, NADP metabolism, Phosphorylation physiology, Calcium metabolism, Calcium Channels metabolism, Endoplasmic Reticulum metabolism, Endosomes metabolism, Intercellular Signaling Peptides and Proteins metabolism, Membranes metabolism, NADP analogs & derivatives
- Abstract
Membrane contact sites are regions of close apposition between organelles that facilitate information transfer. Here, we reveal an essential role for Ca
2+ derived from the endo-lysosomal system in maintaining contact between endosomes and the endoplasmic reticulum (ER). Antagonizing action of the Ca2+ -mobilizing messenger NAADP, inhibiting its target endo-lysosomal ion channel, TPC1, and buffering local Ca2+ fluxes all clustered and enlarged late endosomes/lysosomes. We show that TPC1 localizes to ER-endosome contact sites and is required for their formation. Reducing NAADP-dependent contacts delayed EGF receptor de-phosphorylation consistent with close apposition of endocytosed receptors with the ER-localized phosphatase PTP1B. In accord, downstream MAP kinase activation and mobilization of ER Ca2+ stores by EGF were exaggerated upon NAADP blockade. Membrane contact sites between endosomes and the ER thus emerge as Ca2+ -dependent hubs for signaling., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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