CX3CL1

Summary

CX3CL1 (C-X3-C motif chemokine ligand 1, HGNC:10647) is a protein-coding gene on chromosome 16q21, encoding Fractalkine (P78423). Chemokine that acts as a ligand for both CX3CR1 and integrins ITGAV:ITGB3 and ITGA4:ITGB1.

This gene belongs to the CX3C subgroup of chemokines, characterized by the number of amino acids located between the conserved cysteine residues. This is the only member of the CX3C subgroup, which contains three amino acids between cysteine residues, resulting in a Cys-X-X-X-Cys configuration. The encoded protein contains an extended mucin-like stalk with a chemokine domain on top, and exists in both a membrane-anchored form where it acts as a binding molecule, or, in soluble form, as a chemotactic cytokine. The mature form of this protein can be cleaved at the cell surface, yielding different soluble forms that can interact with the G-protein coupled receptor, C-X3-C motif chemokine receptor 1 gene product. This gene plays a role in a wide range of diseases, including cancer, vasculitis, neuropathies, atherosclerosis, inflammatory diseases, and in human immunodeficiency virus infections.

Source: NCBI Gene 6376 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 91 total
• Druggable target: yes
• MANE Select transcript: NM_002996

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10647
Approved symbol	CX3CL1
Name	C-X3-C motif chemokine ligand 1
Location	16q21
Locus type	gene with protein product
Status	Approved
Aliases	NTN, C3Xkine, ABCD-3, CXC3C, CXC3
Ensembl gene	ENSG00000006210
Ensembl biotype	protein_coding
OMIM	601880
Entrez	6376

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000006053, ENST00000563383, ENST00000564948, ENST00000565912

RefSeq mRNA: 2 — MANE Select: NM_002996 NM_001304392, NM_002996

CCDS: CCDS10779

Canonical transcript exons

ENST00000006053 — 3 exons

Exon	Start	End
ENSE00000685198	57379634	57379754
ENSE00001301983	57372490	57372638
ENSE00001317056	57382030	57385044

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 96.49.

FANTOM5 (CAGE): breadth broad, TPM avg 12.1858 / max 347.2023, expressed in 581 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154372	10.1333	528
154371	1.6626	393
154373	0.2437	116
154374	0.1462	83

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	96.49	gold quality
right coronary artery	UBERON:0001625	96.03	gold quality
prefrontal cortex	UBERON:0000451	95.11	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.82	gold quality
frontal pole	UBERON:0002795	94.52	gold quality
ascending aorta	UBERON:0001496	94.08	gold quality
thoracic aorta	UBERON:0001515	94.05	gold quality
descending thoracic aorta	UBERON:0002345	93.95	gold quality
right frontal lobe	UBERON:0002810	93.60	gold quality
aorta	UBERON:0000947	93.58	gold quality
popliteal artery	UBERON:0002250	93.32	gold quality
tibial artery	UBERON:0007610	93.30	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.27	gold quality
mammary duct	UBERON:0001765	93.23	gold quality
upper lobe of left lung	UBERON:0008952	93.18	gold quality
frontal cortex	UBERON:0001870	93.15	gold quality
upper lobe of lung	UBERON:0008948	92.93	gold quality
Brodmann (1909) area 10	UBERON:0013541	92.86	gold quality
epithelium of mammary gland	UBERON:0003244	92.79	gold quality
apex of heart	UBERON:0002098	92.75	gold quality
minor salivary gland	UBERON:0001830	92.49	gold quality
cingulate cortex	UBERON:0003027	92.47	gold quality
anterior cingulate cortex	UBERON:0009835	92.41	gold quality
caudate nucleus	UBERON:0001873	92.22	gold quality
putamen	UBERON:0001874	92.17	gold quality
neocortex	UBERON:0001950	92.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.10	gold quality
nucleus accumbens	UBERON:0001882	92.06	gold quality
coronary artery	UBERON:0001621	91.91	gold quality
left coronary artery	UBERON:0001626	91.79	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.20

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CX3CL1	Activation
CX3CR1	Activation

Upstream regulators (CollecTRI, top): CX3CL1, DDRGK1, GATA6, GLI1, JUN, PPARA, RELA, RFX4, STAT1, STAT3, TP53, WT1

miRNA regulators (miRDB)

