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CXCL12
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1A15, 1QG7, 1SDF, 1VMC, 2J7Z, 2K01, 2K03, 2K04, 2K05, 2KEC, 2KED, 2KEE, 2KOL, 2NWG, 2SDF, 3GV3, 3HP3, 4LMQ, 4UAI, 2N55
Identifiers
Aliases	CXCL12, IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1, C-X-C motif chemokine ligand 12
External IDs	OMIM: 600835; MGI: 103556; HomoloGene: 128606; GeneCards: CXCL12; OMA:CXCL12 - orthologs
Gene location (Human) Chr. Chromosome 10 (human) Band 10q11.21 Start 44,370,165 bp End 44,386,493 bp
Gene location (Mouse) Chr. Chromosome 6 (mouse) Band 6 54.81 cM|6 F1 Start 117,145,496 bp End 117,158,328 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in synovial joint pericardium lactiferous duct skin of hip trabecular bone parietal pleura synovial membrane superficial temporal artery gallbladder vena cava Top expressed in stroma of bone marrow tibiofemoral joint Gonadal ridge vas deferens internal carotid artery spleen ankle ankle joint external carotid artery thymus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function chemokine receptor binding cytokine activity chemokine activity CXCR chemokine receptor binding chemoattractant activity growth factor activity signaling receptor binding integrin binding protein binding Cellular component plasma membrane extracellular region extracellular exosome external side of plasma membrane extracellular space cytoplasm nucleus collagen-containing extracellular matrix Biological process negative regulation of leukocyte tethering or rolling G protein-coupled receptor signaling pathway regulation of calcium ion transport response to hypoxia positive regulation of endothelial cell proliferation positive regulation of cell migration chemokine-mediated signaling pathway adult locomotory behavior response to mechanical stimulus response to peptide hormone positive regulation of monocyte chemotaxis cellular calcium ion homeostasis response to virus neuron migration response to heat negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage positive regulation of axon extension involved in axon guidance blood circulation telencephalon cell migration chemotaxis regulation of actin polymerization or depolymerization positive regulation of calcium ion import brain development cell adhesion positive regulation of dopamine secretion animal organ regeneration positive regulation of neuron differentiation immune response positive regulation of cell population proliferation cell chemotaxis negative regulation of leukocyte apoptotic process response to radiation positive regulation of T cell migration positive regulation of cell adhesion signal transduction positive chemotaxis induction of positive chemotaxis defense response response to ultrasound antimicrobial humoral immune response mediated by antimicrobial peptide T cell chemotaxis detection of temperature stimulus involved in sensory perception of pain detection of mechanical stimulus involved in sensory perception of pain regulation of signaling receptor activity axon guidance viral process integrin activation chemokine (C-X-C motif) ligand 12 signaling pathway cellular response to chemokine negative regulation of dendritic cell apoptotic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6387 20315 Ensembl ENSG00000107562 ENSMUSG00000061353 UniProt P48061 P40224 RefSeq (mRNA) NM_199168 NM_000609 NM_001033886 NM_001178134 NM_001277990 NM_001012477 NM_013655 NM_021704 RefSeq (protein) NP_000600 NP_001029058 NP_001171605 NP_001264919 NP_954637 NP_001012495 NP_038683 NP_068350 Location (UCSC) Chr 10: 44.37 – 44.39 Mb Chr 6: 117.15 – 117.16 Mb PubMed search
Wikidata
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The 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.

Structure

Gene

The CXCL12 gene resides on chromosome 10 at the band 10q11.21 and contains 4 exons.. This gene produces 7 isoforms through alternative splicing.

Protein

This protein belongs to the intercrine alpha (chemokine CXC) family. SDF-1 is produced in two forms, SDF-1α/CXCL12a and SDF-1β/CXCL12b, by alternate splicing of the same gene. Chemokines are characterized by the presence of four conserved cysteines, which form two disulfide bonds. The CXCL12 proteins belong to the group of CXC chemokines, whose initial pair of cysteines are separated by one intervening amino acid. In addition, the first 8 residues of the CXCL12 N-terminal serve as a receptor binding site, though only Lys-1 and Pro-2 directly participated in activating the receptor. Meanwhile, the RFFESH motif (residues 12-17) in the loop region function as a docking site for CXCL12 receptor binding.

Function

CXCL12 is expressed in many tissues in mice including brain, thymus, heart, lung, liver, kidney, spleen, platelets and bone marrow. CXCL12 is strongly chemotactic for lymphocytes. During embryogenesis, it directs the migration of hematopoietic cells from fetal liver to bone marrow and the formation of large blood vessels. It has also been shown that CXCL12 signalling regulates the expression of CD20 on B cells. CXCL12 is also chemotactic for mesenchymal stem cells and is expressed in the area of inflammatory bone destruction, where it mediates their suppressive effect on osteoclastogenesis.

In adulthood, CXCL12 plays an important role in angiogenesis by recruiting endothelial progenitor cells (EPCs) from the bone marrow through a CXCR4 dependent mechanism.

CXCR4, previously called LESTR or fusin, is the receptor for CXCL12. This CXCL12-CXCR4 interaction used to be considered exclusive (unlike for other chemokines and their receptors), but recently, it was suggested that CXCL12 may also bind the CXCR7 receptor (now called ACKR3). By blocking CXCR4, a major coreceptor for HIV-1 entry, CXCL12 acts as an endogenous inhibitor of CXCR4-tropic HIV-1 strains.

