Human Gene CXCR4 (ENST00000409817.1) from GENCODE V44
  Description: Homo sapiens C-X-C motif chemokine receptor 4 (CXCR4), transcript variant 1, mRNA. (from RefSeq NM_001008540)
RefSeq Summary (NM_001008540): This gene encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. The protein has 7 transmembrane regions and is located on the cell surface. It acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells. Mutations in this gene have been associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008].
Gencode Transcript: ENST00000409817.1
Gencode Gene: ENSG00000121966.8
Transcript (Including UTRs)
   Position: hg38 chr2:136,114,349-136,116,243 Size: 1,895 Total Exon Count: 1 Strand: -
Coding Region
   Position: hg38 chr2:136,114,869-136,115,939 Size: 1,071 Coding Exon Count: 1 

Page IndexSequence and LinksUniProtKB CommentsPrimersMalaCardsCTD
RNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther SpeciesGO Annotations
mRNA DescriptionsPathwaysOther NamesMethods
Data last updated at UCSC: 2023-08-18 00:09:47

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr2:136,114,349-136,116,243)mRNA (may differ from genome)Protein (356 aa)
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-  Comments and Description Text from UniProtKB
  ID: CXCR4_HUMAN
DESCRIPTION: RecName: Full=C-X-C chemokine receptor type 4; Short=CXC-R4; Short=CXCR-4; AltName: Full=FB22; AltName: Full=Fusin; AltName: Full=HM89; AltName: Full=LCR1; AltName: Full=Leukocyte-derived seven transmembrane domain receptor; Short=LESTR; AltName: Full=NPYRL; AltName: Full=Stromal cell-derived factor 1 receptor; Short=SDF-1 receptor; AltName: CD_antigen=CD184;
FUNCTION: Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus.
SUBUNIT: Monomer. Can form dimers. Interacts with CD164. Interacts with HIV-1 surface protein gp120 and Tat. Interacts with ARRB2; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with ARRC; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and modulates calcium mobilization. Interacts (via the cytoplasmic C-terminal) with ITCH (via the WW domains I and II); the interaction, enhanced by CXCL12, ubiquitinates CXCR4 and leads to its degradation. Interacts with extracellular ubiquitin. Interacts with human cytomegalovirus/HHV- 5 protein UL78.
INTERACTION: P35579:MYH9; NbExp=5; IntAct=EBI-489411, EBI-350338;
SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. Note=In unstimulated cells, diffuse pattern on plasma membrane. On agonist stimulation, colocalizes with ITCH at the plasma membrane where it becomes ubiquitinated.
TISSUE SPECIFICITY: Expressed in numerous tissues, such as peripheral blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, cerebellum, cerebral cortex and medulla (in microglia as well as in astrocytes), brain microvascular, coronary artery and umbilical cord endothelial cells. Isoform 1 is predominant in all tissues tested.
DOMAIN: The amino-terminus is critical for ligand binding. Residues in all four extracellular regions contribute to HIV-1 coreceptor activity.
PTM: Phosphorylated on agonist stimulation. Rapidly phosphorylated on serine and threonine residues in the C-terminal. Phosphorylation at Ser-324 and Ser-325 leads to recruitment of ITCH, ubiquitination and protein degradation.
PTM: Ubiquitinated by ITCH at the cell membrane on agonist stimulation. The ubiquitin-dependent mechanism, endosomal sorting complex required for transport (ESCRT), then targets CXCR4 for lysosomal degradation. This process is dependent also on prior Ser-/Thr-phosphorylation in the C-terminal of CXCR4. Also binding of ARRB1 to STAM negatively regulates CXCR4 sorting to lysosomes though modulating ubiquitination of SFR5S.
PTM: Sulfation on Tyr-21 is required for efficient binding of CXCL12/SDF-1alpha and promotes its dimerization. Tyr-7 and Tyr-12 are sulfated in a sequential manner after Tyr-21 is almost fully sulfated, with the binding affinity for CXCL12/SDF-1alpha increasing with the number of sulfotyrosines present. Sulfotyrosines Tyr-7 and Tyr-12 occupy clefts on opposing CXCL12 subunits, thus bridging the CXCL12 dimer interface and promoting CXCL12 dimerization.
PTM: O- and N-glycosylated. Asn-11 is the principal site of N- glycosylation. There appears to be very little or no glycosylation on Asn-176. N-glycosylation masks coreceptor function in both X4 and R5 laboratory-adapted and primary HIV-1 strains through inhibiting interaction with their Env glycoproteins. The O- glycosylation chondroitin sulfate attachment does not affect interaction with CXCL12/SDF-1alpha nor its coreceptor activity.
DISEASE: Defects in CXCR4 are a cause of WHIM syndrome (WHIM) [MIM:193670]; also known as warts, hypogammaglobulinemia, infections and myelokathexis. WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis.
MISCELLANEOUS: Plerixafor (AMD3100), an antagonist of CXCR4 activity, blocks HIV-1 entry, interaction with CXCL12 and subsequent CXCR4 signaling.
SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CAUTION: Was originally (PubMed:8329116 and PubMed:8234909) thought to be a receptor for neuropeptide Y type 3 (NPY3R) (NPY3- R).
SEQUENCE CAUTION: Sequence=CAA12166.1; Type=Miscellaneous discrepancy; Note=Intron retention;
WEB RESOURCE: Name=CXCR4base; Note=CXCR4 mutation db; URL="http://bioinf.uta.fi/CXCR4base/";
WEB RESOURCE: Name=Wikipedia; Note=CXC chemokine receptors entry; URL="http://en.wikipedia.org/wiki/CXC_chemokine_receptors";
WEB RESOURCE: Name=Wikipedia; Note=CXCR4 entry; URL="http://en.wikipedia.org/wiki/CXCR4";
WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/cxcr4/";