59 targeting CX3CL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6871-3P	99.43	68.85	741
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-4505	99.27	67.81	2678

Literature-anchored findings (GeneRIF, showing 40)

• The role of smooth muscle cell-derived fractalkine in vascular inflammation is dependent on the synergism of TNF-alpha and IFN-gamma as well as the activity of fractalkine-cleaving metalloproteinase. (PMID:11777952)
• CX3CR1 tyrosine sulfation enhances fractalkine-induced cell adhesion (PMID:11909868)
• We conclude that inflammatory mechanisms involving chemokine fractalkine and its receptor CX(3)CR1 may have a role in the natural history of Pulmonary Arterial Hypertension. (PMID:12016106)
• Detection of fractalkine in human seminal plasma and its role in infertile patients. (PMID:12042278)
• CX3CR1 defines peripheral blood cytotoxic effector lymphocytes commonly armed with intracellular perforin and granzyme B, which include NK cells, gamma delta T cells, and terminally differentiated CD8+ T cells. (PMID:12055230)
• the fractalkine system is up-regulated during liver damage, and suggests that fractalkine may play a role in the recruitment and adhesion of inflammatory cells and in the biology of liver epithelial cells. (PMID:12076860)
• CX3CR1/fractalkine interactions accounted for 26% of THP-1 cell and 17% of peripheral blood NK cell adhesion to renal tubular epithelial cells, suggesting a functional role in leucocyte adhesion/retention in acute renal inflammation. (PMID:12100035)
• Fractalkine released by injured neurons could induce proliferation, activation and/or migration of microglia at the injured brain sites. (PMID:12125082)
• linkage relationships between CX3CR1 promoter polymorphisms and two previously described CX3CR1 coding polymorphisms associated with human immunodeficiency virus disease progression and arteriosclerosis susceptibility. (PMID:12551893)
• It is present, and its gene expressed, in amniotic fluid during pregnancy. (PMID:12569179)
• endothelial expression of membrane-associated fractalkine may be an important contributing mechanism by which monocytes are selectively recruited to inflamed tissue (PMID:12616493)
• intrathecal fractalkine release was observed in the majority of patients with HIV infections, with highest levels in CSF and serum of HIV-iduced CNS disorders. (PMID:12639246)
• The finding of increased levels of fractalkine in the blood during subacute and chronic CNS inflammation suggests that it may be an interesting regulator of leukocyte extravasation into the inflamed brain. (PMID:12667665)
• Expressed in human skin keratinocytes (PMID:12727021)
• These results demonstrate that fractalkine preferentially mediates arrest and migration of CD16+ monocytes. (PMID:12810688)
• CX3CL1 directly promotes monocyte antiinflammatory and antiprocoagulant responses (PMID:12824004)
• expression of the fractalkine receptor on platelets (PMID:12969973)
• Review. New concepts underlying fractalkine-mediated leukocyte migration & tissue damage, the pathophysiological roles of fractalkine in various clinical conditions, especially in atherosclerosis & vascular injury, are reviewed. (PMID:12969992)
• Fractalkine might contribute to direct mononuclear cells into peritubular interstitium and enhance their adhesion property, which in turn would favor inflammation and disease progression. (PMID:14514721)
• CX3CL1 is constitutively expressed in human brain; no evidence for expression differences of CX3CL1 is found between control patients and multiple sclerosis patients. (PMID:14533779)
• Results show that hypoxia inhibited the expression of fractalkine mRNA and protein by interferon-gamma, and this effect was observed with concomitant increase in vascular endothelial growth factor expression. (PMID:14580149)
• a subset of mononuclear cells expresses high levels of fractalkine in human coronary atherosclerotic plaques and smooth muscle cells within the neointima express the fractalkine receptor CX3CR1 (PMID:14581400)
• increased circulating levels in symptomatic allergic rhinitis and asthmatic patients (PMID:14657873)
• CX3CL1 acts as a receptor for pRBCs, and this may contribute to furthering our present understanding of cytoadherence in the pathology of falciparum malaria (PMID:14665693)
• Soluble fractalkine antagonizes the chemoattractant effect of monocyte chemoattractant protein-1 on monocytes, probably by inhibiting crucial signaling pathways like those of stress-activated protein kinase 2/p38 and matrix metalloproteinase-2. (PMID:14688370)
• existence of CX(3)CR1 (fractalkine receptor) in ejaculated sperm and present findings suggest that fractalkine in the Fallopian tube contributes to immunodefence mechanism during fertilization and to sperm motion in the oviduct (PMID:14747189)
• IL-4 and TNF-alpha induced expression of fractalkine in fibroblasts, and subsequent monocyte chemotactic activity in the culture supernatant (PMID:15013759)
• fractalkine expression is induced by TNFalpha in arterial endothelial cells (PMID:15111313)
• fractalkine (FKN) and CX(3)CR1 expression in the skin, serum sFKN levels, and CX(3)CR1 expression on blood leukocytes in patients with atopic dermatitis (PMID:15131578)
• Higher serum levels in moderate-severe depression (PMID:15223613)
• Replacement of the fractalkine N terminus with the cognate domain of vMIP-II disrupted the ability of FKN to bind CX3CR1. (PMID:15361546)
• Fractalkine-CX3CR1 protein system may be involved in the inflammatory response to traumatic brain injury (PMID:15529011)
• examined production and localization of fractalkine in endometrium at different stages of the menstrual cycle corresponding to known leukocyte accumulation, in early pregnancy and in women using progestin-only contraceptives (PMID:15579768)
• trend toward higher glomerular Fractalkine expression among patients with more severe kidney transplantation rejection (PMID:15621116)
• Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts. (PMID:15726664)
• dynamic, SNARE-mediated recycling of CX(3)CL1 from the cell surface to and from an endomembrane storage compartment (PMID:15774461)
• CX3CL1/CX3CR1 dyad may contribute to atherogenesis and plaque destabilization in human coronary artery disease (PMID:16224053)
• study demonstrates a significant association between the CX3CR1-T280M polymorphism and severe respiratory syncytial virus -induced bronchiolitis (PMID:16645504)
• This review examines new concepts underlying fractalkine-mediated leukocyte migration and tissue damage, focusing primarily on the pathophysiological roles of fractalkine in rheumatic diseases (PMID:16767549)
• This study suggests that FKN may play an important role in the pathophysiological process of inflammatory angiogenesis. (PMID:16877565)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cxcl32b.1	ENSDARG00000071499
mus_musculus	Cx3cl1	ENSMUSG00000031778
rattus_norvegicus	Cx3cl1	ENSRNOG00000016326

