CXCL12

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CXCL12
CXCL12
Ribbon model of the CXCL12A dimer according to PDB  1A15

Existing structural data : 1a15 , 1qg7 , 1sdf , 1vmc , 2j7z , 2nwg , 2sdf

Properties of human protein
Mass / length primary structure 72 AS ; 8.5  kDa
Isoforms alpha, beta
Identifier
Gene names CXCL12  ; PBSF; SCYB12; SDF-1a; SDF-1b; SDF1; SDF1A; SDF1B; TLSF-a; TLSF-b; TPAR1
External IDs
Occurrence
Homology family Small inducible cytokines
Parent taxon Vertebrates
Orthologue
human House mouse
Entrez 6387 20315
Ensemble ENSG00000107562 ENSMUSG00000061353
UniProt P48061 P40224
Refseq (mRNA) NM_000609 NM_001012477
Refseq (protein) NP_000600 NP_001012495
Gene locus Chr 10: 44.29 - 44.39 Mb Chr 6: 117.17 - 117.18 Mb
PubMed search 6387 20315

CXCL12 (short for CXC motif chemokine 12 , also stromal cell-derived factor 1 (SDF-1) or pre-B cell growth-stimulating factor (PBSF) ) is an endogenous messenger substance from the group of CXC motif chemokines . As a chemotactic cytokine , that is, it controls cell movement , this peptide plays a key role in the mobilization and targeted migration of stem cells into their storage (e.g. fetal liver , bone marrow ) or their places of use in the formation of organs ( organogenesis ) as well organ and wound healing . CXCL12 is also involved in the growth and metastatic spread of tumors , as well as in inflammatory processes. This chemokine mediates its effects by binding to two different chemokine receptors , CXCR4 and CXCR7 .

Occurrence

CXCL12 is produced in high concentrations in the bone marrow and is used here to recruit and anchor haematopoietic stem cells . In addition, CXCL12 is released from other organs, especially the lungs , spleen and liver . An increased expression of CXCL12 can be detected in various tumor types.

biochemistry

structure

CXCL12 is a protein with a molar mass of about 8  kDa , which is encoded by a gene on chromosome 10 gene locus q11. The amino acid sequence of this basic protein is largely conserved within mammals , which shows the 99% homology between human and mouse CXCL12. Various isoforms of CXCL12 formed by alternative splicing are known, SDF-1α and SDF-1β in particular being of physiological importance. Like all CXC chemokines, CXCL12 is characterized by two cysteine pairs, with the first N-terminal cysteines separated from one another by an amino acid .

Receptor activation

CXCL12 mediates its effects by binding and activating the chemokine receptors CXCR4 or CXCR7 expressed on the cell surface. These receptors belong to the family of G protein-coupled receptors . The binding and activation of CXCL12 to CXCR4 is believed to be a two-step process. In a first step, CXCL12 binds to the extracellular N-terminus of the receptor. The N-terminal end of the chemokine can then dip into the binding pocket of CXCR4, which lies within the transmembrane domains of the receptor, and activate it. The activation of CXCR7, on the other hand, is considered to be less well investigated.

function

Stem cell mobilization

The main function of CXCL12 is to control the migration of stem cells that express the CXCL12 receptor CXCR4. In connection with this, CXCL12 plays a crucial role in anchoring stem cells in their storage locations and in organogenesis. Knockout mice lacking CXCL12 or its CXCR4 receptor are not viable due to severe organ damage. After birth, CXCL12 plays an important role in angiogenesis , wound healing and organ repair.

Inflammation

Increased synthesis of CXCL12 in inflamed tissues and a chemotactic effect on CXCR4-expressing lymphocytes has been implicated in a role in inflammatory diseases.

cancer

Since the great majority of all tumors express the CXCL12 receptors CXCR4 or CXCR7, CXCL12 shows a chemotactic effect on most tumor cells. This chemotactic effect is one of the main causes of the formation of metastases , which particularly affect places with high CXCL12 production rates, especially the bone marrow, lungs and liver. In addition, CXCL12 supports tumor growth by promoting angiogenesis.

HIV

In addition to the chemotactic effect of CXCL12 on stem cells, tumor cells and inflammatory cells, an inhibitory effect on HI viruses was demonstrated for CXCL12 . This is attributed to a CXCL12-induced internalization of the receptor CXCR4, a co-receptor for the uptake of HIV-1 into the host cell.

Individual evidence

  1. ↑ Burns et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med . 203: 2201-2213, 2006.
  2. ↑ Gupta SK, Pillarisetti K, Thomas RA, Aiyar N: Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1alpha: implications for development of selective CXCR4 antagonists . In: Immunology letters . 78, No. 1, August 2001, pp. 29-34. doi : 10.1016 / S0165-2478 (01) 00228-0 . PMID 11470148 .
  3. ↑ Crump MP, Gong JH, Loetscher P, et al. : Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1 . In: The EMBO journal . 16, No. 23, December 1997, pp. 6996-7007. doi : 10.1093 / emboj / 16.23.6996 . PMID 9384579 . PMC 1170303 (free full text).
  4. ↑ Ma Q. et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc. Natl. Acad. Sci. 95: 9448-9453,1998.
  5. ↑ Nagasawa T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF / SDF-1. Nature 382: 635-637, 1996.
  6. ↑ Zou YR et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393: 595-599, 1998.
  7. ↑ Bleul CC et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR / fusin and blocks HIV-1 entry. Nature 382: 829-833, 1996.