biostudies-literatureHahn HNCI NIH HHSWellcome TrustJapan Science and Technology AgencyNIGMS NIH HHSBiotechnology and Biological Sciences Research CouncilLEO FondetJapan Society for the Promotion of ScienceRP99373https://www.ebi.ac.uk/biostudies/studies/S-EPMC11850004biostudies-literatureUnknown13Chemokine receptors are GPCRs that regulate the chemotactic migration of a wide variety of cells including immune and cancer cells. Most chemokine receptors contain features associated with the ability to stimulate G protein signaling during β-arrestin-mediated receptor internalization into endosomes. As endosomal signaling of certain non-GPCR receptors plays a major role in cell migration, we chose to investigate the potential role of endosomal chemokine receptor signaling on mechanisms governing this function. Applying a combination of pharmacological and cell biological approaches, we demonstrate that the model chemokine receptor CCR7 recruits G protein and β-arrestin simultaneously upon chemokine stimulation, which enables internalized receptors to activate G protein from endosomes. FueLifeEndosomal chemokine receptor signalosomes regulate central mechanisms underlying cell migration.PMC11850004R35GM147088215229/Z/19/ZJP24K2128110.52926/JPMJFR215TJP21H0511310.35802/215229JPJSBP12021880110.52926/JPMJMS2023JP21H04791JPJSBP120213501R35 GM147088BB/X002578/1R21 CA243052R21CA243052LF18043Flores-Espinoza EHahn HPerry-Hauser NAInoue AThomsen ARBPlouffe BDaly CLittle JfalseEndosomal chemokine receptor signalosomes regulate central mechanisms underlying cell migration.Chemokine receptors are GPCRs that regulate the chemotactic migration of a wide variety of cells including immune and cancer cells. Most chemokine receptors contain features associated with the ability to stimulate G protein signaling during β-arrestin-mediated receptor internalization into endosomes. As endosomal signaling of certain non-GPCR receptors plays a major role in cell migration, we chose to investigate the potential role of endosomal chemokine receptor signaling on mechanisms governing this function. Applying a combination of pharmacological and cell biological approaches, we demonstrate that the model chemokine receptor CCR7 recruits G protein and β-arrestin simultaneously upon chemokine stimulation, which enables internalized receptors to activate G protein from endosomes. Fu2025-01-01T00:00:00Z2025 Feb2025-04-03T23:44:22.913Z2025-04-03T23:44:22.913ZS-EPMC118500043999271110.7554/eLife.99373