Paralogs (26): CCL26 (ENSG00000006606), CCL22 (ENSG00000102962), CCL17 (ENSG00000102970), CCL24 (ENSG00000106178), CCL7 (ENSG00000108688), CCL2 (ENSG00000108691), CCL8 (ENSG00000108700), CCL1 (ENSG00000108702), CCL20 (ENSG00000115009), CCL25 (ENSG00000131142), CCL21 (ENSG00000137077), XCL1 (ENSG00000143184), XCL2 (ENSG00000143185), CCL11 (ENSG00000172156), CCL19 (ENSG00000172724), CCL13 (ENSG00000181374), CCL5 (ENSG00000271503), CCL23 (ENSG00000274736), CCL16 (ENSG00000275152), CCL4 (ENSG00000275302), CCL18 (ENSG00000275385), CCL15 (ENSG00000275718), CCL4L2 (ENSG00000276070), CCL3L3 (ENSG00000276085), CCL14 (ENSG00000276409), CCL3 (ENSG00000277632)

Protein

Protein identifiers

Fractalkine — P78423 (reviewed: P78423)

Alternative names: C-X3-C motif chemokine 1, CX3C membrane-anchored chemokine, Neurotactin, Small-inducible cytokine D1

All UniProt accessions (5): P78423, A0N0N7, H3BSR6, H3BV86, J3QRA1

UniProt curated annotations — full annotation on UniProt →

Function. Chemokine that acts as a ligand for both CX3CR1 and integrins ITGAV:ITGB3 and ITGA4:ITGB1. The CX3CR1-CX3CL1 signaling exerts distinct functions in different tissue compartments, such as immune response, inflammation, cell adhesion and chemotaxis. Regulates leukocyte adhesion and migration processes at the endothelium. Can activate integrins in both a CX3CR1-dependent and CX3CR1-independent manner. In the presence of CX3CR1, activates integrins by binding to the classical ligand-binding site (site 1) in integrins. In the absence of CX3CR1, binds to a second site (site 2) in integrins which is distinct from site 1 and enhances the binding of other integrin ligands to site 1. The soluble form is chemotactic for T-cells and monocytes, but not for neutrophils. The membrane-bound form promotes adhesion of those leukocytes to endothelial cells. (Microbial infection) Mediates the cytoadherence of erythrocytes infected with parasite P.falciparum (strain 3D7) with endothelial cells by interacting with P.falciparum CBP1 and CBP2 expressed at the surface of erythrocytes. The adhesion prevents the elimination of infected erythrocytes by the spleen.