-  Primer design for this transcript
 

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-  MalaCards Disease Associations
  MalaCards Gene Search: CXCR4
Diseases sorted by gene-association score: whim syndrome* (1398), hiv-1 (16), aids dementia complex (15), macroglobulinemia (14), g6pc3 deficiency (13), lymphoplasmacytic lymphoma (11), intraocular lymphoma (11), primary immunodeficiency disease (8), human immunodeficiency virus infectious disease (8), neutropenia (7), waldenstrom macroglobulinemia (7), chronic inflammatory demyelinating polyradiculoneuropathy (6), plasma protein metabolism disease (5), stevens-johnson syndrome/toxic epidermal necrolysis (5), mitral valve disease (4), breast cancer (4), avoidant personality disorder (4), congenital muscular dystrophy due to lmna mutation (4), retinal hemangioblastoma (4), uveal melanoma (3), chronic lymphocytic leukemia (3), viral infectious disease (3), kidney cancer (3), acute lymphocytic leukemia (2), oral squamous cell carcinoma (2), asthma (2), nasopharyngeal carcinoma (2), pancreatic cancer (2), multiple myeloma (2), esophageal cancer (2), myocardial infarction (2), hematologic cancer (2), colorectal cancer (2), osteosarcoma, somatic (2), lymphoma, non-hodgkin (1), leukemia, acute myeloid (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 238.89 RPKM in Whole Blood
Total median expression: 993.55 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -87.10304-0.287 Picture PostScript Text
3' UTR -103.30520-0.199 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR000276 - 7TM_GPCR_Rhodpsn
IPR001277 - Chemokine_CXCR4
IPR022726 - Chemokine_CXCR4_N
IPR000355 - Chemokine_rcpt
IPR017452 - GPCR_Rhodpsn_supfam

Pfam Domains:
PF00001 - 7 transmembrane receptor (rhodopsin family)
PF12109 - CXCR4 Chemokine receptor N terminal

Protein Data Bank (PDB) 3-D Structure
MuPIT help
2K03 - NMR MuPIT 2K04 - NMR MuPIT 2K05 - NMR MuPIT 3ODU - X-ray MuPIT 3OE0 - X-ray MuPIT 3OE6 - X-ray MuPIT 3OE8 - X-ray MuPIT 3OE9 - X-ray MuPIT


