Fig. 1.

Chemokine signaling through CCR5 and CXCR4. Both CCR5 and CXCR4 can signal through a multitude of pathways, only some of which are represented here. A In response to its cognate ligands CCL3, CCL4, and CCL5 (CCL4 shown as a representative ligand), CCR5 can signal through a variety of G-protein dependent and independent pathways. These signaling processes broadly modulate chemotaxis and inflammation. While CCR5 acts through G_αi, G_αq (not shown) and G_βγ, the G_βγ subunit may regulate the majority of downstream signaling, including PLCβ activation, PI3K activation, and the downstream activation of AMPKs and MAPKs, particularly p38 MAPK. G_αi can also interact with Src family kinases, leading to the activation of MAPKs via small GTPase activation, which in turn regulates the chemotactic effects of this receptor. Independent of G proteins, CCR5 signaling can also be mediated through interaction with β-arrestins and the JAK family, activating ERK1/2 and STAT respectively. B CXCR4 signaling is also mediated through G_αi and G_βγ, and in certain contexts CXCR4 can also couple to G_α13. In addition to regulating chemotaxis, CXCR4 signaling also has significant effects on cell survival and proliferation. As with CCR5, PI3K and MAPK activation are central to these signaling pathways and are largely responsible for mediating the effects of CXCL12-CXCR4. The similarities in the signaling pathways between these two receptors highlight how the same effectors can regulate vastly different physiological effects, demonstrating the complexity of studying chemokine receptor signaling. Solid arrows represent defined, published pathways while dashed arrows represent pathways that have not been directly demonstrated but are likely to occur based on the current understanding of GPCR signaling