Subunit / interactions. Monomer. Forms a ternary complex with CX3CR1 and ITGAV:ITGB3 or ITGA4:ITGB1. (Microbial infection) Interacts with pox virus crmD; this inhibits cell migration mediated by CX3CL1. (Microbial infection) Interacts (via N-terminus) with human cytomegalovirus (HHV-5) US28. (Microbial infection) Interacts with P.falciparum (strain 3D7) CBP1 and CBP2 (via their extracellular domains); the interaction mediates the adhesion of infected erythrocytes with endothelial cells.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Expressed in the seminal plasma, endometrial fluid and follicular fluid (at protein level). Small intestine, colon, testis, prostate, heart, brain, lung, skeletal muscle, kidney and pancreas. Most abundant in the brain and heart.

Post-translational modifications. A soluble short 95 kDa form may be released by proteolytic cleavage from the long membrane-anchored form. O-glycosylated with core 1 or possibly core 8 glycans.

Induction. By TNF and IL1/interleukin-1 in pulmonary endothelial cells and umbilical vein endothelial cells.

Similarity. Belongs to the intercrine delta family.

RefSeq proteins (2): NP_001291321, NP_002987* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001811	Chemokine_IL8-like_dom	Domain
IPR034127	Chemokine_CX3C	Domain
IPR036048	Interleukin_8-like_sf	Homologous_superfamily
IPR039809	Chemokine_b/g/d	Family

Pfam: PF00048

UniProt features (40 total): mutagenesis site 8, helix 5, strand 5, glycosylation site 4, region of interest 4, compositionally biased region 3, chain 2, disulfide bond 2, topological domain 2, signal peptide 1, site 1, sequence variant 1, turn 1, transmembrane region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
1F2L	X-RAY DIFFRACTION	2
3ONA	X-RAY DIFFRACTION	2.6
4XT1	X-RAY DIFFRACTION	2.89
7XBX	ELECTRON MICROSCOPY	3.4
5WB2	X-RAY DIFFRACTION	3.5
7RKM	ELECTRON MICROSCOPY	3.5
7RKN	ELECTRON MICROSCOPY	3.6
4XT3	X-RAY DIFFRACTION	3.8
7RKF	ELECTRON MICROSCOPY	4
1B2T	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78423-F1	56.75	0.14

Antibody-complex structures (SAbDab): 5 — 4XT1, 5WB2, 7RKF, 7RKM, 7RKN

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 339–340 (cleavage; to produce soluble form)

Disulfide bonds (2): 32–58, 36–74

Glycosylation sites (4): 33, 183, 253, 329

Mutagenesis-validated functional residues (8):

Position	Phenotype
60	reduced binding to integrin itgav:itgb3, but no effect on binding to cx3cr1; when associated with a-61.
60	dominant-negative mutant, reduced binding to integrins itgav:itgb3 and itga4:itgb1, no effect on binding to cx3cr1, defe
61	reduced binding to integrin itgav:itgb3, but no effect on binding to cx3cr1; when associated with a-60.
61	dominant-negative mutant, reduced binding to integrins itgav:itgb3 and itga4:itgb1, no effect on binding to cx3cr1, defe
71	loss of binding to cx3cr1 and ability to induce chemotaxis but no effect on binding to integrins.
78	little or no effect on binding to integrin itgav:itgb3.
78	little or no effect on binding to integrin itgav:itgb3; when associated with a-83.
83	little or no effect on binding to integrin itgav:itgb3; when associated with a-78.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-380108	Chemokine receptors bind chemokines
R-HSA-418594	G alpha (i) signalling events