ModBase Predicted Comparative 3D Structure on P61073
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-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
MGIRGD    
Protein SequenceProtein Sequence    
AlignmentAlignment    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0001618 virus receptor activity
GO:0003779 actin binding
GO:0004871 signal transducer activity
GO:0004930 G-protein coupled receptor activity
GO:0004950 chemokine receptor activity
GO:0005515 protein binding
GO:0015026 coreceptor activity
GO:0016494 C-X-C chemokine receptor activity
GO:0019955 cytokine binding
GO:0019957 C-C chemokine binding
GO:0031625 ubiquitin protein ligase binding
GO:0032027 myosin light chain binding
GO:0043130 ubiquitin binding

Biological Process:
GO:0000187 activation of MAPK activity
GO:0001666 response to hypoxia
GO:0002407 dendritic cell chemotaxis
GO:0006915 apoptotic process
GO:0006935 chemotaxis
GO:0006954 inflammatory response
GO:0007165 signal transduction
GO:0007186 G-protein coupled receptor signaling pathway
GO:0007204 positive regulation of cytosolic calcium ion concentration
GO:0007411 axon guidance
GO:0009615 response to virus
GO:0016032 viral process
GO:0019064 fusion of virus membrane with host plasma membrane
GO:0019722 calcium-mediated signaling
GO:0030260 entry into host cell
GO:0043217 myelin maintenance
GO:0048714 positive regulation of oligodendrocyte differentiation
GO:0050920 regulation of chemotaxis
GO:0070098 chemokine-mediated signaling pathway
GO:0071345 cellular response to cytokine stimulus

Cellular Component:
GO:0005737 cytoplasm
GO:0005764 lysosome
GO:0005768 endosome
GO:0005769 early endosome
GO:0005770 late endosome
GO:0005886 plasma membrane
GO:0009986 cell surface
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0030054 cell junction
GO:0031252 cell leading edge
GO:0031410 cytoplasmic vesicle
GO:0032991 macromolecular complex
GO:0070062 extracellular exosome


-  Descriptions from all associated GenBank mRNAs
  AF147204 - Homo sapiens chemokine receptor CXCR4-Lo (CXCR4) mRNA, alternatively spliced, complete cds.
FW340083 - Screening.
BC020968 - Homo sapiens chemokine (C-X-C motif) receptor 4, mRNA (cDNA clone MGC:9199 IMAGE:3846345), complete cds.
L06797 - Human (clone L5) orphan G protein-coupled receptor mRNA, complete cds.
D10924 - Homo sapiens mRNA for HM89, complete cds.
X71635 - H.sapiens mRNA for neuropeptide Y-like receptor.
AK129916 - Homo sapiens cDNA FLJ26406 fis, clone HRT09192, highly similar to C-X-C chemokine receptor type 4.
M99293 - Homo sapiens seven transmembrane segment receptor mRNA, complete cds.
JD297068 - Sequence 278092 from Patent EP1572962.
JD120612 - Sequence 101636 from Patent EP1572962.
JD310111 - Sequence 291135 from Patent EP1572962.
AK296674 - Homo sapiens cDNA FLJ51543 complete cds, highly similar to C-X-C chemokine receptor type 4.
AK309885 - Homo sapiens cDNA, FLJ99926.
L01639 - Human (clone HSY3RR) neuropeptide Y receptor (NPYR) mRNA, complete cds.
AK309641 - Homo sapiens cDNA, FLJ99682.
JD494384 - Sequence 475408 from Patent EP1572962.
AF025375 - Homo sapiens chemokine receptor-4 (CXCR4) mRNA, complete cds.
AY242129 - Homo sapiens chemokine (C-X-C motif) receptor 4 (CXCR4) mRNA, complete cds.
KU245646 - Homo sapiens chemokine receptor isoform 3 (CXCR4) mRNA, complete cds, alternatively spliced.
KU245647 - Homo sapiens chemokine receptor isoform 4 (CXCR4) mRNA, complete cds, alternatively spliced.
AF348491 - Homo sapiens chemokine receptor CXCR4 mRNA, complete cds.
AK312244 - Homo sapiens cDNA, FLJ92538, highly similar to Homo sapiens chemokine (C-X-C motif) receptor 4 (CXCR4), mRNA.
BT006660 - Homo sapiens chemokine (C-X-C motif) receptor 4 mRNA, complete cds.
JF432649 - Synthetic construct Homo sapiens clone IMAGE:100073886 chemokine (C-X-C motif) receptor 4 (CXCR4) gene, encodes complete protein.
KJ892441 - Synthetic construct Homo sapiens clone ccsbBroadEn_01835 CXCR4 gene, encodes complete protein.
EU831811 - Synthetic construct Homo sapiens clone HAIB:100066840; DKFZo008F0721 chemokine (C-X-C motif) receptor 4 protein (CXCR4) gene, encodes complete protein.
EU831888 - Synthetic construct Homo sapiens clone HAIB:100066917; DKFZo004F0722 chemokine (C-X-C motif) receptor 4 protein (CXCR4) gene, encodes complete protein.
AB529237 - Synthetic construct DNA, clone: pF1KE0801, Homo sapiens CXCR4 gene for chemokine (C-X-C motif) receptor 4, without stop codon, in Flexi system.
AY826773 - Homo sapiens clone CXCR4-3 chemokine receptor 4 (CXCR4) mRNA, partial cds.
MF125227 - Homo sapiens bio-material MLL_11932 case PVT1/CXCR4 fusion mRNA, partial sequence.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04060 - Cytokine-cytokine receptor interaction
hsa04062 - Chemokine signaling pathway
hsa04144 - Endocytosis
hsa04360 - Axon guidance
hsa04670 - Leukocyte transendothelial migration
hsa04672 - Intestinal immune network for IgA production

