title: Spatially restricted G protein-coupled receptor activity via divergent endocytic compartments.
abstract: Postendocytic sorting of G protein-coupled receptors (GPCRs) is driven by their interactions between highly diverse receptor sequence motifs with their interacting proteins, such as postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), zonula occludens-1 protein (zo-1) (PDZ) domain proteins. However, whether these diverse interactions provide an underlying functional specificity, in addition to driving sorting, is unknown. Here we identify GPCRs that recycle via distinct PDZ ligand/PDZ protein pairs that exploit their recycling machinery primarily for targeted endosomal localization and signaling specificity. The luteinizing hormone receptor (LHR) and β2-adrenergic receptor (B2AR), two GPCRs sorted to the regulated recycling pathway, underwent divergent trafficking to distinct endosomal compartments. Unlike B2AR, which traffics to early endosomes (EE), LHR internalizes to distinct pre-early endosomes (pre-EEs) for its recycling. Pre-EE localization required interactions of the LHR C-terminal tail with the PDZ protein GAIP-interacting protein C terminus, inhibiting its traffic to EEs. Rerouting the LHR to EEs, or EE-localized GPCRs to pre-EEs, spatially reprograms MAPK signaling. Furthermore, LHR-mediated activation of MAPK signaling requires internalization and is maintained upon loss of the EE compartment. We propose that combinatorial specificity between GPCR sorting sequences and interacting proteins dictates an unprecedented spatiotemporal control in GPCR signal activity.
authors.affiliation: From the Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom and.
authors.forename: Frederic
authors.initials: F
authors.lastname: Jean-Alphonse
authors.forename: Shanna
authors.initials: S
authors.lastname: Bowersox
authors.forename: Stanford
authors.initials: S
authors.lastname: Chen
authors.forename: Gemma
authors.initials: G
authors.lastname: Beard
authors.forename: Manojkumar A
authors.initials: MA
authors.lastname: Puthenveedu
authors.forename: Aylin C
authors.initials: AC
authors.lastname: Hanyaloglu
mesh_terms: D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein
keywords: Endocytosis; Endosomes; G Protein-coupled Receptor (GPCR); GAIP-interacting Protein C Terminus (GIPC); Receptor Recycling; Signaling; Sorting