MSigDB gene sets: 484 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_92, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, MODY_HIPPOCAMPUS_POSTNATAL, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_NEGATIVE_REGULATION_OF_INTERLEUKIN_1_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, RORA1_01, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (66): microglial cell activation (GO:0001774), positive regulation of cell-matrix adhesion (GO:0001954), positive regulation of neuroblast proliferation (GO:0002052), leukocyte migration involved in inflammatory response (GO:0002523), response to ischemia (GO:0002931), chemotaxis (GO:0006935), defense response (GO:0006952), inflammatory response (GO:0006954), immune response (GO:0006955), cell adhesion (GO:0007155), G protein-coupled receptor signaling pathway (GO:0007186), cell-cell signaling (GO:0007267), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell-substrate adhesion (GO:0010812), positive regulation of neuron projection development (GO:0010976), neuron remodeling (GO:0016322), cytokine-mediated signaling pathway (GO:0019221), positive regulation of cell migration (GO:0030335), negative regulation of cell migration (GO:0030336), neutrophil chemotaxis (GO:0030593), leukocyte chemotaxis (GO:0030595), regulation of lipopolysaccharide-mediated signaling pathway (GO:0031664), positive regulation of actin filament bundle assembly (GO:0032233), negative regulation of interleukin-1 alpha production (GO:0032690), negative regulation of interleukin-1 beta production (GO:0032691), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), positive regulation of transforming growth factor beta1 production (GO:0032914), integrin activation (GO:0033622), autocrine signaling (GO:0035425), negative regulation of apoptotic process (GO:0043066), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of MAPK cascade (GO:0043410), positive regulation of angiogenesis (GO:0045766), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of synaptic plasticity (GO:0048167), eosinophil chemotaxis (GO:0048245), macrophage chemotaxis (GO:0048246), lymphocyte chemotaxis (GO:0048247), positive regulation of smooth muscle cell proliferation (GO:0048661)

GO Molecular Function (9): signaling receptor binding (GO:0005102), integrin binding (GO:0005178), chemokine activity (GO:0008009), CX3C chemokine receptor binding (GO:0031737), chemoattractant activity (GO:0042056), CXCR1 chemokine receptor binding (GO:0045237), CCR chemokine receptor binding (GO:0048020), cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (10): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), cell projection (GO:0042995), neuron projection (GO:0043005), neuronal cell body (GO:0043025), perinuclear region of cytoplasm (GO:0048471), cell body (GO:0044297)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide ligand-binding receptors	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
chemokine receptor binding	3
response to stress	2
cell migration	2
regulation of cell migration	2
receptor ligand activity	2
leukocyte activation involved in inflammatory response	1
macrophage activation	1
glial cell activation	1
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
positive regulation of cell-substrate adhesion	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
inflammatory response	1
leukocyte migration	1
response to chemical	1
taxis	1
defense response	1
immune system process	1
response to stimulus	1
cellular process	1
G protein-coupled receptor activity	1
signal transduction	1
cell communication	1
signaling	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
negative regulation of cell adhesion	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
neuron maturation	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1

Protein interactions and networks

STRING

2500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CX3CL1	CX3CR1	P49238	999
CX3CL1	CCR2	P41597	994
CX3CL1	CCL11	P50877	992
CX3CL1	CXCR4	P30991	988
CX3CL1	CXCR1	P25024	985
CX3CL1	CXCR3	P49682	975
CX3CL1	CD200R1	Q8TD46	972
CX3CL1	FGF2	P09038	970
CX3CL1	FGF13	Q92913	968
CX3CL1	EGF	P01133	961
CX3CL1	CSF2	P04141	950
CX3CL1	CCL5	P13501	943
CX3CL1	CSF3	P09919	942
CX3CL1	CCR5	P51681	937
CX3CL1	IFNG	P01579	921

IntAct

37 interactions, top by confidence:

