P70658 (CXCR4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	Cxcr4
Synonyms:	Cmkar4, Lestr, Sdf1r

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	359 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

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. Ref.9 Ref.10 Ref.11
Subunit structure	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. Ref.13
Subcellular location	Cell membrane; Multi-pass membrane protein 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.
Tissue specificity	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. Ref.9 Ref.10
Developmental stage	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. Ref.12
Post-translational modification	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. 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. 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.
Disruption phenotype	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. Ref.9 Ref.10 Ref.11
Sequence similarities	Belongs to the G-protein coupled receptor 1 family.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing
Domain	Transmembrane Transmembrane helix
Molecular function	G-protein coupled receptor Receptor Transducer
PTM	Disulfide bond Glycoprotein Phosphoprotein Proteoglycan Sulfation Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	T cell proliferation Inferred from mutant phenotype PubMed 12707343. Source: MGI ameboidal cell migration Inferred from mutant phenotype PubMed 15626744. Source: MGI brain development Inferred from mutant phenotype PubMed 12183377. Source: MGI calcium-mediated signaling Inferred from sequence orthology PubMed 19064997. Source: MGI chemokine-mediated signaling pathway Inferred from electronic annotation. Source: GOC elevation of cytosolic calcium ion concentration Inferred from electronic annotation. Source: InterPro germ cell development Inferred from mutant phenotype PubMed 12900445. Source: MGI germ cell migration Inferred from mutant phenotype PubMed 12900445. Source: MGI motor neuron axon guidance Inferred from mutant phenotype PubMed 16129397PubMed 18031680. Source: MGI myelin maintenance Inferred from mutant phenotype PubMed 20534485. Source: BHF-UCL neural precursor cell proliferation Inferred from expression pattern PubMed 20882566. Source: DFLAT neuron migration Inferred from direct assay PubMed 12900445. Source: MGI neutrophil activation Inferred from electronic annotation. Source: InterPro organ morphogenesis Traceable author statement Ref.9. Source: ProtInc patterning of blood vessels Inferred from mutant phenotype PubMed 15626744. Source: MGI positive regulation of oligodendrocyte differentiation Inferred from mutant phenotype PubMed 20534485. Source: BHF-UCL regulation of cell migration Inferred from mutant phenotype PubMed 12183377PubMed 12900445. Source: MGI regulation of chemotaxis Inferred from electronic annotation. Source: Compara response to hypoxia Inferred from electronic annotation. Source: Compara
Cellular_component	cell leading edge Inferred from electronic annotation. Source: Compara cytoplasmic membrane-bounded vesicle Inferred from electronic annotation. Source: Compara external side of plasma membrane Inferred from direct assay PubMed 19008373. Source: MGI growth cone Inferred from direct assay PubMed 16129397. Source: MGI integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	C-X-C chemokine receptor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform CXCR4-B (identifier: P70658-1)

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.

Isoform CXCR4-A (identifier: P70658-2)

Also known as: LESTR-A;

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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 359	359	C-X-C chemokine receptor type 4		PRO_0000069355
Regions
	Topological domain	1 – 40	40	Extracellular By similarity
	Transmembrane	41 – 65	25	Helical; Name=1; By similarity
	Topological domain	66 – 79	14	Cytoplasmic By similarity
	Transmembrane	80 – 101	22	Helical; Name=2; By similarity
	Topological domain	102 – 112	11	Extracellular By similarity
	Transmembrane	113 – 132	20	Helical; Name=3; By similarity
	Topological domain	133 – 156	24	Cytoplasmic By similarity
	Transmembrane	157 – 176	20	Helical; Name=4; By similarity
	Topological domain	177 – 202	26	Extracellular By similarity
	Transmembrane	203 – 223	21	Helical; Name=5; By similarity
	Topological domain	224 – 248	25	Cytoplasmic By similarity
	Transmembrane	249 – 268	20	Helical; Name=6; By similarity
	Topological domain	269 – 289	21	Extracellular By similarity
	Transmembrane	290 – 309	20	Helical; Name=7; By similarity
	Topological domain	310 – 359	50	Cytoplasmic By similarity
	Region	1 – 23	23	Important for chemokine binding and signaling By similarity
	Region	96 – 99	4	Chemokine binding By similarity
	Region	115 – 119	5	Chemokine binding By similarity
	Region	137 – 149	13	Involved in dimerization; when bound to chemokine By similarity
	Region	193 – 197	5	Chemokine binding, important for signaling By similarity
	Region	198 – 217	20	Involved in dimerization By similarity
	Region	273 – 275	3	Involved in dimerization By similarity
	Motif	135 – 137	3	Important for signaling By similarity
Sites
	Binding site	173	1	Chemokine By similarity
	Binding site	295	1	Chemokine By similarity
Amino acid modifications
	Modified residue	9	1	Sulfotyrosine By similarity
	Modified residue	14	1	Sulfotyrosine By similarity
	Modified residue	23	1	Sulfotyrosine By similarity
	Modified residue	326	1	Phosphoserine By similarity
	Modified residue	328	1	Phosphoserine By similarity
	Modified residue	331	1	Phosphoserine; by PKC and GRK6 By similarity
	Modified residue	332	1	Phosphoserine; by PKC and GRK6 By similarity
	Modified residue	337	1	Phosphoserine; by GRK6 By similarity
	Modified residue	346	1	Phosphoserine; by GRK6 By similarity
	Modified residue	355	1	Phosphoserine By similarity
	Modified residue	358	1	Phosphoserine By similarity
	Glycosylation	13	1	N-linked (GlcNAc...) By similarity
	Glycosylation	20	1	O-linked (Xyl...) (chondroitin sulfate) By similarity
	Disulfide bond	30 ↔ 281		By similarity
	Disulfide bond	111 ↔ 193		By similarity
Natural variations
	Alternative sequence	6 – 7	2	Missing in isoform CXCR4-A.		VSP_001891
Experimental info
	Sequence conflict	216	1	I → V in CAA67893. Ref.4
	Sequence conflict	216	1	I → V in BAA19187. Ref.6

