Alternative titles; symbols
HGNC Approved Gene Symbol: PF4V1
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:73,853,296-73,854,483 (from NCBI)
The chemokine family of chemotactic cytokines contains small proteins that signal via G protein-coupled receptors, designated CC chemokine receptors (CCRs; see 601159) or CXC chemokine receptors (CXCRs; see 146929). Chemokines regulate leukocyte recruitment to inflammatory sites, as well as leukocyte traffic between immunologic compartments. Other target cells of chemokines include tumor cells and endothelial cells, and consequently chemokines play a role in tumor development. PF4V1, or CXCL4L1, is a chemokine with angiostatic and chemotactic activities that are mediated by CXCR3 (300574) (Struyf et al., 2011).
Green et al. (1989) used a synthetic DNA probe designed to detect coding sequences for platelet factor-4 (PF4; 173460) and connective tissue-activating peptide III (121010), both human platelet alpha-granule proteins, to identify a variant of the PF4 gene, PF4V1. PF4V1 contains a 34-amino acid hydrophobic leader sequence that shares 70% sequence homology with the leader sequence of PF4, followed by a 42-amino acid segment that is 100% identical with the corresponding segment of the mature PF4 sequence, and a 28-residue C-terminal region corresponding to a domain specifying heparin-binding and cellular chemotaxis.
Eisman et al. (1990) also cloned the PF4A gene. Compared with PF4, the PF4A gene shows 14% DNA and 38% amino acid divergence in the signal peptide region, and 2.6% DNA and 4.3% amino acid divergence in the coding region of the mature protein.
By binding analyses, Struyf et al. (2011) found that human CXCL4L1 had lower affinity for heparin and chondroitin sulfate-E than did CXCL4 (PF4) and that CXCL10 (147310) and CXCL4L1 could displace each other on human microvascular endothelial cells. CXCL4L1 bound to both isoforms of CXCR3, CXCR3A and CXCR3B. Antibodies to CXCR3 blocked CXCL4L1 antiangiogenic activity, and human CXCL4L1 activity was reduced in mice treated with anti-human CXCR3 or in mice lacking Cxcr3, as assessed by tumor growth and vascularization of Lewis lung carcinoma. Like CXCL4, CXCL4L1 attracted activated T, natural killer, and dendritic cells, but preincubation with CXCL10 and CXCL11 (604852), pertussis toxin, or anti-CXCR3 reduced or neutralized this activity. Struyf et al. (2011) concluded that CXCR3A and CXCR3B are involved in the chemotactic and vascular effects of CXCL4L1.
Green et al. (1989) reported that the PF4V1 gene contains 3 exons.
Human Gene Mapping Workshop 10.5 assigned the PF4V1 gene to chromosome 4q12-q21, the same region as that which carries the PF4, IP10 (147310), and MGSA (155730) genes. Green et al. (1989) suggested that the polymorphism detected in the PF4 gene by Guzzo et al. (1987) was in fact a polymorphism of the PF4V1 gene.
By means of pulsed field gel electrophoresis, Poncz et al. (1991) demonstrated that the PF4V1 and beta-thromboglobulin genes are located in a region of less than 190 kb. The 2 PF4 genes lie within about 6 kb of each other and are oriented in the same 5-prime to 3-prime direction. The beta-thromboglobulin gene lies upstream of the PF4 gene.
Using PCR of a radiation hybrid panel, Modi and Chen (1998) mapped the PF4V1 gene to a 1.8-cR interval on 4q. This tight cluster contains many members of the CXC chemokine subfamily, and 2 additional genes, IL8 and MIG (601704), are located about 6 cR distal to this group. Modi and Chen (1998) suggested that these chemokine genes are all derived through tandem gene duplication from an ancestral gene located on chromosome 4, and that the position of SDF1 (600835) on chromosome 10 represents a translocation event.
Eisman, R., Surrey, S., Ramachandran, B., Schwartz, E., Poncz, M. Structural and functional comparison of the genes for human platelet factor 4 and PF4-alt. Blood 76: 336-344, 1990. [PubMed: 1695112]
Green, C. J., St. Charles, R., Edwards, B. F. P., Johnson, P. H. Identification and characterization of PF4var1, a human gene variant of platelet factor 4. Molec. Cell. Biol. 9: 1445-1451, 1989. [PubMed: 2725510] [Full Text: https://doi.org/10.1128/mcb.9.4.1445-1451.1989]
Guzzo, C., Weiner, M., Rappaport, E., LaRocco, P., Surrey, S., Poncz, M., Schwartz, E. An EcoRI polymorphism of a human platelet factor 4 (PF4) gene. Nucleic Acids Res. 15: 380 only, 1987. [PubMed: 2881257] [Full Text: https://doi.org/10.1093/nar/15.1.380]
Modi, W. S., Chen, Z.-Q. Localization of the human CXC chemokine subfamily on the long arm of chromosome 4 using radiation hybrids. Genomics 47: 136-139, 1998. [PubMed: 9465307] [Full Text: https://doi.org/10.1006/geno.1997.5100]
Poncz, M., Majumdar, S., Tunnacliffe, A. Characterization of the human platelet factor 4 (PF4)/beta-thromboglobulin (beta-TG) complex: a gene locus expressed in a megakaryocyte-specific fashion. (Abstract) Clin. Res. 39: 327A only, 1991.
Struyf, S., Salogni, L., Burdick, M. D., Vandercappellen, J., Gouwy, M., Noppen, S., Proost, P., Opdenakker, G., Parmentier, M., Gerard, C., Sozzani, S., Strieter, R. M., Van Damme, J. Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3. Blood 117: 480-488, 2011. [PubMed: 20980681] [Full Text: https://doi.org/10.1182/blood-2009-11-253591]