PF4V1 (Platelet Factor 4 Variant 1)

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PF4V1 (Platelet Factor 4 Variant 1)

Written	2014-06	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

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)	SCYB4V1
	CXCL4V1
	CXCL4L1
Other alias	PF4-ALT
	PF4A
HGNC (Hugo)	PF4V1
LocusID (NCBI)	5197
Atlas_Id	44606
Location	4q13.3 [Link to chromosome band 4q13]
Location_base_pair	Starts at 73853296 and ends at 73854484 bp from pter ( according to hg19-Feb_2009) [Mapping PF4V1.png]

Note

The CXC chemokine CXCL4L1 is a nonallelic variant of the earlier identified platelet factor CXCL4. These rather atypical chemokines display a less prominent leukocyte chemoattractant activity, yet influence a large range of other processes. CXCL4L1 was characterized as an especially potent angiostatic chemokine (Struyf et al., 2004). Consequently, this platelet factor is an inhibitor of tumor growth and metastasis. The therapeutic potential of CXCL4L1 has been evidenced in preclinical B16 melanoma, Lewis lung carcinoma and A549 adenocarcinoma animal models, as it inhibited both tumor growth and metastasis by preventing tumor neovascularization (Struyf et al., 2007). Furthermore, the carboxy-terminal peptide CXCL4L1_47-70 retains its potential to suppress B16 melanoma growth in mice (Vandercappellen et al., 2010). Additionally, the recently highlighted impact of CXCL4L1 on lymphatic endothelial cells in vitro, corroborates a potential inhibitory effect on tumor dissemination in vivo (Prats et al., 2013; Van Raemdonck et al., 2014). Compared to CXCL4, the affinity of CXCL4L1 for glycosaminoglycans (GAG) is rather moderate (Dubrac et al., 2010; Struyf et al., 2011), strongly increasing its in vivo half-life and diffusibility.

Note	The gene and mRNA for CXCL4L1 are 1293 and 741 bp in length, respectively.


	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.

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).

Note

Entity	Osteosarcoma
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	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	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	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.

