PF4V1 (Platelet Factor 4 Variant 1)

2014-06-01   Katrien Van Raemdonck , Paul Proost , Jo Van Damme , Sofie Struyf 

Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of Microbiology, Immunology, KU Leuven, Leuven, Belgium

Identity

HGNC
LOCATION
4q13.3
LOCUSID
ALIAS
CXCL4L1,CXCL4V1,PF4-ALT,PF4A,SCYB4V1

DNA/RNA

Note

The gene and mRNA for CXCL4L1 are 1293 and 741 bp in length, respectively.
Atlas Image
Figure 1. Structure of the human CXCL4L1 gene. This figure schematically depicts the structure of the human CXCL4L1 gene as described in the NCBI database (NM_002620). Lines represent the introns, whereas rectangular exons are coloured blue, yellow and green to represent the non-coding domains, the signal peptide and the mature protein, respectively. Grey numbers indicate the basepairs (bp) spanning the exons. Red numbers apply to the amino acids (aa) encoded.

Description

The CXCL4L1 mRNA is encoded by three exons. Duplication of the CXCL4 gene, giving rise to the homologous CXCL4L1 gene, is conserved in human and other primates including gorilla, chimpanzee, orangutan, gibbon and macaque.

Transcription

The existence of a CXCL4 variant was first evidenced by Eisman et al. (1990) and Green et al. (Eisman et al., 1990; Green et al., 1989). The CXCL4L1 mRNA is predominantly present in platelets, but has also been detected in vascular smooth muscle cells and to a lesser extent in T cells, monocytes and endothelial cells (Lasagni et al., 2007). CXCL4L1 mRNA detected in ovarian tissue has been attributed to macrophage CXCL4L1 expression (Furuya et al., 2012). CXCL4L1 expression was also observed in the HCT-8 colon adenocarcinoma cell line as evidenced by qPCR analysis (Verbeke et al., 2010).

Pseudogene

None.

Proteins

Note

CXCL4L1 precursor: 104 amino acids (aa), 11553 Da; CXCL4L1 mature: 70 aa, 7805.8 Da.

Description

CXCL4L1 is a member of the CXC chemokine family of chemoattractant cytokines. CXCL4L1 is a non-ELR CXC chemokine, meaning that it lacks the sequence glutamic acid-leucine-arginine just in front of the two NH2-terminally located conserved cysteine residues.

Expression

Blood platelets release both CXCL4 and CXCL4L1 after activation. The exact location of CXCL4L1 inside the platelet is not yet determined, whereas platelet CXCL4 is stored in the alpha-granules. In other cell types as well, CXCL4 is stored in secretory granules and released in response to protein kinase C activation, whereas CXCL4L1 is continuously synthesized and secreted through a constitutive pathway (Lasagni et al., 2007). For instance, human aortic smooth muscle cells and human coronary smooth muscle cells constitutively release CXCL4L1. Specific cancer cell lines have also been shown to produce CXCL4L1. Secretion of CXCL4L1 in tumoral tissue was evidenced in vitro on stimulated osteosarcoma cells through the use of ELISA and further corroborated by immunohistochemical staining of different human sarcoma tissue sections (osteosarcoma, leiomyosarcoma and liposarcoma) (Vandercappellen et al., 2007). Furthermore, CXCL4L1 was strongly detected in colorectal adenocarcinoma biopsy specimens (Verbeke et al., 2010).

Localisation

Secreted.