Sequences

	Sequence		Length	Mass (Da)
	Isoform CXCR4-B (LESTR-B) [UniParc]. Last modified November 1, 1997. Version 2. Checksum: 33D1B5552A31595B	FASTA	359	40,426
	10 20 30 40 50 60 MEPISVSIYT SDNYSEEVGS GDYDSNKEPC FRDENVHFNR IFLPTIYFII FLTGIVGNGL 70 80 90 100 110 120 VILVMGYQKK LRSMTDKYRL HLSVADLLFV ITLPFWAVDA MADWYFGKFL CKAVHIIYTV 130 140 150 160 170 180 NLYSSVLILA FISLDRYLAI VHATNSQRPR KLLAEKAVYV GVWIPALLLT IPDFIFADVS 190 200 210 220 230 240 QGDISQGDDR YICDRLYPDS LWMVVFQFQH IMVGLILPGI VILSCYCIII SKLSHSKGHQ 250 260 270 280 290 300 KRKALKTTVI LILAFFACWL PYYVGISIDS FILLGVIKQG CDFESIVHKW ISITEALAFF 310 320 330 340 350 HCCLNPILYA FLGAKFKSSA QHALNSMSRG SSLKILSKGK RGGHSSVSTE SESSSFHSS
	Isoform CXCR4-A (LESTR-A) [UniParc]. Checksum: 648C8835307AD5EC	FASTA	357	40,240
	10 20 30 40 50 60 MEPISIYTSD NYSEEVGSGD YDSNKEPCFR DENVHFNRIF LPTIYFIIFL TGIVGNGLVI 70 80 90 100 110 120 LVMGYQKKLR SMTDKYRLHL SVADLLFVIT LPFWAVDAMA DWYFGKFLCK AVHIIYTVNL 130 140 150 160 170 180 YSSVLILAFI SLDRYLAIVH ATNSQRPRKL LAEKAVYVGV WIPALLLTIP DFIFADVSQG 190 200 210 220 230 240 DISQGDDRYI CDRLYPDSLW MVVFQFQHIM VGLILPGIVI LSCYCIIISK LSHSKGHQKR 250 260 270 280 290 300 KALKTTVILI LAFFACWLPY YVGISIDSFI LLGVIKQGCD FESIVHKWIS ITEALAFFHC 310 320 330 340 350 CLNPILYAFL GAKFKSSAQH ALNSMSRGSS LKILSKGKRG GHSSVSTESE SSSFHSS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning of the mouse fusin gene, homologue to a human HIV-1 co-factor." Heesen M., Berman M.A., Benson J.D., Gerard C., Dorf M.E. J. Immunol. 157:5455-5460(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM CXCR4-B). Strain: 129/Sv and C57BL/6J. Tissue: Peritoneal exudate.
[2]	"Molecular cloning and characterization of a murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin." Nagasawa T., Nakajima T., Tachibana K., Iizasa H., Bleul C.C., Yoshie O., Matsushima K., Yoshida N., Springer T.A., Kishimoto T. Proc. Natl. Acad. Sci. U.S.A. 93:14726-14729(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM CXCR4-B). Tissue: Pre-B cell.
[3]	Schubel A., Burgstahler R., Lipp M. Submitted (SEP-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM CXCR4-B). Strain: 129/Sv. Tissue: Thymus.
[4]	"Two murine homologues of the human chemokine receptor CXCR4 mediating stromal cell-derived factor 1alpha activation of Gi2 are differentially expressed in vivo." Moepps B., Frodl R., Rodewald H.-R., Baggiolini M., Gierschik P. Eur. J. Immunol. 27:2102-2112(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS CXCR4-A AND CXCR4-B). Strain: C57BL/6J X CBA/J. Tissue: Thymus.
[5]	"Alternate splicing of mouse fusin/CXC chemokine receptor-4: stromal cell-derived factor-1alpha is a ligand for both CXC chemokine receptor-4 isoforms." Heesen M., Berman M.A., Hoepken U.E., Gerard N.P., Dorf M.E. J. Immunol. 158:3561-3564(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS CXCR4-A AND CXCR4-B).
[6]	Suzuki G., Nakata Y., Uzawa A., Shirasawa T., Saito T., Mita K. Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM CXCR4-B). Strain: C57BL/6. Tissue: Thymus.
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM CXCR4-B). Strain: FVB/N. Tissue: Mammary gland.
[8]	"Genomic organization and expression of the CXCR4 gene in mouse and man: absence of a splice variant corresponding to mouse CXCR4-B in human tissues." Frodl R., Gierschik P., Moepps B. J. Recept. Signal Transduct. 18:321-344(1998) [PubMed] [Europe PMC] [Abstract] Cited for: ALTERNATIVE SPLICING.
