An Endosomal NAADP-Sensitive Two-Pore Ca2+ Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Bethan S. Kilpatrick, Emily R. Eden, Leanne N. Hockey, Elizabeth Yates, Clare E. Futter, Sandip Patel
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.

Graphical abstract

Teaser

Endosomes form junctions with the ER, but how this contact is regulated remains unclear. Kilpatrick et al. find that Ca²⁺ release by an endosomal ion channel facilitates inter-organellar coupling to temper signals mediated by an internalized growth factor receptor. Endosome-ER contact sites thus emerge as Ca²⁺-dependent signaling hubs.


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