CNS

During embryonic development, CXCL12 plays a role in cerebellar formation through the migration of neurons. Within the CNS, CXCL12 contributes to cell proliferation, neurogenesis (nervous tissue development and growth), as well as neuroinflammation. Neural progenitor cells (NPCs) are stem cells that differentiate into glial and neuronal cells. CXCL12 promotes their migration to lesion sites within the brain, specifically over extensive ranges. Once at the site of damage, NPCs may begin stem cell based tissue repair to the lesion. The CXCL12/CXCR4 axis provides guidance cues for axons and neurites hence promoting neurite outgrowth (neurons forming projections) and neurogenesis. Like other chemokines, CXCL12 is involved with cell migration that contributes to inflammation. In regards to the CNS, CXCL12 plays a role in neuroinflammation by attracting leukocytes across the blood brain barrier. however, excessive production and accumulation of CXCL12 can become toxic and the inflammation produced may result in serious consequences.

Clinical significance

In humans, CXCL12 has been implicated in a wide variety of biomedical conditions involving several organ systems. Furthermore, CXCL12 signaling in conjunction with CXCR7 signaling has been implicated in the progression of pancreatic cancer. In the urinary tract system, methylation of the CXCL12 promoter and expression of PD-L1 may be powerful prognostic biomarkers for biochemical recurrence in prostate carcinoma patients after radical prostatectomy, and further studies are ongoing to confirm if CXCL12 methylation may aid in active surveillance strategies. In the field of oncology, melanoma associated fibroblasts are stimulated by stimulation of the A2B adenosine receptor followed by stimulation of fibroblast growth factor and increased expression of CXCL12.

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the CXCL12 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).

Multiple Sclerosis

A neurological condition that results from a faulty interaction between the immune and nervous systems in multiple sclerosis. MS is characterized by demyelination of nerves due to the body's immune system attacking the CNS. Elevated levels of CXCL12 are observed in the cerebral spinal fluid of patients with MS. CXCL12 crosses the blood–brain barrier and causes neuroinflammation that contributes to axonal damage and therefore the progression of multiple sclerosis.

Alzheimer's disease

Though CXCL12 may be detrimental for those with MS, recent research is suggesting that this chemokine may be beneficial in decreasing the progression of patients with Alzheimer's. Alzheimer's is another neurological condition and the most common form of dementia where cognition significantly declines. One main characteristic of Alzheimer's is the accumulation of a brain plaque known as beta-amyloid. There are neuroprotective aspects of CXCL12 in mice with these plaques/Alzheimer's. PAK is a protein associated with maintaining dendritic spines, which are essential at synapses in receiving information from axons. Mislocalization of PAK occurs in patients with Alzheimer's, however pretreatment of neurons in mice with CXCL12 showed a suppression of that mislocalization. Additionally, this pretreatment with CXCL decreased the prevalence of apoptosis and oxidative damage normally caused by the presence of the beta-amyloid plaque.

As a drug target

Chemokines and chemokine receptors, of which CXCR stands out, regulate multiple processes such as morphogenesis, angiogenesis, and immune responses and are considered potential targets for drug development. It is indicated by clinical samples that a high expression level of CXCR4 in idiopathic pulmonary fibrosis lungs. Experimental evidence further indicate that CXCR4/CXCR12 is associated with the pathogenesis of lung fibrosis. In the gastrointestinal tract system, the CXCL12-CXCR4 axis is under investigation as an anti-fibrotic therapy in the treatment for chronic pancreatitis. For instance, blocking CXCR4, the receptor for CXCL12, with Plerixafor (AMD-3100) increased the effectiveness of combretastatin in a mouse model of breast cancer, presumably by preventing macrophages from being recruited to tumours. AMD-3100 is also widely used in combination with G-CSF for mobilizing hematopoietic stem cells into the blood stream, allowing collection for bone marrow transplant.

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Further reading

• Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ (August 2005). "Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis". Stem Cells. 23 (7): 879–94. doi:10.1634/stemcells.2004-0342. PMID 15888687. S2CID 22504846.
• Kryczek I, Wei S, Keller E, Liu R, Zou W (March 2007). "Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis". American Journal of Physiology. Cell Physiology. 292 (3): C987–95. doi:10.1152/ajpcell.00406.2006. PMID 16943240. S2CID 7423893.
• Stellos K, Gawaz M (March 2007). "Platelets and stromal cell-derived factor-1 in progenitor cell recruitment". Seminars in Thrombosis and Hemostasis. 33 (2): 159–64. doi:10.1055/s-2007-969029. PMID 17340464. S2CID 260320898.
• Wang J, Liu X, Lu H, Jiang C, Cui X, Yu L, Fu X, Li Q, Wang J (March 2015). "CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice". Brain, Behavior, and Immunity. 45: 98–108. doi:10.1016/j.bbi.2014.12.015. PMC 4342301. PMID 25526817.
• Arya M, Ahmed H, Silhi N, Williamson M, Patel HR (2007). "Clinical importance and therapeutic implications of the pivotal CXCL12-CXCR4 (chemokine ligand-receptor) interaction in cancer cell migration". Tumour Biology. 28 (3): 123–31. doi:10.1159/000102979. PMID 17510563. S2CID 44356923.

• Genes on human chromosome 10
• Cytokines