Kilpatrick, BS;
Eden, ER;
Hockey, LN;
Yates, E;
Futter, CE;
Patel, S;
(2017)
An Endosomal NAADP-Sensitive Two-Pore Ca(2+) Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling.
Cell Rep
, 18
(7)
pp. 1636-1645.
10.1016/j.celrep.2017.01.052.
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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 Ca(2+)-mobilizing messenger NAADP, inhibiting its target endo-lysosomal ion channel, TPC1, and buffering local Ca(2+) 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 Ca(2+) stores by EGF were exaggerated upon NAADP blockade. Membrane contact sites between endosomes and the ER thus emerge as Ca(2+)-dependent hubs for signaling.
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