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Protein

C-X-C chemokine receptor type 4

Gene

Cxcr4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (By similarity). 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.By similarity3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei173ChemokineBy similarity1
Binding sitei295ChemokineBy similarity1

GO - Molecular functioni

GO - Biological processi

  • ameboidal-type cell migration Source: MGI
  • animal organ morphogenesis Source: ProtInc
  • aorta development Source: MGI
  • brain development Source: MGI
  • calcium-mediated signaling Source: MGI
  • cellular response to cytokine stimulus Source: UniProtKB
  • generation of neurons Source: DFLAT
  • germ cell development Source: MGI
  • germ cell migration Source: MGI
  • G-protein coupled receptor signaling pathway Source: MGI
  • hematopoietic stem cell migration Source: MGI
  • motor neuron axon guidance Source: MGI
  • myelin maintenance Source: BHF-UCL
  • nervous system development Source: ProtInc
  • neural precursor cell proliferation Source: DFLAT
  • neuron migration Source: MGI
  • patterning of blood vessels Source: MGI
  • positive regulation of calcium ion import Source: MGI
  • positive regulation of oligodendrocyte differentiation Source: BHF-UCL
  • positive regulation of protein phosphorylation Source: MGI
  • regulation of cell migration Source: MGI
  • regulation of chemotaxis Source: MGI
  • T cell proliferation Source: MGI
  • ventricular septum development Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

G-protein coupled receptor, Receptor, Transducer

Names & Taxonomyi

Protein namesi
Recommended name:
C-X-C chemokine receptor type 4
Short name:
CXC-R4
Short name:
CXCR-4
Alternative name(s):
Fusin
Leukocyte-derived seven transmembrane domain receptor
Short name:
LESTR
Pre-B-cell-derived chemokine receptor
Short name:
PB-CKR
Stromal cell-derived factor 1 receptor
Short name:
SDF-1 receptor
CD_antigen: CD184
Gene namesi
Name:Cxcr4
Synonyms:Cmkar4, Lestr, Sdf1r
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:109563. Cxcr4.

Subcellular locationi

  • Cell membrane By similarity; Multi-pass membrane protein By similarity
  • Cell junction By similarity
  • Early endosome By similarity
  • Late endosome By similarity
  • Lysosome By similarity

  • Note: In unstimulated cells, diffuse pattern on plasma membrane. On agonist stimulation, colocalizes with ITCH at the plasma membrane where it becomes ubiquitinated (By similarity). In the presence of antigen, distributes to the immunological synapse forming at the T-cell-APC contact area, where it localizes at the peripheral and distal supramolecular activation cluster (SMAC) (By similarity).By similarity

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 40ExtracellularBy similarityAdd BLAST40
Transmembranei41 – 65Helical; Name=1By similarityAdd BLAST25
Topological domaini66 – 79CytoplasmicBy similarityAdd BLAST14
Transmembranei80 – 101Helical; Name=2By similarityAdd BLAST22
Topological domaini102 – 112ExtracellularBy similarityAdd BLAST11
Transmembranei113 – 132Helical; Name=3By similarityAdd BLAST20
Topological domaini133 – 156CytoplasmicBy similarityAdd BLAST24
Transmembranei157 – 176Helical; Name=4By similarityAdd BLAST20
Topological domaini177 – 202ExtracellularBy similarityAdd BLAST26
Transmembranei203 – 223Helical; Name=5By similarityAdd BLAST21
Topological domaini224 – 248CytoplasmicBy similarityAdd BLAST25
Transmembranei249 – 268Helical; Name=6By similarityAdd BLAST20
Topological domaini269 – 289ExtracellularBy similarityAdd BLAST21
Transmembranei290 – 309Helical; Name=7By similarityAdd BLAST20
Topological domaini310 – 359CytoplasmicBy similarityAdd BLAST50

GO - Cellular componenti

  • cell-cell junction Source: MGI
  • cell leading edge Source: MGI
  • cell surface Source: BHF-UCL
  • cytoplasmic, membrane-bounded vesicle Source: MGI
  • cytoplasmic vesicle Source: MGI
  • early endosome Source: UniProtKB
  • external side of plasma membrane Source: MGI
  • extracellular exosome Source: MGI
  • growth cone Source: MGI
  • integral component of membrane Source: UniProtKB-KW
  • late endosome Source: UniProtKB
  • lysosome Source: UniProtKB
  • plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Endosome, Lysosome, Membrane

