Stromal cell-derived factor 1

Chemokine (C-X-C motif) ligand 12
PDB rendering based on 1a15.
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​
Identifiers
Symbols	CXCL12 ; IRH; PBSF; SCYB12; SDF1; TLSF; TPAR1
External IDs	OMIM: 600835 MGI: 103556 HomoloGene: 128606 GeneCards: CXCL12 Gene
Gene ontology Molecular function • receptor binding • chemokine activity • growth factor activity • chemokine receptor binding • CXCR chemokine receptor binding Cellular component • extracellular region • extracellular space • external side of plasma membrane • extracellular exosome Biological process • patterning of blood vessels • response to hypoxia • ameboidal-type cell migration • neuron migration • positive regulation of endothelial cell proliferation • cellular calcium ion homeostasis • chemotaxis • immune response • cell adhesion • signal transduction • G-protein coupled receptor signaling pathway • germ cell development • blood circulation • motor neuron axon guidance • regulation of actin polymerization or depolymerization • adult locomotory behavior • germ cell migration • response to radiation • response to heat • response to mechanical stimulus • response to virus • telencephalon cell migration • organ regeneration • positive regulation of dopamine secretion • T cell proliferation • response to peptide hormone • positive regulation of cell adhesion • positive regulation of axon extension involved in axon guidance • induction of positive chemotaxis • cell chemotaxis • chemokine-mediated signaling pathway • positive regulation of monocyte chemotaxis • positive regulation of calcium ion import • positive regulation of myoblast fusion • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage • negative regulation of leukocyte tethering or rolling • negative regulation of leukocyte apoptotic process • positive regulation of T cell migration Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6387	20315
Ensembl	ENSG00000107562	ENSMUSG00000061353
UniProt	P48061	P40224
RefSeq (mRNA)	NM_000609	NM_001012477
RefSeq (protein)	NP_000600	NP_001012495
Location (UCSC)	Chr 10: 44.37 – 44.39 Mb	Chr 6: 117.17 – 117.18 Mb
PubMed search

The stromal cell-derived factor 1 (SDF1) also known as C-X-C motif chemokine 12 (CXCL12) is a chemokine protein that in humans is encoded by the CXCL12 gene.

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.^[1]

Structure

SDF-1 is produced in two forms, SDF-1α/CXCL12a and SDF-1β/CXCL12b, by alternate splicing of the same gene.^[2] 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.

Function

Chemotaxis

CXCL12 is strongly chemotactic for lymphocytes.^[3][4][5][6] During embryogenesis it directs the migration of hematopoietic cells from foetal liver to bone marrow and the formation of large blood vessels. Mice that were knocked-out for CXCL12 gene were lethal before the birth or within just 1 hour of life.

In adulthood, CXCL12 plays an important role in angiogenesis by recruiting endothelial progenitor cells (EPCs) from the bone marrow through a CXCR4 dependent mechanism.^[7] It is this function of CXCL12 that makes it a very important factor in carcinogenesis and the neovascularisation linked to tumour progression.^[8] CXCL12 also has a role in tumor metastasis where cancer cells that express the receptor CXCR4 are attracted to metastasis target tissues that release the ligand, CXCL12.^[9] In breast cancer, however, increased expression of CXCL12 determines a reduced risk of distant metastasis.^[10][11]

In 2011, CXCL12 was shown to be responsible for recruiting macrophages to breast tumours in mice in response to the experimental anti-cancer drug combretastatin A-4 phosphate, which damages tumour blood vessels. This macrophage recruitment is believed to stimulate tumour blood vessel growth, counteracting the effects of the drug.

Blocking CXCR4, the receptor for CXCL12, with Plerixafor (AMD-3100) increased the effectiveness of combretastatin in a mouse model of breast cancer, it is presumed by preventing macrophages from being recruited to tumours.^[12][13]

CXCL12 is expressed in the area of inflammatory bone destruction. It is chemotactic for mesenchymal stem cells and mediates their suppressive effect on osteoclastogenesis.^[14]

Other

By blocking CXCR4, a major coreceptor for HIV-1 entry, CXCL12 acts as an endogenous inhibitor of CXCR4-tropic HIV-1 strains.^[15] CXCL12 was shown to be expressed in many tissues in mice (including brain, thymus, heart, lung, liver, kidney, spleen and bone marrow).

Receptor

The receptor for this chemokine is CXCR4, which was previously called LESTR or fusin.^[16] 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.^[17][18][19]

Gene

The gene for CXCL12 is located on human chromosome 10.^[20][21] In human and mouse both CXCL12 and CXCR4 show high identity of sequence: 99% and 90%, respectively.

