CXCL12
Description
The CXCL12 (C-X-C motif chemokine ligand 12) is a protein-coding gene located on chromosome 10.
Stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is a chemokine protein that in humans is encoded by the CXCL12 gene on chromosome 10. It is ubiquitously expressed in many tissues and cell types. Stromal cell-derived factors 1-alpha and 1-beta are small cytokines that belong to the chemokine family, members of which activate leukocytes and are often induced by proinflammatory stimuli such as lipopolysaccharide, TNF, or IL1. The chemokines are characterized by the presence of 4 conserved cysteines that form 2 disulfide bonds. They can be classified into 2 subfamilies. In the CC subfamily, the cysteine residues are adjacent to each other. In the CXC subfamily, they are separated by an intervening amino acid. The SDF1 proteins belong to the latter group. CXCL12 signaling has been observed in several cancers. The CXCL12 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
CXCL12 is a chemoattractant for T-lymphocytes and monocytes, but not neutrophils. It activates the chemokine receptor CXCR4, leading to a rapid increase in intracellular calcium levels and cell migration (chemotaxis). Shorter forms of CXCL12, SDF-1-beta(3-72) and SDF-1-alpha(3-67), have reduced chemotactic activity. Binding of CXCL12 to cell surface proteoglycans inhibits the formation of SDF-1-alpha(3-67), preserving its activity locally. CXCL12 also interacts with the atypical chemokine receptor ACKR3, triggering the beta-arrestin pathway and acting as a scavenger for CXCL12. It binds to the allosteric site of integrins, activating ITGAV:ITGB3, ITGA4:ITGB1, and ITGA5:ITGB1 independently of CXCR4. CXCL12 positively regulates monocyte migration and negatively regulates monocyte adhesion through the LYN kinase. It promotes migration of monocytes and T-lymphocytes through CXCR4 and ACKR3, and reduces monocyte adherence to ICAM-1, a ligand for beta-2 integrins. The SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1-mediated adhesion of monocytes to ICAM-1 through LYN kinase. CXCL12 inhibits CXCR4-mediated infection by T-cell line-adapted HIV-1. It plays a protective role after myocardial infarction and induces downregulation and internalization of ACKR3 in various cells. CXCL12 is crucial for embryonic development, required for B-cell lymphopoiesis, myelopoiesis in bone marrow, and heart ventricular septum formation. It stimulates the proliferation of bone marrow-derived B-cell progenitors in the presence of IL7 and the growth of stromal cell-dependent pre-B-cells. CXCL12 exists as a monomer or homodimer, with dimer formation induced by non-acidic pH, multivalent anions, and binding to CXCR4 or heparin. The monomeric form is necessary for full chemotactic activity and resistance to ischemia/reperfusion injury, while the dimeric form acts as a partial agonist of CXCR4, stimulating Ca2+ mobilization but without chemotactic activity. Instead, the dimeric form acts as a selective antagonist, blocking chemotaxis induced by the monomeric form. CXCL12 interacts with the N-terminus of ACKR3, the integrin subunit ITGB3 (via the allosteric site), and TNFAIP6 (via the Link domain). It also interacts with the molluscum contagiosum virus protein MC148.
CXCL12 is also known as IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1.