Pathology & Biotechi

Disruption phenotypei

Half of the embryos die by E17.5-E18.5 and neonates die within a few hours. Mutants display defective vascular development, cerebellar development, B-lymphopoiesis, myelopoiesis, and cardiogenesis with defective formation of the large vessels supplying the gastrointestinal tract.3 Publications

Chemistry databases

ChEMBLiCHEMBL1250365.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000693551 – 359C-X-C chemokine receptor type 4Add BLAST359

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei9SulfotyrosineBy similarity1
Glycosylationi13N-linked (GlcNAc...)By similarity1
Modified residuei14SulfotyrosineBy similarity1
Glycosylationi20O-linked (Xyl...) (chondroitin sulfate)By similarity1
Modified residuei23SulfotyrosineBy similarity1
Disulfide bondi30 ↔ 281PROSITE-ProRule annotation
Disulfide bondi111 ↔ 193PROSITE-ProRule annotation
Modified residuei326PhosphoserineCombined sources1
Modified residuei328PhosphoserineBy similarity1
Modified residuei331Phosphoserine; by PKC and GRK6By similarity1
Modified residuei332Phosphoserine; by PKC and GRK6By similarity1
Modified residuei337Phosphoserine; by GRK6By similarity1
Modified residuei346Phosphoserine; by GRK6By similarity1
Modified residuei355PhosphoserineBy similarity1
Modified residuei358PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated on agonist stimulation. Rapidly phosphorylated on serine and threonine residues in the C-terminal. Phosphorylation at Ser-331 and Ser-332 leads to recruitment of ITCH, ubiquitination and protein degradation (By similarity).By similarity
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 (By similarity).By similarity
Sulfation is required for efficient binding of CXCL12/SDF-1alpha and promotes its dimerization.By similarity
O- and N-glycosylated. N-glycosylation can mask coreceptor function. The O-glycosylation chondroitin sulfate attachment does not affect interaction with CXCL12/SDF-1alpha nor its coreceptor activity (By similarity).By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Proteoglycan, Sulfation, Ubl conjugation

Proteomic databases

MaxQBiP70658.
PaxDbiP70658.
PeptideAtlasiP70658.
PRIDEiP70658.

PTM databases

iPTMnetiP70658.
PhosphoSitePlusiP70658.

Expressioni

Tissue specificityi

Lymphocytes, macrophages, neutrophils, microglial cells and astrocytes. Found in spleen, thymus, bone marrow, lymph nodes and, at lower levels in brain, small intestine, stomach and kidney. CXCR4-A is predominant in all tissues tested. During embryonic development, high levels are detected in the endothelium of developing blood vessels and in many regions of the developing brain including the olfactory epithelium, olfactory bulb, hippocampus, cerebellum and spinal cord.2 Publications

Developmental stagei

High expression during embryonic development does not seem to be associated with the differentiation of any particular cell type, but is widely utilized when there is a requirement for cell movement. Frequently associated with less differentiated cell types and down-regulated with subsequent differentiation. Detected in sites with hemopoietic potential: the yolk sac (7.5, 8.5 and 12.5 dpc) and fetal liver (12.5 dpc). During gastrulation, at 7.2 to 7.8 dpc, expressed in the mesoderm and the definitive endoderm. As gastrulation pattern fades (8.5 dpc), expression in the mesoderm is down-regulated, while it becomes predominant in neural ectoderm. Endodermal expression is retained in the foregut and later in a subset of foregut derivatives, including the stomach (10.5 dpc), the cystic ducts of the gall bladder and the lung epithelium (12.5 dpc). In neuronal tissue: at 10.5 and 12.5 dpc, expressed in the dorsal root ganglia, in the ventral mantle layer of the spinal cord (or basal plates), in the hindbrain. At 14.5 dpc, expression more tightly confined to the neural epithelium lining the ventricular space and to the external granular layer of the ventral rhombic lip (the developing cerebellum). Expressed in the outpocketing of the diencephalic floor at 10.5 dpc and in the developing thalamus and, to a lesser extent, the developing hypothalamus. At 14.5 dpc, restricted to the region where thalamus and hypothalamus meet. Detected in a discrete band of cells at the edge of the olfactory bulb. In the vascular system: expressed in the endothelium of numerous blood vessels, but not all, at 10.5, 11.5 and 12.5 dpc, such as vitelline/umbilical vessels, cardiac ventricular wall capillaries, facial vessels and, at 14.5 dpc, in the vasculature of the herniated gut. Expression seems to be associated with expanding vascular networks. In the heart development, expressed at 10.5 dpc in the precursor to the aortopulmonary (AP) septum. At 12.5 dpc, detected in the AP septum at the base of the outflow tract and in the atrioventricular valves. Detected in cranofacial ectoderm from 10.5 to 14.5 dpc. At 10.5 and 11.5 dpc, expressed in the Rathke pouch.1 Publication