A	B	Type	Score
FN1	ITGB1	psi-mi:“MI:0915”(physical association)	0.750
FN1	ITGB3	psi-mi:“MI:0915”(physical association)	0.750
Itga5	ITGB3	psi-mi:“MI:0915”(physical association)	0.700
CX3CL1	ITGB3	psi-mi:“MI:0915”(physical association)	0.690
FGG	ITGB3	psi-mi:“MI:0915”(physical association)	0.660
CX3CL1	Itga5	psi-mi:“MI:0915”(physical association)	0.660
US28	CX3CL1	psi-mi:“MI:0915”(physical association)	0.650
US28	CX3CL1	psi-mi:“MI:0407”(direct interaction)	0.650
Itga5	FGG	psi-mi:“MI:0915”(physical association)	0.590
ITGB1	CX3CL1	psi-mi:“MI:0915”(physical association)	0.520
ADAM15	ITGB3	psi-mi:“MI:0915”(physical association)	0.400
CX3CL1	ITGB2	psi-mi:“MI:0915”(physical association)	0.400
CX3CL1	ITGB4	psi-mi:“MI:0915”(physical association)	0.400
Itgb1	FN1	psi-mi:“MI:0915”(physical association)	0.400
CX3CR1	CX3CL1	psi-mi:“MI:0915”(physical association)	0.400
ITGA4	CX3CR1	psi-mi:“MI:0914”(association)	0.350

BioGRID (71): CX3CR1 (Co-crystal Structure), CX3CL1 (Co-crystal Structure), TENM3 (Affinity Capture-MS), DENND6A (Affinity Capture-MS), UGCG (Affinity Capture-MS), STX5 (Affinity Capture-MS), NDFIP1 (Affinity Capture-MS), SLC9A1 (Affinity Capture-MS), ERBB2 (Affinity Capture-MS), FTSJ1 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), ATP7B (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), SLC29A1 (Affinity Capture-MS), ACAD10 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GV85, A2ALI5, A2APT9, B0BN44, B1ARY8, B6ZI38, O14836, O35188, O55145, O60279, O60667, P07141, P09603, P0C8S2, P28906, P40225, P40226, P42705, P78423, Q06154, Q08DV9, Q13261, Q1ERP8, Q28270, Q2TB54, Q3UY90, Q4V9H3, Q4W8E7, Q5F267, Q5R770, Q60819, Q64314, Q6PAL1, Q6PCP7, Q6UXB8, Q80XI1, Q8BLK9, Q8CAE9, Q8CBC4, Q8JZQ0

Diamond homologs: F5HET8, O00175, O00585, O00626, O55145, O88430, O97919, P10147, P10148, P10855, P13236, P13500, P13501, P14097, P14844, P16619, P27784, P28291, P28292, P30882, P42831, P46632, P47993, P49873, P50229, P50230, P50231, P51670, P51671, P52203, P55773, P55774, P61274, P61275, P78423, P80075, P80098, P80343, P82943, P97272

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CX3CL1	up-regulates	CX3CR1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Integrin cell surface interactions	6	80.6×	6e-09
Cell surface interactions at the vascular wall	5	47.6×	6e-07
Extracellular matrix organization	6	37.9×	1e-07
Hemostasis	5	18.0×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
cell-matrix adhesion	8	119.0×	4e-14
integrin-mediated signaling pathway	8	116.7×	4e-14
cell adhesion	7	23.8×	2e-07

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

91 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	10
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

364 predictions. Top by Δscore:

Variant	Effect	Δscore
16:57382025:T:TA	acceptor_gain	1.0000
16:57382027:TAGCT:T	acceptor_loss	1.0000
16:57382028:A:AC	acceptor_loss	1.0000
16:57382028:A:AG	acceptor_gain	1.0000
16:57382028:AGCTT:A	acceptor_gain	1.0000
16:57382029:G:GA	acceptor_gain	1.0000
16:57382029:GC:G	acceptor_gain	1.0000
16:57382029:GCT:G	acceptor_gain	1.0000
16:57382029:GCTT:G	acceptor_gain	1.0000
16:57382029:GCTTG:G	acceptor_gain	1.0000
16:57372634:GGCTG:G	donor_gain	0.9900
16:57372635:GCTGG:G	donor_gain	0.9900
16:57372639:G:GA	donor_loss	0.9900
16:57372639:G:GG	donor_gain	0.9900
16:57379632:A:AG	acceptor_gain	0.9900
16:57379633:G:GG	acceptor_gain	0.9900
16:57379633:GGACA:G	acceptor_gain	0.9900
16:57379755:G:GG	donor_gain	0.9900
16:57372635:GCTG:G	donor_gain	0.9800
16:57379631:CA:C	acceptor_loss	0.9800
16:57379632:A:AC	acceptor_loss	0.9800
16:57382025:TGTAG:T	acceptor_gain	0.9800
16:57382027:TAGC:T	acceptor_gain	0.9800
16:57382028:AG:A	acceptor_gain	0.9800
16:57382029:G:T	acceptor_gain	0.9800
16:57382030:CTTGG:C	acceptor_gain	0.9800
16:57379632:AG:A	acceptor_gain	0.9700
16:57379633:GG:G	acceptor_gain	0.9700
16:57379633:GGA:G	acceptor_gain	0.9700
16:57379751:TCAT:T	donor_gain	0.9700