Function

CXCL4L1 has been described to be a strong inhibitor of angiogenesis. Together with its potential to chemoattract T cells, natural killer cells and immature dendritic cells, the vascular effects contribute to the antitumoral action of CXCL4L1 (Struyf et al., 2011). Struyf et al. (Struyf et al., 2007) indeed indicated the angiostatic platelet factor to exert an antitumoral effect by inhibiting branching of the vascular network and metastasis. Considering neutrophils and monocytes, CXCL4L1 as opposed to CXCL4 would not attract these pro-tumoral phagocytes (Vandercappellen et al., 2007).
Lasagni et al. identified a splice variant of CXCR3, which was named CXCR3B, as a functional GPCR for CXCL4 (Lasagni et al., 2003). Currently, both CXCL4 and CXCL4L1 are known to activate CXCR3A, as well as CXCR3B (Mueller et al., 2008; Struyf et al., 2011; Van Raemdonck et al., 2014). In general, proliferative and positive migratory effects are supposed to be mediated by CXCR3A, whereas inhibition of chemotaxis, anti-proliferative and apoptotic effects are postulated to be provoked via CXCR3B (Lasagni et al., 2003). Besides endothelial cells and T cells, CXCR3 expressing cell types can be extended to fibroblasts, mesangial cells, airway epithelial and smooth muscle cells, pneumocytes and several sarcoma, carcinoma and myeloma cell types (Billottet et al., 2013).
CXCL4 exerts its action through many different mechanisms, including binding to GAG and heteromultimerisation with other chemokines and growth factors, whereas in the case of CXCL4L1 its distorted structure and unique protruding C-terminal helix are assumed to conflict with this mode of action. The open formation characteristic of CXCL4L1 decreases GAG-binding, however simultaneously enhancing anti-angiogenic and anti-tumoral effects (Dubrac et al., 2010; Kuo et al., 2013). Additionally, CXCL4L1 forms more stable homodimers due to a loss in positive charge. This gained stability is likely to interfere with the ability to form heteromers which requires initial dissociation of the homomultimers (Kuo et al., 2013).

Homology

CXCL4L1 is a non-allelic variant of CXCL4. Unlike CXCL4, its variant appears only in primates. In men, mature proteins only differ in 3 amino acids. On the other hand, the signal peptide of human CXCL4L1 displays 38% amino acid divergence compared to human CXCL4, affecting its subcellular localization and regulated secretion mechanism, as was described by Lasagni et al. (Lasagni et al., 2007).

Implicated in

Entity name
Disease
Secretion of CXCL4L1 in tumoral tissue was evidenced in vitro on stimulated osteosarcoma cells through the use of ELISA and further corroborated by immunohistochemical staining of different human sarcoma tissue sections (osteosarcoma, leiomyosarcoma and liposarcoma) (Vandercappellen et al., 2007). On the other hand, osteosarcoma cells also express the CXCR3 receptor guiding initial tumor dissemination to metastatic sites were CXCR3 ligands such as CXCL4L1 are expressed (Pradelli et al., 2009).
Entity name
Colorectal cancer
Disease
Study of CXCL4L1 expression in human epithelial tumors revealed a distinct presence of CXCL4L1 in colorectal cancer cells, whereas its expression in esophageal cancer was weak to undetectable (Verbeke et al., 2010). ELISA, qRT-PCR, immunocytochemistry as well as ex vivo immunohistochemistry support the hypothesis that CXCL4L1 is secreted by colorectal adenocarcinoma cells and may affect the complex process of tumor development. However, no correlation was found between the intensity or extent of CXCL4L1 staining of patient biopsies and the TNM stage. On the other hand, intratumorally administered CXCL4L1 has been shown to reduce tumor vascularization and, consequently, tumor growth and metastasis of A549 adenocarcinoma in mice, similar to its therapeutic benefit observed in preclinical studies on B16 melanoma and Lewis lung carcinoma (Struyf et al., 2007).
Entity name
Endometriosis-associated ovarian cancer (EAOC)
Oncogenesis
Both clear cell and endometrioid types of ovarian cancers occasionally develop on the bases of endometriosis. CXCL4L1 is expressed in normal ovaries and especially during endometriosis (Furuya et al., 2012). However, CXCL4L1 mRNA levels were significantly lower in cancerous lesions. Endometriosis-associated ovarian cancers (EAOC) were reported to be infiltrated by CD68+ tumor-associated macrophages. CXCL4 and CXCL4L1 expression by those macrophages was studied at the protein level by Furuya and colleagues. However, antibodies not distinguishing CXCL4 from its variant were used. The tumor-associated macrophages displayed an impaired expression of either CXCL4, CXCL4L1 or possibly both. In conclusion, macrophage expression of the platelet factors appears to be associated with EAOC disease state and may prove to be a useful disease marker.
Entity name
Coronary artery disease
Prognosis
Recently, a possible prognostic significance for CXCL4L1 was evaluated in patients suffering from coronary artery disease (CAD) (De Sutter et al., 2012). Specifically in a selection of patients with stable CAD and preserved left ventricular function, CXCL4L1 levels significantly correlated to age, creatinine and circulating platelet number, as well as to N-terminal pro-B-type natriuretic peptide (NT-proBNP), a well validated prognostic marker in stable CAD. More importantly, CXCL4L1 showed an additional prognostic value on top of NT-proBNP as lower levels of CXCL4L1 predicted a higher event rate and worse outcome. Surprisingly, in these patients with stable CAD the prognostic value of CXCL4L1 is independent of NT-proBNP.