Gene expression databases

BgeeiENSMUSG00000045382.
CleanExiMM_CXCR4.

Interactioni

Subunit structurei

Monomer (By similarity). Can form dimers (By similarity). 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; the interaction enhances intracellular calcium ions and reduces cellular cAMP levels (By similarity). Interacts with CD164. Interacts with DBN1; this interaction is enhanced by antigenic stimulation (By similarity). Following LPS binding, may form a complex with GDF5, HSP90AA1 and HSPA8 (By similarity).By similarity

GO - Molecular functioni

Protein-protein interaction databases

IntActiP70658. 1 interactor.
STRINGi10090.ENSMUSP00000053489.

Chemistry databases

BindingDBiP70658.

Structurei

3D structure databases

ProteinModelPortaliP70658.
SMRiP70658.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 23Important for chemokine binding and signalingBy similarityAdd BLAST23
Regioni96 – 99Chemokine bindingBy similarity4
Regioni115 – 119Chemokine bindingBy similarity5
Regioni137 – 149Involved in dimerization; when bound to chemokineBy similarityAdd BLAST13
Regioni193 – 197Chemokine binding, important for signalingBy similarity5
Regioni198 – 217Involved in dimerizationBy similarityAdd BLAST20
Regioni273 – 275Involved in dimerizationBy similarity3

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi135 – 137Important for signalingBy similarity3

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3656. Eukaryota.
ENOG410XRW9. LUCA.
HOGENOMiHOG000234122.
HOVERGENiHBG106917.
InParanoidiP70658.
KOiK04189.
PhylomeDBiP70658.
TreeFamiTF330966.

Family and domain databases

InterProiIPR022726. Chemokine_CXCR4_N_dom.
IPR000355. Chemokine_rcpt.
IPR033039. CXCR4.
IPR001277. CXCR4/ACKR2.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
[Graphical view]
PANTHERiPTHR10489:SF594. PTHR10489:SF594. 1 hit.
PfamiPF00001. 7tm_1. 1 hit.
PF12109. CXCR4_N. 1 hit.
[Graphical view]
PRINTSiPR00657. CCCHEMOKINER.
PR00645. CXCCHMKINER4.
PR00237. GPCRRHODOPSN.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform CXCR4-B (identifier: P70658-1) [UniParc]FASTAAdd to basket
Also known as: LESTR-B

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MEPISVSIYT SDNYSEEVGS GDYDSNKEPC FRDENVHFNR IFLPTIYFII
60 70 80 90 100
FLTGIVGNGL VILVMGYQKK LRSMTDKYRL HLSVADLLFV ITLPFWAVDA
110 120 130 140 150
MADWYFGKFL CKAVHIIYTV NLYSSVLILA FISLDRYLAI VHATNSQRPR
160 170 180 190 200
KLLAEKAVYV GVWIPALLLT IPDFIFADVS QGDISQGDDR YICDRLYPDS
210 220 230 240 250
LWMVVFQFQH IMVGLILPGI VILSCYCIII SKLSHSKGHQ KRKALKTTVI
260 270 280 290 300
LILAFFACWL PYYVGISIDS FILLGVIKQG CDFESIVHKW ISITEALAFF
310 320 330 340 350
HCCLNPILYA FLGAKFKSSA QHALNSMSRG SSLKILSKGK RGGHSSVSTE

SESSSFHSS
Length:359
Mass (Da):40,426
Last modified:November 1, 1997 - v2
Checksum:i33D1B5552A31595B
GO
Isoform CXCR4-A (identifier: P70658-2) [UniParc]FASTAAdd to basket
Also known as: LESTR-A

The sequence of this isoform differs from the canonical sequence as follows:
     6-7: Missing.

