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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.

SUBMITTER: Kilpatrick BS 

PROVIDER: S-EPMC5318655 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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An Endosomal NAADP-Sensitive Two-Pore Ca<sup>2+</sup> Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling.

Kilpatrick Bethan S BS   Eden Emily R ER   Hockey Leanne N LN   Yates Elizabeth E   Futter Clare E CE   Patel Sandip S  

Cell reports 20170201 7


Membrane contact sites are regions of close apposition between organelles that facilitate information transfer. Here, we reveal an essential role for Ca<sup>2+</sup> derived from the endo-lysosomal system in maintaining contact between endosomes and the endoplasmic reticulum (ER). Antagonizing action of the Ca<sup>2+</sup>-mobilizing messenger NAADP, inhibiting its target endo-lysosomal ion channel, TPC1, and buffering local Ca<sup>2+</sup> fluxes all clustered and enlarged late endosomes/lysoso  ...[more]

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