title: An Endosomal NAADP-Sensitive Two-Pore Ca2+Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling.
abstract: Membrane contact sites are regions of close apposition between organelles that facilitate information transfer. Here, we reveal an essential role for Ca2+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.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Bethan S
authors.initials: BS
authors.lastname: Kilpatrick
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Eden
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Leanne N
authors.initials: LN
authors.lastname: Hockey
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Yates
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, UK. Electronic address: c.futter@ucl.ac.uk.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Futter
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK. Electronic address: patel.s@ucl.ac.uk.
authors.forename: Sandip
authors.initials: S
authors.lastname: Patel
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008566:Membranes / Q000378:metabolism*; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology
chemical_list: D015220:Calcium Channels; D036341:Intercellular Signaling Peptides and Proteins; D009249:NADP; C024376:NAADP; D002118:Calcium
keywords: Ca(2+); EGF; NAADP; TPC1; TPC2; acidic Ca(2+) stores; endoplasmic reticulum; endosomes; lysosomes; membrane contact sites