[9]	"The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract." Tachibana K., Hirota S., Iizasa H., Yoshida H., Kawabata K., Kataoka Y., Kitamura Y., Matsushima K., Yoshida N., Nishikawa S., Kishimoto T., Nagasawa T. Nature 393:591-594(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE.
[10]	"Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development." Zou Y.-R., Kottmann A.H., Kuroda M., Taniuchi I., Littman D.R. Nature 393:595-599(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE.
[11]	"Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice." Ma Q., Jones D., Borghesani P.R., Segal R.A., Nagasawa T., Kishimoto T., Bronson R.T., Springer T.A. Proc. Natl. Acad. Sci. U.S.A. 95:9448-9453(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[12]	"Embryonic expression and function of the chemokine SDF-1 and its receptor, CXCR4." McGrath K.E., Koniski A.D., Maltby K.M., McGann J.K., Palis J. Dev. Biol. 213:442-456(1999) [PubMed] [Europe PMC] [Abstract] Cited for: DEVELOPMENTAL STAGE. Strain: ICR.
[13]	"Regulation of myoblast motility and fusion by the CXCR4-associated sialomucin, CD164." Bae G.-U., Gaio U., Yang Y.-J., Lee H.-J., Kang J.-S., Krauss R.S. J. Biol. Chem. 283:8301-8309(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CD164.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00111763. IPI00849797.
RefSeq	NP_034041.2. NM_009911.3.
UniGene	Mm.1401.
3D structure databases
ProteinModelPortal	P70658.
SMR	P70658. Positions 29-324.
ModBase	Search...
Protein-protein interaction databases
IntAct	P70658. 1 interaction.
Protein family/group databases
GPCRDB	Search...
PTM databases
PhosphoSite	P70658.
Proteomic databases
PRIDE	P70658.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000052172; ENSMUSP00000053489; ENSMUSG00000045382.
GeneID	12767.
KEGG	mmu:12767.
UCSC	uc007cls.1. mouse. uc007clt.1. mouse.
Organism-specific databases
CTD	7852.
MGI	MGI:109563. Cxcr4.
Phylogenomic databases
eggNOG	NOG328039.
GeneTree	ENSGT00640000091250.
HOGENOM	HOG000234122.
HOVERGEN	HBG106917.
InParanoid	P70658.
KO	K04189.
OrthoDB	EOG46MBKB.
Gene expression databases
ArrayExpress	P70658.
Bgee	P70658.
CleanEx	MM_CXCR4.
Genevestigator	P70658.
GermOnline	ENSMUSG00000045382. Mus musculus.
Family and domain databases
InterPro	IPR001277. Chemokine_CXCR4. IPR022726. Chemokine_CXCR4_N_dom. IPR000355. Chemokine_rcpt. IPR000276. GPCR_Rhodpsn. IPR017452. GPCR_Rhodpsn_7TM. [Graphical view]
PANTHER	PTHR24227. PTHR24227. 1 hit. PTHR24227:SF7. PTHR24227:SF7. 1 hit.
Pfam	PF00001. 7tm_1. 1 hit. PF12109. CXCR4_N. 1 hit. [Graphical view]
PRINTS	PR00657. CCCHEMOKINER. PR00645. CXCCHMKINER4. PR00237. GPCRRHODOPSN.
PROSITE	PS00237. G_PROTEIN_RECEP_F1_1. 1 hit. PS50262. G_PROTEIN_RECEP_F1_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P70658.
ChEMBL	CHEMBL1250365.
ChiTaRS	CXCR4. mouse.
NextBio	282130.
SOURCE	Search...

Entry information

Entry name

CXCR4_MOUSE

Accession

Primary (citable) accession number: P70658
Secondary accession number(s): O09059 , O09062, P70233, P70346, Q4KMW1

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1997
Last modified:	May 29, 2013
This is version 122 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program