BioCarta from NCI Cancer Genome Anatomy Project
h_Ccr5Pathway - Pertussis toxin-insensitive CCR5 Signaling in Macrophage
h_vifPathway - HIV-1 defeats host-mediated resistance by CEM15
h_nktPathway - Selective expression of chemokine receptors during T-cell polarization
h_cxcr4Pathway - CXCR4 Signaling Pathway

Reactome (by CSHL, EBI, and GO)

Protein P61073 (Reactome details) participates in the following event(s):

R-HSA-8986258 SLIT2:ROBO1 binds CXCR4
R-HSA-164507 CD4:gp120 binds to chemokine co-receptor CCR5/CXCR4
R-HSA-374214 Receptors CXCR4 and 7 bind CXCL12 ligand
R-HSA-164524 Fusion of viral membrane with host cell membrane
R-HSA-749454 The Ligand:GPCR:Gi complex dissociates
R-HSA-164500 Conformational changes in gp120 exposes gp41
R-HSA-164521 Insertion of gp41 fusion peptide into the target membrane
R-HSA-164515 Fusogenic activation of gp41
R-HSA-164508 N and C terminal heptad repeat helices of gp41 form six-helix bundle
R-HSA-749456 Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi
R-HSA-380073 Liganded Gi-activating GPCR acts as a GEF for Gi
R-HSA-376176 Signaling by ROBO receptors
R-HSA-173107 Binding and entry of HIV virion
R-HSA-380108 Chemokine receptors bind chemokines
R-HSA-422475 Axon guidance
R-HSA-162594 Early Phase of HIV Life Cycle
R-HSA-418594 G alpha (i) signalling events
R-HSA-375276 Peptide ligand-binding receptors
R-HSA-1266738 Developmental Biology
R-HSA-162587 HIV Life Cycle
R-HSA-388396 GPCR downstream signalling
R-HSA-373076 Class A/1 (Rhodopsin-like receptors)
R-HSA-162906 HIV Infection
R-HSA-372790 Signaling by GPCR
R-HSA-500792 GPCR ligand binding
R-HSA-5663205 Infectious disease
R-HSA-162582 Signal Transduction
R-HSA-1643685 Disease

-  Other Names for This Gene
  Alternate Gene Symbols: B2R5N0, CXCR4_HUMAN, NM_001008540, O60835, P30991, P56438, P61073, Q53S69, Q9BXA0, Q9UKN2, uc002tuy.1, uc002tuy.2, uc002tuy.3
UCSC ID: ENST00000409817.1
RefSeq Accession: NM_001008540
Protein: P61073 (aka CXCR4_HUMAN or CCR4_HUMAN)
CCDS: CCDS33295.1, CCDS46420.1

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.