	Nomenclature
HGNC (Hugo)	PF4V1 8862
	Cards
Atlas	PF4V1ID44606ch4q13
Entrez_Gene (NCBI)	PF4V1 5197 platelet factor 4 variant 1
Aliases	CXCL4L1; CXCL4V1; PF4-ALT; PF4A;
	SCYB4V1
GeneCards (Weizmann)	PF4V1
Ensembl hg19 (Hinxton)	ENSG00000109272 [Gene_View]
Ensembl hg38 (Hinxton)	ENSG00000109272 [Gene_View] chr4:73853296-73854484 [Contig_View] PF4V1 [Vega]
ICGC DataPortal	ENSG00000109272
TCGA cBioPortal	PF4V1
AceView (NCBI)	PF4V1
Genatlas (Paris)	PF4V1
WikiGenes	5197
SOURCE (Princeton)	PF4V1
Genetics Home Reference (NIH)	PF4V1
	Genomic and cartography
GoldenPath hg38 (UCSC)	PF4V1 - chr4:73853296-73854484 + 4q13.3 [Description] (hg38-Dec_2013)
GoldenPath hg19 (UCSC)	PF4V1 - 4q13.3 [Description] (hg19-Feb_2009)
Ensembl	PF4V1 - 4q13.3 [CytoView hg19] PF4V1 - 4q13.3 [CytoView hg38]
Mapping of homologs : NCBI	PF4V1 [Mapview hg19] PF4V1 [Mapview hg38]
OMIM	173461
	Gene and transcription
Genbank (Entrez)	BC130653 BC130657 HQ258042
RefSeq transcript (Entrez)	NM_002620
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)	PF4V1
Cluster EST : Unigene	Hs.72933 [ NCBI ]
CGAP (NCI)	Hs.72933
Alternative Splicing Gallery	ENSG00000109272
Gene Expression	PF4V1 [ NCBI-GEO ] PF4V1 [ EBI - ARRAY_EXPRESS ] PF4V1 [ SEEK ] PF4V1 [ MEM ]
Gene Expression Viewer (FireBrowse)	PF4V1 [ Firebrowse - Broad ]
SOURCE (Princeton)	Expression in : [Datasets] [Normal Tissue Atlas] [carcinoma Classsification] [NCI60]
Genevisible	Expression in : [tissues] [cell-lines] [cancer] [perturbations]
BioGPS (Tissue expression)	5197
GTEX Portal (Tissue expression)	PF4V1
	Protein : pattern, domain, 3D structure
UniProt/SwissProt	P10720 [function] [subcellular_location] [family_and_domains] [pathology_and_biotech] [ptm_processing] [expression] [interaction]
NextProt	P10720 [Sequence] [Exons] [Medical] [Publications]
With graphics : InterPro	P10720
Splice isoforms : SwissVar	P10720
PhosPhoSitePlus	P10720
Domaine pattern : Prosite (Expaxy)	SMALL_CYTOKINES_CXC (PS00471)
Domains : Interpro (EBI)	Chemokine_CXC Chemokine_CXC_CS Chemokine_IL8-like_dom CXC_Chemokine_domain PF4
Domain families : Pfam (Sanger)	IL8 (PF00048)
Domain families : Pfam (NCBI)	pfam00048
Domain families : Smart (EMBL)	SCY (SM00199)
Conserved Domain (NCBI)	PF4V1
DMDM Disease mutations	5197
Blocks (Seattle)	PF4V1
PDB (SRS)	4HSV
PDB (PDBSum)	4HSV
PDB (IMB)	4HSV
PDB (RSDB)	4HSV
Structural Biology KnowledgeBase	4HSV
SCOP (Structural Classification of Proteins)	4HSV
CATH (Classification of proteins structures)	4HSV
Superfamily	P10720
Human Protein Atlas	ENSG00000109272
Peptide Atlas	P10720
HPRD	01427
IPI	IPI00022295
	Protein Interaction databases
DIP (DOE-UCLA)	P10720
IntAct (EBI)	P10720
FunCoup	ENSG00000109272
BioGRID	PF4V1
STRING (EMBL)	PF4V1
ZODIAC	PF4V1
	Ontologies - Pathways
QuickGO	P10720
Ontology : AmiGO	extracellular space inflammatory response immune response G-protein coupled receptor signaling pathway chemokine activity heparin binding platelet activation leukocyte chemotaxis response to lipopolysaccharide regulation of cell proliferation CXCR chemokine receptor binding chemokine-mediated signaling pathway positive regulation of neutrophil chemotaxis
Ontology : EGO-EBI	extracellular space inflammatory response immune response G-protein coupled receptor signaling pathway chemokine activity heparin binding platelet activation leukocyte chemotaxis response to lipopolysaccharide regulation of cell proliferation CXCR chemokine receptor binding chemokine-mediated signaling pathway positive regulation of neutrophil chemotaxis
Pathways : KEGG	Cytokine-cytokine receptor interaction Chemokine signaling pathway
REACTOME	P10720 [protein]
REACTOME Pathways	R-HSA-202733 [pathway]
NDEx Network	PF4V1
Atlas of Cancer Signalling Network	PF4V1
Wikipedia pathways	PF4V1
	Orthology - Evolution
OrthoDB	5197
GeneTree (enSembl)	ENSG00000109272
Phylogenetic Trees/Animal Genes : TreeFam	PF4V1
HOVERGEN	P10720
HOGENOM	P10720
Homologs : HomoloGene	PF4V1
Homology/Alignments : Family Browser (UCSC)	PF4V1
	Gene fusions - Rearrangements
	Polymorphisms : SNP and Copy number variants
NCBI Variation Viewer	PF4V1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)	PF4V1
dbVar	PF4V1
ClinVar	PF4V1
1000_Genomes	PF4V1
Exome Variant Server	PF4V1
ExAC (Exome Aggregation Consortium)	PF4V1 (select the gene name)
Genetic variants : HAPMAP	5197
Genomic Variants (DGV)	PF4V1 [DGVbeta]
DECIPHER	PF4V1 [patients] [syndromes] [variants] [genes]
CONAN: Copy Number Analysis	PF4V1
	Mutations
ICGC Data Portal	PF4V1
TCGA Data Portal	PF4V1
Broad Tumor Portal	PF4V1
OASIS Portal	PF4V1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMIC	PF4V1 [overview] [genome browser] [tissue] [distribution]
Mutations and Diseases : HGMD	PF4V1
LOVD (Leiden Open Variation Database)	Whole genome datasets
LOVD (Leiden Open Variation Database)	LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)	LOVD 3.0 shared installation
BioMuta	search PF4V1
DgiDB (Drug Gene Interaction Database)	PF4V1
DoCM (Curated mutations)	PF4V1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)	PF4V1 (select a term)
intoGen	PF4V1
NCG5 (London)	PF4V1
Cancer3D	PF4V1(select the gene name)
Impact of mutations	[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
	Diseases
OMIM	173461
Orphanet
Medgen	PF4V1
Genetic Testing Registry	PF4V1
NextProt	P10720 [Medical]
TSGene	5197
GENETests	PF4V1
Target Validation	PF4V1
Huge Navigator	PF4V1 [HugePedia]
snp3D : Map Gene to Disease	5197
BioCentury BCIQ	PF4V1
ClinGen	PF4V1
	Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD	5197
Chemical/Pharm GKB Gene	PA33204
Clinical trial	PF4V1
	Miscellaneous
canSAR (ICR)	PF4V1 (select the gene name)
	Probes
	Litterature
PubMed	20 Pubmed reference(s) in Entrez
GeneRIFs	Gene References Into Functions (Entrez)
CoreMine	PF4V1
EVEX	PF4V1
GoPubMed	PF4V1
iHOP	PF4V1

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed