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CX3CL1 (chemokine (C-X3-C motif) ligand 1)

Written2013-09Philippe Deterre
Immunite et Infection, UMR-S 945 INSERM UPMC, Paris, France

(Note : for Links provided by Atlas : click)

Identity

Alias_namesSCYD1
small inducible cytokine subfamily D (Cys-X3-Cys), member 1 (fractalkine, neurotactin)
chemokine (C-X3-C motif) ligand 1
Alias_symbol (synonym)NTN
C3Xkine
ABCD-3
CXC3C
CXC3
fractalkine
neurotactin
Other aliasNTT
HGNC (Hugo) CX3CL1
LocusID (NCBI) 6376
Atlas_Id 46756
Location 16q21  [Link to chromosome band 16q21]
Location_base_pair Starts at 57372458 and ends at 57385048 bp from pter ( according to hg19-Feb_2009)  [Mapping CX3CL1.png]
 
  Chromosome 16; NC_000016.9.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Note CX3CL1 gene is located on the long arm of chromosome 16 at position 13 and contains three exons. This gene encodes for a protein of 397 aa. The first 24 aa represents the peptide signal.
 
  The CX3CL1 gene comprises 3 exons. The first codes for the peptide signal.
Transcription Only one type of transcript has been described. The 1194-nucleotide transcript encodes a protein of 397 amino acid residues. The primary structure of human CX3CL1 consists of an N-terminal 24-amino acid signal sequence followed by the chemokine domain of CX3CL1, a mucin-like stalk, a transmembrane domain and an intracellular part.
Pseudogene None described so far.

Protein

 
  Secondary structure of the membrane form of CX3CL1 (Bazan et al., 1997; Fong et al., 2000).
Description CX3CL1 is synthesized as a membrane protein consisting of the chemokine domain, a highly glycosylated mucin-like stalk, a transmembrane domain and an intracellular part. Cleavage by some metalloproteinases like ADAM-10 (Hundhausen et al., 2003), ADAM-17 (Garton et al., 2001; Tsou et al., 2001), MMP-2 (Bourd-Boittin et al., 2009) and cathepsin-S (Clark et al., 2009) gives raise to the soluble form of CX3CL1 consisting of the chemokine domain and the glycosylated mucin-like stalk (Bazan et al., 1997; Schulte et al., 2007). The C-terminal part contains two putative adaptor protein-2 (AP-2)-binding motifs, that control the constitutive endocytosis of the whole protein (Huang et al., 2009) mediated by clathrin and dynamin-1 (Robinson et al., 2002).
Expression The chemokine CX3CL1 is constituvely expressed in microglial cells (Cross and Woodroofe, 1999), astrocytes (Hatori et al., 2002) and some neurons (Harrison et al., 1998; Cross and Woodroofe, 1999; Maciejewski-Lenoir et al., 1999; Deiva et al., 2004). Its expression is stimulated by inflammatory ligands in vascular endothelial cells (Fong et al., 1998; Imaizumi et al., 2000; Fraticelli et al., 2001; Schäfer et al., 2007), renal endothelial (Cross and Woodroofe, 1999) and epithelial cells (Chakravorty et al., 2002), in aortic (Ludwig et al., 2002; Ollivier et al., 2003) and pulmonary (Sukkar et al., 2004) smooth muscle cells and in dendritic cells (Papadopoulos et al., 1999; Dichmann et al., 2001; Pallandre et al., 2008).
Localisation The chemokine CX3CL1 is mainly localized at the plasma membrane (Bazan et al., 1997; Fong et al., 2000). Its biosynthesis in the Golgi and/or ER organelles starts as an non glycosylated and intracellular.
Function The function of CX3CL1 relies on both of its forms: the soluble form, released by metalloproteinases, is chemoattractant while the membrane form mediates stable adhesion of leukocytes such as integrins (Fong et al., 1998; Haskell et al., 1999).

Implicated in

Note
  
Entity Glioblastoma
Note Both CX3CL1 and CX3CR1 are expressed in human surgical glioma samples. The expression of CX3CL1 was inversely correlated with patient overall survival (Erreni et al., 2010). The presence of the rare variant CX3CR1 was shown to be associate with a longer mean survival (Rodero et al., 2008).
  
  
Entity Atherosclerosis
Note The CX3CL1 molecule, with its unique CX3CR1 receptor (Imai et al., 1997), has been shown to be central in cellular processes leading to atherosclerosis. In animal models, the deletion of CX3CR1 genes lead to decreased disease (Combadière et al., 2003; Lesnik et al., 2003). In human, the presence of the rare variant CX3CR1 I249 is an independent genetic risk factor for coronary artery disease (Moatti et al., 2001).
  
  
Entity Neurotoxicity
Note By binding to its receptor CX3CR1, the CX3CL1 molecule decreases the microglial neurotoxicity mediated by inflammatory molecules (reactive species, matrix metalloproteinase, inflammatory cytokines) (Cardona et al., 2006). CX3CL1 acts by binding to CX3CR1 present on microglia to modulate microglial activation (Cho et al., 2011). However converse data also exist. During focal cerebral ischemia, elimination of CX3CL1 signaling was associated with smaller infarct and enhanced recovery (Dénes et al., 2008).
  

Bibliography

A new class of membrane-bound chemokine with a CX3C motif.
Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ.
Nature. 1997 Feb 13;385(6617):640-4.
PMID 9024663
 
CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver.
Bourd-Boittin K, Basset L, Bonnier D, L'helgoualc'h A, Samson M, Theret N.
J Cell Mol Med. 2009 Aug;13(8A):1526-35. doi: 10.1111/j.1582-4934.2009.00787.x. Epub 2009 May 11.
PMID 19432809
 
Control of microglial neurotoxicity by the fractalkine receptor.
Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM.
Nat Neurosci. 2006 Jul;9(7):917-24. Epub 2006 Jun 18.
PMID 16732273
 
Fractalkine expression on human renal tubular epithelial cells: potential role in mononuclear cell adhesion.
Chakravorty SJ, Cockwell P, Girdlestone J, Brooks CJ, Savage CO.
Clin Exp Immunol. 2002 Jul;129(1):150-9.
PMID 12100035
 
CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease.
Cho SH, Sun B, Zhou Y, Kauppinen TM, Halabisky B, Wes P, Ransohoff RM, Gan L.
J Biol Chem. 2011 Sep 16;286(37):32713-22. doi: 10.1074/jbc.M111.254268. Epub 2011 Jul 19.
PMID 21771791
 
The liberation of fractalkine in the dorsal horn requires microglial cathepsin S.
Clark AK, Yip PK, Malcangio M.
J Neurosci. 2009 May 27;29(21):6945-54. doi: 10.1523/JNEUROSCI.0828-09.2009.
PMID 19474321
 
Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice.
Combadiere C, Potteaux S, Gao JL, Esposito B, Casanova S, Lee EJ, Debre P, Tedgui A, Murphy PM, Mallat Z.
Circulation. 2003 Feb 25;107(7):1009-16.
PMID 12600915
 
Chemokine modulation of matrix metalloproteinase and TIMP production in adult rat brain microglia and a human microglial cell line in vitro.
Cross AK, Woodroofe MN.
Glia. 1999 Dec;28(3):183-9.
PMID 10559777
 
Fractalkine reduces N-methyl-d-aspartate-induced calcium flux and apoptosis in human neurons through extracellular signal-regulated kinase activation.
Deiva K, Geeraerts T, Salim H, Leclerc P, Hery C, Hugel B, Freyssinet JM, Tardieu M.
Eur J Neurosci. 2004 Dec;20(12):3222-32.
PMID 15610155
 
Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse.
Denes A, Ferenczi S, Halasz J, Kornyei Z, Kovacs KJ.
J Cereb Blood Flow Metab. 2008 Oct;28(10):1707-21. doi: 10.1038/jcbfm.2008.64. Epub 2008 Jun 25.
PMID 18575457
 
Fractalkine induces chemotaxis and actin polymerization in human dendritic cells.
Dichmann S, Herouy Y, Purlis D, Rheinen H, Gebicke-Harter P, Norgauer J.
Inflamm Res. 2001 Nov;50(11):529-33.
PMID 11766992
 
Human glioblastoma tumours and neural cancer stem cells express the chemokine CX3CL1 and its receptor CX3CR1.
Erreni M, Solinas G, Brescia P, Osti D, Zunino F, Colombo P, Destro A, Roncalli M, Mantovani A, Draghi R, Levi D, Rodriguez Y Baena R, Gaetani P, Pelicci G, Allavena P.
Eur J Cancer. 2010 Dec;46(18):3383-92. doi: 10.1016/j.ejca.2010.07.022. Epub 2010 Aug 19.
PMID 20728344
 
Ultrastructure and function of the fractalkine mucin domain in CX(3)C chemokine domain presentation.
Fong AM, Erickson HP, Zachariah JP, Poon S, Schamberg NJ, Imai T, Patel DD.
J Biol Chem. 2000 Feb 11;275(6):3781-6.
PMID 10660527
 
Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow.
Fong AM, Robinson LA, Steeber DA, Tedder TF, Yoshie O, Imai T, Patel DD.
J Exp Med. 1998 Oct 19;188(8):1413-9.
PMID 9782118
 
Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses.
Fraticelli P, Sironi M, Bianchi G, D'Ambrosio D, Albanesi C, Stoppacciaro A, Chieppa M, Allavena P, Ruco L, Girolomoni G, Sinigaglia F, Vecchi A, Mantovani A.
J Clin Invest. 2001 May;107(9):1173-81.
PMID 11342581
 
Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1).
Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ, Raines EW.
J Biol Chem. 2001 Oct 12;276(41):37993-8001. Epub 2001 Aug 8.
PMID 11495925
 
Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia.
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L.
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10896-901.
PMID 9724801
 
Molecular uncoupling of fractalkine-mediated cell adhesion and signal transduction. Rapid flow arrest of CX3CR1-expressing cells is independent of G-protein activation.
Haskell CA, Cleary MD, Charo IF.
J Biol Chem. 1999 Apr 9;274(15):10053-8.
PMID 10187784
 
Fractalkine and fractalkine receptors in human neurons and glial cells.
Hatori K, Nagai A, Heisel R, Ryu JK, Kim SU.
J Neurosci Res. 2002 Aug 1;69(3):418-26.
PMID 12125082
 
Constitutive endocytosis of the chemokine CX3CL1 prevents its degradation by cell surface metalloproteases.
Huang YW, Su P, Liu GY, Crow MR, Chaukos D, Yan H, Robinson LA.
J Biol Chem. 2009 Oct 23;284(43):29644-53. doi: 10.1074/jbc.M109.045682. Epub 2009 Sep 1.
PMID 19723636
 
The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion.
Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Reiss K, Hartmann D, Fahrenholz F, Postina R, Matthews V, Kallen KJ, Rose-John S, Ludwig A.
Blood. 2003 Aug 15;102(4):1186-95. Epub 2003 Apr 24.
PMID 12714508
 
Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion.
Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M, Kakizaki M, Takagi S, Nomiyama H, Schall TJ, Yoshie O.
Cell. 1997 Nov 14;91(4):521-30.
PMID 9390561
 
Interferon-gamma stimulates the expression of CX3CL1/fractalkine in cultured human endothelial cells.
Imaizumi T, Matsumiya T, Fujimoto K, Okamoto K, Cui X, Ohtaki U, Hidemi, Yoshida, Satoh K.
Tohoku J Exp Med. 2000 Oct;192(2):127-39.
PMID 11211312
 
Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis.
Lesnik P, Haskell CA, Charo IF.
J Clin Invest. 2003 Feb;111(3):333-40.
PMID 12569158
 
Fractalkine is expressed by smooth muscle cells in response to IFN-gamma and TNF-alpha and is modulated by metalloproteinase activity.
Ludwig A, Berkhout T, Moores K, Groot P, Chapman G.
J Immunol. 2002 Jan 15;168(2):604-12.
PMID 11777952
 
Characterization of fractalkine in rat brain cells: migratory and activation signals for CX3CR-1-expressing microglia.
Maciejewski-Lenoir D, Chen S, Feng L, Maki R, Bacon KB.
J Immunol. 1999 Aug 1;163(3):1628-35.
PMID 10415068
 
Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease.
Moatti D, Faure S, Fumeron F, Amara Mel-W, Seknadji P, McDermott DH, Debre P, Aumont MC, Murphy PM, de Prost D, Combadiere C.
Blood. 2001 Apr 1;97(7):1925-8.
PMID 11264153
 
Fractalkine/CX3CL1 production by human aortic smooth muscle cells impairs monocyte procoagulant and inflammatory responses.
Ollivier V, Faure S, Tarantino N, Chollet-Martin S, Deterre P, Combadiere C, de Prost D.
Cytokine. 2003 Mar 21;21(6):303-11.
PMID 12824004
 
Dendritic cell and natural killer cell cross-talk: a pivotal role of CX3CL1 in NK cytoskeleton organization and activation.
Pallandre JR, Krzewski K, Bedel R, Ryffel B, Caignard A, Rohrlich PS, Pivot X, Tiberghien P, Zitvogel L, Strominger JL, Borg C.
Blood. 2008 Dec 1;112(12):4420-4. doi: 10.1182/blood-2007-12-126888. Epub 2008 Aug 5.
PMID 18682600
 
Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation.
Papadopoulos EJ, Sassetti C, Saeki H, Yamada N, Kawamura T, Fitzhugh DJ, Saraf MA, Schall T, Blauvelt A, Rosen SD, Hwang ST.
Eur J Immunol. 1999 Aug;29(8):2551-9.
PMID 10458770
 
Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-alpha.
Robinson SC, Scott KA, Balkwill FR.
Eur J Immunol. 2002 Feb;32(2):404-12.
PMID 11813159
 
Polymorphism in the microglial cell-mobilizing CX3CR1 gene is associated with survival in patients with glioblastoma.
Rodero M, Marie Y, Coudert M, Blondet E, Mokhtari K, Rousseau A, Raoul W, Carpentier C, Sennlaub F, Deterre P, Delattre JY, Debre P, Sanson M, Combadiere C.
J Clin Oncol. 2008 Dec 20;26(36):5957-64. doi: 10.1200/JCO.2008.17.2833. Epub 2008 Nov 10.
PMID 19001328
 
