Endosomal chemokine receptor signalosomes regulate central mechanisms underlying cell migration

Chemokine receptors are GPCRs that regulate 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 proteins during β-arrestin-mediated 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 cell biological approaches and spatiotemporal-resolved proteome profiling, we demonstrate that the model chemokine receptor CCR7 recruits G protein and β-arrestin simultaneously upon chemokine stimulation enabling internalized receptors to activate G protein from endosomes. Furthermore, endosomal CCR7 uniquely enriches specific Rho-GTPase regulators as compared to plasma membrane CCR7, which is associated with enhanced activity of Rho-GTPase Rac1. As Rac1 drives the formation of membrane protrusions during chemotaxis, our findings suggest an important integrated function of endosomal chemokine receptor signaling in cell migration.