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

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Sposini, Silvia, Jean-Alphonse, Frederic G., Ayoub, Mohammed A., Oqua, Affiong, West, Camilla, Lavery, Stuart, Brosens, Jan J., Reiter, Eric and Hanyaloglu, Aylin C. (2017) Integration of GPCR signaling and sorting from very early endosomes via opposing APPL1 mechanisms. Cell Reports, 21 (10). pp. 2855-2867. doi:10.1016/j.celrep.2017.11.023 ISSN 2211-1247.

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Official URL: http://dx.doi.org/10.1016/j.celrep.2017.11.023

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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.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Luteinizing hormone -- Receptors, Endosomes, Cell receptors
Journal or Publication Title: Cell Reports
Publisher: Elsevier Inc.
ISSN: 2211-1247
Official Date: 5 December 2017
Dates:
DateEvent
5 December 2017Published
3 November 2017Accepted
Volume: 21
Number: 10
Page Range: pp. 2855-2867
DOI: 10.1016/j.celrep.2017.11.023
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 7 December 2017
Date of first compliant Open Access: 7 December 2017
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
WT085099MAWellcome Trusthttp://dx.doi.org/10.13039/100004440
P15844 Genesis Research Trusthttp://dx.doi.org/10.13039/100012156
P67019Genesis Research Trusthttp://dx.doi.org/10.13039/100012156
President’s ScholarshipImperial College Londonhttp://dx.doi.org/10.13039/501100000761
UNSPECIFIEDStudium Loire Valley-Institute for Advanced Studieshttp://dx.doi.org/10.13039/501100009377
UNSPECIFIEDAgreenSkills (Organisation)UNSPECIFIED

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