Bibliography

Pubmed IDLast YearTitleAuthors
239945492013CXCR3, a double-edged sword in tumor progression and angiogenesis.Billottet C et al
223840112012PF-4var/CXCL4L1 predicts outcome in stable coronary artery disease patients with preserved left ventricular function.De Sutter J et al
206889602010Functional divergence between 2 chemokines is conferred by single amino acid change.Dubrac A et al
16951121990Structural and functional comparison of the genes for human platelet factor 4 and PF4alt.Eisman R et al
225558032012Impaired CXCL4 expression in tumor-associated macrophages (TAMs) of ovarian cancers arising in endometriosis.Furuya M et al
27255101989Identification and characterization of PF4varl, a human gene variant of platelet factor 4.Green CJ et al
235361832013Alternative C-terminal helix orientation alters chemokine function: structure of the anti-angiogenic chemokine, CXCL4L1.Kuo JH et al
127827162003An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4.Lasagni L et al
172183822007PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion.Lasagni L et al
181743622008CXCL4-induced migration of activated T lymphocytes is mediated by the chemokine receptor CXCR3.Mueller A et al
195445602009Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs.Pradelli E et al
237479872013CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis.Prats AC et al
175751642007Platelet factor-4 variant chemokine CXCL4L1 inhibits melanoma and lung carcinoma growth and metastasis by preventing angiogenesis.Struyf S et al
209806812011Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3.Struyf S et al
244690692014CXCL4L1 and CXCL4 signaling in human lymphatic and microvascular endothelial cells and activated lymphocytes: involvement of mitogen-activated protein (MAP) kinases, Src and p70S6 kinase.Van Raemdonck K et al
202154252010The COOH-terminal peptide of platelet factor-4 variant (CXCL4L1/PF-4var47-70) strongly inhibits angiogenesis and suppresses B16 melanoma growth in vivo.Vandercappellen J et al
203348992010Expression of angiostatic platelet factor-4var/CXCL4L1 counterbalances angiogenic impulses of vascular endothelial growth factor, interleukin-8/CXCL8, and stromal cell-derived factor 1/CXCL12 in esophageal and colorectal cancer.Verbeke H et al

Other Information

Locus ID:

NCBI: 5197
MIM: 173461
HGNC: 8862
Ensembl: ENSG00000109272

Variants:

dbSNP: 5197
ClinVar: 5197
TCGA: ENSG00000109272
COSMIC: PF4V1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000109272ENST00000226524P10720

Expression (GTEx)

0
1
2
3
4

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Cytokine-cytokine receptor interactionKEGGhsa04060
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
HemostasisREACTOMER-HSA-109582
Formation of Fibrin Clot (Clotting Cascade)REACTOMER-HSA-140877
Common Pathway of Fibrin Clot FormationREACTOMER-HSA-140875
Cell surface interactions at the vascular wallREACTOMER-HSA-202733

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
211116662011The role of the CXC chemokines platelet factor-4 (CXCL4/PF-4) and its variant (CXCL4L1/PF-4var) in inflammation, angiogenesis and cancer.43
209806812011Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3.31
202374962010New genetic associations detected in a host response study to hepatitis B vaccine.27
185631702008Modulation of cystic fibrosis lung disease by variants in interleukin-8.21
209613942011CXCL4L1 inhibits angiogenesis and induces undirected endothelial cell migration without affecting endothelial cell proliferation and monocyte recruitment.14
206889602010Functional divergence between 2 chemokines is conferred by single amino acid change.11
237479872013CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis.10
237479872013CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis.10
235361832013Alternative C-terminal helix orientation alters chemokine function: structure of the anti-angiogenic chemokine, CXCL4L1.7
244690692014CXCL4L1 and CXCL4 signaling in human lymphatic and microvascular endothelial cells and activated lymphocytes: involvement of mitogen-activated protein (MAP) kinases, Src and p70S6 kinase.5

Citation

Katrien Van Raemdonck ; Paul Proost ; Jo Van Damme ; Sofie Struyf

PF4V1 (Platelet Factor 4 Variant 1)

Atlas Genet Cytogenet Oncol Haematol. 2014-06-01

Online version: http://atlasgeneticsoncology.org/gene/44606/pf4v1