The CX3C chemokine fractalkine induces vascular dysfunction by generation of superoxide anions.
Schafer A, Schulz C, Fraccarollo D, Tas P, Leutke M, Eigenthaler M, Seidl S, Heider P, Ertl G, Massberg S, Bauersachs J.
Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):55-62. Epub 2006 Nov 2.
PMID 17082482
 
Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases.
Schulte A, Schulz B, Andrzejewski MG, Hundhausen C, Mletzko S, Achilles J, Reiss K, Paliga K, Weber C, John SR, Ludwig A.
Biochem Biophys Res Commun. 2007 Jun 22;358(1):233-40. Epub 2007 Apr 24.
PMID 17467666
 
Fractalkine/CX3CL1 production by human airway smooth muscle cells: induction by IFN-gamma and TNF-alpha and regulation by TGF-beta and corticosteroids.
Sukkar MB, Issa R, Xie S, Oltmanns U, Newton R, Chung KF.
Am J Physiol Lung Cell Mol Physiol. 2004 Dec;287(6):L1230-40. Epub 2004 Aug 20.
PMID 15321787
 
Tumor necrosis factor-alpha-converting enzyme mediates the inducible cleavage of fractalkine.
Tsou CL, Haskell CA, Charo IF.
J Biol Chem. 2001 Nov 30;276(48):44622-6. Epub 2001 Sep 24.
PMID 11571300
 

Citation

This paper should be referenced as such :
Deterre, P
CX3CL1 (chemokine (C-X3-C motif) ligand 1)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(4):260-263.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CX3CL1ID46756ch16q13.html


External links

Nomenclature
HGNC (Hugo)CX3CL1   10647
Cards
AtlasCX3CL1ID46756ch16q13
Entrez_Gene (NCBI)CX3CL1  6376  C-X3-C motif chemokine ligand 1
AliasesABCD-3; C3Xkine; CXC3; CXC3C; 
NTN; NTT; SCYD1; fractalkine; neurotactin
GeneCards (Weizmann)CX3CL1
Ensembl hg19 (Hinxton)ENSG00000006210 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000006210 [Gene_View]  ENSG00000006210 [Sequence]  chr16:57372458-57385048 [Contig_View]  CX3CL1 [Vega]
ICGC DataPortalENSG00000006210
TCGA cBioPortalCX3CL1
AceView (NCBI)CX3CL1
Genatlas (Paris)CX3CL1
WikiGenes6376
SOURCE (Princeton)CX3CL1
Genetics Home Reference (NIH)CX3CL1
Genomic and cartography
GoldenPath hg38 (UCSC)CX3CL1  -     chr16:57372458-57385048 +  16q21   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CX3CL1  -     16q21   [Description]    (hg19-Feb_2009)
GoldenPathCX3CL1 - 16q21 [CytoView hg19]  CX3CL1 - 16q21 [CytoView hg38]
ImmunoBaseENSG00000006210
Mapping of homologs : NCBICX3CL1 [Mapview hg19]  CX3CL1 [Mapview hg38]
OMIM601880   
Gene and transcription
Genbank (Entrez)AB209037 AK222692 AK223351 AK313806 BC001163
RefSeq transcript (Entrez)NM_001304392 NM_002996
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CX3CL1
Alternative Splicing GalleryENSG00000006210
Gene ExpressionCX3CL1 [ NCBI-GEO ]   CX3CL1 [ EBI - ARRAY_EXPRESS ]   CX3CL1 [ SEEK ]   CX3CL1 [ MEM ]
Gene Expression Viewer (FireBrowse)CX3CL1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)6376
GTEX Portal (Tissue expression)CX3CL1
Human Protein AtlasENSG00000006210-CX3CL1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)CX3CL1
DMDM Disease mutations6376
Blocks (Seattle)CX3CL1
Human Protein Atlas [tissue]ENSG00000006210-CX3CL1 [tissue]
HPRD03529
IPIIPI00019771   
Protein Interaction databases
FunCoupENSG00000006210
BioGRIDCX3CL1
STRING (EMBL)CX3CL1
ZODIACCX3CL1
Ontologies - Pathways
Huge Navigator CX3CL1 [HugePedia]
snp3D : Map Gene to Disease6376
BioCentury BCIQCX3CL1
ClinGenCX3CL1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6376
Chemical/Pharm GKB GenePA35577
Clinical trialCX3CL1
Miscellaneous
canSAR (ICR)CX3CL1 (select the gene name)
DataMed IndexCX3CL1
Probes
Litterature
PubMed283 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCX3CL1
EVEXCX3CL1
GoPubMedCX3CL1
iHOPCX3CL1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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