References

1. "Entrez Gene: CXCL12 chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1)".
2. De La Luz Sierra M, Yang F, Narazaki M, Salvucci O, Davis D, Yarchoan R, Zhang HH, Fales H, Tosato G (Apr 2004). "Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity". Blood 103 (7): 2452–9. doi:10.1182/blood-2003-08-2857. PMID 14525775.
3. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA (Sep 1996). "A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1)". The Journal of Experimental Medicine 184 (3): 1101–9. doi:10.1084/jem.184.3.1101. PMC 2192798. PMID 9064327.
4. Ara T, Nakamura Y, Egawa T, Sugiyama T, Abe K, Kishimoto T, Matsui Y, Nagasawa T (Apr 2003). "Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1)". Proceedings of the National Academy of Sciences of the United States of America 100 (9): 5319–23. doi:10.1073/pnas.0730719100. PMC 154343. PMID 12684531.
5. Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS (Aug 2003). "Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy". Lancet 362 (9385): 697–703. doi:10.1016/S0140-6736(03)14232-8. PMID 12957092.
6. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA (Aug 1998). "Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice". Proceedings of the National Academy of Sciences of the United States of America 95 (16): 9448–53. doi:10.1073/pnas.95.16.9448. PMC 21358. PMID 9689100.
7. Zheng H, Fu G, Dai T, Huang H (Sep 2007). "Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1alpha/CXCR4 via PI3K/Akt/eNOS signal transduction pathway". Journal of Cardiovascular Pharmacology 50 (3): 274–80. doi:10.1097/FJC.0b013e318093ec8f. PMID 17878755.
8. Kryczek I, Wei S, Keller E, Liu R, Zou W (Mar 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.
9. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A (Mar 2001). "Involvement of chemokine receptors in breast cancer metastasis". Nature 410 (6824): 50–6. doi:10.1038/35065016. PMID 11242036.
10. Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A, Pfeffer U (Sep 2009). "CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival". European Journal of Cancer 45 (14): 2579–87. doi:10.1016/j.ejca.2009.06.026. PMID 19646861.
11. Wendt MK, Cooper AN, Dwinell MB (Feb 2008). "Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells". Oncogene 27 (10): 1461–71. doi:10.1038/sj.onc.1210751. PMID 17724466.
12. Welford AF, Biziato D, Coffelt SB, Nucera S, Fisher M, Pucci F, Di Serio C, Naldini L, De Palma M, Tozer GM, Lewis CE (May 2011). "TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice". The Journal of Clinical Investigation 121 (5): 1969–73. doi:10.1172/JCI44562. PMC 3083764. PMID 21490397.
13. , Cancer Research UK blog.
14. Takano T, Li YJ, Kukita A, Yamaza T, Ayukawa Y, Moriyama K, Uehara N, Nomiyama H, Koyano K, Kukita T (Mar 2014). "Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis". Laboratory Investigation 94 (3): 286–96. doi:10.1038/labinvest.2013.152. PMID 24395111.
15. Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF, Loetscher M, Baggiolini M, Moser B (Aug 1996). "The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1". Nature 382 (6594): 833–5. doi:10.1038/382833a0. PMID 8752281.
16. Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, Springer TA (Aug 1996). "The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry". Nature 382 (6594): 829–33. doi:10.1038/382829a0. PMID 8752280.
17. Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F (Oct 2005). "The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes". The Journal of Biological Chemistry 280 (42): 35760–6. doi:10.1074/jbc.M508234200. PMID 16107333.
18. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ (Sep 2006). "A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development". The Journal of Experimental Medicine 203 (9): 2201–13. doi:10.1084/jem.20052144. PMC 2118398. PMID 16940167.
19. Cruz-Orengo L, Holman DW, Dorsey D, Zhou L, Zhang P, Wright M, McCandless EE, Patel JR, Luker GD, Littman DR, Russell JH, Klein RS (Feb 2011). "CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity". The Journal of Experimental Medicine 208 (2): 327–39. doi:10.1084/jem.20102010. PMC 3039853. PMID 21300915.
20. Shirozu M, Nakano T, Inazawa J, Tashiro K, Tada H, Shinohara T, Honjo T (Aug 1995). "Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene". Genomics 28 (3): 495–500. doi:10.1006/geno.1995.1180. PMID 7490086.
21. Deloukas P, Earthrowl ME, Grafham DV, Rubenfield M, French L, Steward CA, et al. (May 2004). "The DNA sequence and comparative analysis of human chromosome 10". Nature 429 (6990): 375–81. doi:10.1038/nature02462. PMID 15164054.

Further reading

• Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ (Aug 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.
• Kryczek I, Wei S, Keller E, Liu R, Zou W (Mar 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.
• Stellos K, Gawaz M (Mar 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.
• Wang J, Liu X, Lu H, Jiang C, Cui X, Yu L, Fu X, Li Q, Wang J (Mar 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.