CXCL12 (stromal cell-derived factor-1, SDF1) is a chemokine that regulates development in hematopoietic, cardiovascular and nervous systems, and also regulates diverse cell functions, including differentiation, immune synapse formation, proliferation and survival in the immune system []. CXCL12 has two known receptors, CXCR4 and ACKR3/RDC [, ]. Binding of CXCL12 to CXCR4 induces trimeric G protein signaling leading to activation of the Src, phosphoinositide-3 kinase (PI3K)/AKT, ERK, and JNK pathways, contributing to pro-inflammatory function such as protease production and cellular migration [, ].CXCL12 is constitutively expressed in many tissues. It may also be upregulated in the context of infection and inflammation, acting both as a homeostatic and inflammatory chemokine [].
CXC chemokine receptor 4 (CXCR4), also known as fusin, which is a specific receptor for a CXCL12 (or SDF1). CXCR4 has a wide cellular distribution, with expression on most immature and mature hematopoietic cell types [, , , , ]. In addition, CXCR4 can also be found on vascular endothelial cells and neuronal/nerve cells []. Upon binding to CXCR4, CXCL12 causes mobilisation of intracellular calcium and chemotaxis [, , ]. CXCL12 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. CXCR4 has a rather broad activity, and has been linked to cardiac, cerebellar gastric vasculature development [, ]and to hematopoiesis []. Atypical chemokine receptor 2 (ACKR2/D6) []is a chemokine-scavenging receptor or chemokine decoy receptor. It is capable of internalising and effectively scavenging its ligands through beta-arrestin-dependent activation of the cofilin pathway [, ]. ACKR2 is highly promiscuous and can bin the majority of (if not all) inflammatory CC-chemokines []. It plays an essential role in the resolution of the inflammatory response [, , ]. Although it lacks the canonical DRYLAIV motif necessary for classical signalling, ACKR2/D6 may be involved in 'atypical' signaling pathways downstream of ligand binding []. It has been shown to be involved in regulating vessel density [].
Synaptotagmin-3 (SYT3) belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains. Most of the synaptotagmins have a unique N-terminal domain that is involved in membrane anchoring or specific ligand binding. SYT3 is required for the formation and delivery of cargo to the perinuclear endocytic recycling compartment (ERC) []. Among synaptotagmins 1-11, SYT3 is the only one that is expressed in T cells. It is essential for chemokine receptor CXCR4 recycling in T cells and thereby affects CXCL12 chemokine-induced migration [].
Just like classical chemokine receptors, atypical chemokine receptors (ACKRs) are seven-transmembrane-helix (7TM) receptors that bind chemokines []. However, they lack the canonical DRYLAIV motif necessary for GPCR coupling to G proteins and induction of classical signalling pathways. Instead, ACKRs internalise their chemokine ligands, which may subsequently affect chemokine availability. The ACKR family comprises five members: Duffy Antigen Receptor for Chemokines (DARC, ACKR1), D6 (ACKR2), CXCR7 (ACKR3), CCRL1 (ACKR4) and CCRL2 (ACKR5) [].Atypical chemokine receptor 3 (ACKR3), previously known as CXC chemokine receptor 7 (CXCR7), is regarded as a scavenger for CXCL12 and, to a lesser extent, for CXCL11 []. Unlike other CXC chemokine receptors, ACKR3 does not elicit classical chemokine receptor signalling via typical G protein-mediated pathways [], but instead induces beta-arrestin recruitment, leading to ligand internalisation and activation of MAPK signaling pathway [, ].ACKR3/CXCR7 has been identified on memory B cells and in mammals is found in bone, brain, heart and kidney [, ]. It has been shown to act as a novel coreceptor for several immunodeficiency virus strains, which infect brain-derived cells []. Studies in zebrafish have also revealed a critical role in vascular formation and angiogenesis during development []. ACKR3/CXCR7 is a functional receptor for CXCL12 in astrocytomas/glioblastomas and mediates resistance to drug-induced apoptosis []. It has been shown to promote growth of tumors formed from breast and lung cancer cells [].
