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Integration of GPCR signaling and sorting from very early endosomes via opposing APPL1 mechanisms

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Title: Integration of GPCR signaling and sorting from very early endosomes via opposing APPL1 mechanisms
Authors: Sposini, S
Jean-Alphonse, FG
Ayoub, MA
Oqua, A
West, C
Lavery, S
Brosens, JJ
Reiter, E
Hanyaloglu, AC
Item Type: Journal Article
Abstract: Endocytic trafficking is a critical mechanism for cells to decode complex signaling pathways, including those activated by G-protein-coupled receptors (GPCRs). Heterogeneity in the endosomal network enables GPCR activity to be spatially restricted between early endosomes (EEs) and the recently discovered endosomal compartment, the very early endosome (VEE). However, the molecular machinery driving GPCR activity from the VEE is unknown. Using luteinizing hormone receptor (LHR) as a prototype GPCR for this compartment, along with additional VEE-localized GPCRs, we identify a role for the adaptor protein APPL1 in rapid recycling and endosomal cAMP signaling without impacting the EE-localized β2-adrenergic receptor. LHR recycling is driven by receptor-mediated Gαs/cAMP signaling from the VEE and PKA-dependent phosphorylation of APPL1 at serine 410. Receptor/Gαs endosomal signaling is localized to microdomains of heterogeneous VEE populations and regulated by APPL1 phosphorylation. Our study uncovers a highly integrated inter-endosomal communication system enabling cells to tightly regulate spatially encoded signaling.
Issue Date: 5-Dec-2017
Date of Acceptance: 3-Nov-2017
URI: http://hdl.handle.net/10044/1/53191
DOI: https://dx.doi.org/10.1016/j.celrep.2017.11.023
ISSN: 2211-1247
Publisher: Elsevier
Start Page: 2855
End Page: 2867
Journal / Book Title: Cell Reports
Volume: 21
Issue: 10
Copyright Statement: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Genesis Research Trust
Wellcome Trust
Genesis Research Trust
Genesis Research Trust
Funder's Grant Number: n/a
085099/Z/08/Z
01053
1075
Publication Status: Published
Appears in Collections:Department of Surgery and Cancer