AlphaMissense

2549 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:57382081:G:C	W81C	0.998
16:57382081:G:T	W81C	0.998
16:57382079:T:A	W81R	0.993
16:57382079:T:C	W81R	0.993
16:57382058:T:A	C74S	0.991
16:57382059:G:C	C74S	0.991
16:57382032:T:C	L65S	0.986
16:57382059:G:A	C74Y	0.985
16:57382886:G:C	G350R	0.983
16:57382058:T:C	C74R	0.982
16:57382091:G:C	A85P	0.982
16:57379706:T:A	L48H	0.981
16:57382060:T:G	C74W	0.979
16:57382898:T:C	C354R	0.979
16:57382145:T:C	F103L	0.978
16:57382147:C:A	F103L	0.978
16:57382147:C:G	F103L	0.978
16:57379657:T:A	C32S	0.977
16:57379658:G:C	C32S	0.977
16:57379735:T:A	C58S	0.977
16:57379736:G:C	C58S	0.977
16:57382083:T:A	V82D	0.977
16:57379669:T:A	C36S	0.976
16:57379670:G:C	C36S	0.976
16:57379691:T:C	I43T	0.974
16:57382062:C:A	A75D	0.972
16:57382887:G:A	G350D	0.972
16:57382058:T:G	C74G	0.971
16:57382059:G:T	C74F	0.971
16:57382916:T:C	F360L	0.971

dbSNP variants (sampled 300 via entrez): RS1000237648 (16:57382973 G>A,T), RS1000511047 (16:57372054 A>C), RS1000542233 (16:57372177 T>C), RS1000836186 (16:57377510 A>G), RS1001847255 (16:57383629 G>A), RS1001901130 (16:57383845 A>G), RS1001912673 (16:57384071 G>C), RS1002184866 (16:57372879 C>T), RS1002415436 (16:57378594 G>C), RS1002849729 (16:57375462 G>T), RS1003146632 (16:57380973 C>T), RS1003547879 (16:57385088 C>T), RS1004524861 (16:57376724 G>A), RS1004663004 (16:57371398 C>G,T), RS1004864770 (16:57382420 C>A,T)

Disease associations

OMIM: gene MIM:601880 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006585_1859	Blood protein levels	9.000000e-11
GCST009731_64	Blood protein levels in cardiovascular risk	7.000000e-25
GCST010732_9	Sensory peripheral neuropathy in microtubule targeting agent-treated breast cancer	3.000000e-06
GCST90002381_91	Eosinophil count	5.000000e-12
GCST90002382_442	Eosinophil percentage of white cells	4.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009419	CX3CL1 measurement
EFO:0005260	response to antimicrotubule agent
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630883 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

78 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	6
Resveratrol	affects cotreatment, decreases expression, decreases reaction, increases expression	3
Plant Extracts	decreases reaction, increases abundance, increases expression, affects cotreatment, decreases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
sodium arsenite	increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Aerosols	decreases expression, increases expression	2
Benzo(a)pyrene	increases methylation, decreases expression	2
Estradiol	increases expression, affects cotreatment, decreases expression	2
Glucose	decreases reaction, increases expression	2
Lipopolysaccharides	decreases reaction, increases secretion, increases expression	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
peracetylated N-azidoacetylmannosamine	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
bisphenol A	affects expression	1
deoxynivalenol	increases expression	1
trichostatin A	affects expression, decreases reaction	1
tris(2-butoxyethyl) phosphate	affects expression	1
o,p’-DDT	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
nickel chloride	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
4-cresol	decreases reaction, increases expression	1
enzacamene	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
beta-methylcholine	affects expression	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
prolinedithiocarbamate	decreases reaction, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8E9	Abcam HCT 116 CX3CL1 KO	Cancer cell line	Male
CVCL_B9GI	Abcam A-549 CX3CL1 KO	Cancer cell line	Male
CVCL_D2EN	Abcam MCF-7 CX3CL1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.