Show »
Length:357
Mass (Da):40,240
Checksum:i648C8835307AD5EC
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti216I → V in CAA67893 (PubMed:9295051).Curated1
Sequence conflicti216I → V in BAA19187 (Ref. 6) Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0018916 – 7Missing in isoform CXCR4-A. 1 Publication2

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U59760 mRNA. Translation: AAB07725.1.
U65580 Genomic DNA. Translation: AAC52953.1.
D87747 mRNA. Translation: BAA13451.1.
Z80111 mRNA. Translation: CAB02201.1.
Z80112 mRNA. Translation: CAB02202.1.
X99581 Genomic DNA. Translation: CAA67893.1.
X99582 mRNA. Translation: CAA67894.1.
AB000803 mRNA. Translation: BAA19187.1.
BC031665 mRNA. Translation: AAH31665.1.
BC098322 mRNA. Translation: AAH98322.1.
CCDSiCCDS15254.1. [P70658-1]
RefSeqiNP_034041.2. NM_009911.3.
UniGeneiMm.1401.

Genome annotation databases

GeneIDi12767.
KEGGimmu:12767.
UCSCiuc007cls.1. mouse. [P70658-2]
uc007clt.1. mouse. [P70658-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U59760 mRNA. Translation: AAB07725.1.
U65580 Genomic DNA. Translation: AAC52953.1.
D87747 mRNA. Translation: BAA13451.1.
Z80111 mRNA. Translation: CAB02201.1.
Z80112 mRNA. Translation: CAB02202.1.
X99581 Genomic DNA. Translation: CAA67893.1.
X99582 mRNA. Translation: CAA67894.1.
AB000803 mRNA. Translation: BAA19187.1.
BC031665 mRNA. Translation: AAH31665.1.
BC098322 mRNA. Translation: AAH98322.1.
CCDSiCCDS15254.1. [P70658-1]
RefSeqiNP_034041.2. NM_009911.3.
UniGeneiMm.1401.

3D structure databases

ProteinModelPortaliP70658.
SMRiP70658.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP70658. 1 interactor.
STRINGi10090.ENSMUSP00000053489.

Chemistry databases

BindingDBiP70658.
ChEMBLiCHEMBL1250365.

Protein family/group databases

GPCRDBiSearch...

PTM databases

iPTMnetiP70658.
PhosphoSitePlusiP70658.

Proteomic databases

MaxQBiP70658.
PaxDbiP70658.
PeptideAtlasiP70658.
PRIDEiP70658.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi12767.
KEGGimmu:12767.
UCSCiuc007cls.1. mouse. [P70658-2]
uc007clt.1. mouse. [P70658-1]

Organism-specific databases

CTDi7852.
MGIiMGI:109563. Cxcr4.

Phylogenomic databases

eggNOGiKOG3656. Eukaryota.
ENOG410XRW9. LUCA.
HOGENOMiHOG000234122.
HOVERGENiHBG106917.
InParanoidiP70658.
KOiK04189.
PhylomeDBiP70658.
TreeFamiTF330966.

Miscellaneous databases

ChiTaRSiCxcr4. mouse.
PROiP70658.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000045382.
CleanExiMM_CXCR4.

Family and domain databases

InterProiIPR022726. Chemokine_CXCR4_N_dom.
IPR000355. Chemokine_rcpt.
IPR033039. CXCR4.
IPR001277. CXCR4/ACKR2.
IPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
[Graphical view]
PANTHERiPTHR10489:SF594. PTHR10489:SF594. 1 hit.
PfamiPF00001. 7tm_1. 1 hit.
PF12109. CXCR4_N. 1 hit.
[Graphical view]
PRINTSiPR00657. CCCHEMOKINER.
PR00645. CXCCHMKINER4.
PR00237. GPCRRHODOPSN.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCXCR4_MOUSE
AccessioniPrimary (citable) accession number: P70658
Secondary accession number(s): O09059
, O09062, P70233, P70346, Q4KMW1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: November 2, 2016
This is version 155 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.