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CXCR4

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 71

Nomenclature: CXCR4

Family: Chemokine receptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 352 2q22.1 CXCR4 C-X-C motif chemokine receptor 4 16,41
Mouse 7 359 1 56.43 cM Cxcr4 chemokine (C-X-C motif) receptor 4 23,47
Rat 7 349 13q13 Cxcr4 C-X-C motif chemokine receptor 4 32,66
Previous and Unofficial Names Click here for help
fusin [8,16,23] | LCR1 [66] | LESTR [41,47] | HM89 | HUMSTSR | CD184 | NPY3R | NPYY3R | CXCR-4 | CXC-R4 | SDF-1 receptor | stromal cell-derived factor 1 receptor | Cmkar4 | HSY3RR | chemokine (C-X-C motif) receptor 4
Database Links Click here for help
Specialist databases
GPCRDB cxcr4_human (Hs), cxcr4_mouse (Mm), cxcr4_rat (Rn)
Other databases
ChEMBL Target CHEMBL2107 (Hs), CHEMBL1250365 (Mm), CHEMBL5556 (Rn)
DrugBank Target P61073 (Hs)
Ensembl Gene ENSG00000121966 (Hs), ENSMUSG00000045382 (Mm), ENSRNOG00000003866 (Rn)
Entrez Gene 7852 (Hs), 12767 (Mm), 60628 (Rn)
Human Protein Atlas ENSG00000121966 (Hs)
KEGG Gene hsa:7852 (Hs), mmu:12767 (Mm), rno:60628 (Rn)
OMIM 162643 (Hs)
Orphanet ORPHA120914 (Hs)
Pharos P61073 (Hs)
RefSeq Nucleotide NM_003467 (Hs), NM_009911 (Mm), NM_022205 (Rn)
RefSeq Protein NP_003458 (Hs), NP_034041 (Mm), NP_071541 (Rn)
SynPHARM 6612 (in complex with isothiourea-1t)
6614 (in complex with isothiourea-1t)
UniProtKB P61073 (Hs), P70658 (Mm), O08565 (Rn)
Wikipedia CXCR4 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  CXCR4 chemokine receptor in complex with small molecule antagonist
PDB Id:  3ODU
Ligand:  isothiourea-1t
Resolution:  2.5Å
Species:  Human
References:  68
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the CXCR4 chemokine receptor in complex with a cyclic peptide antagonist CVX15
PDB Id:  3OE0
Resolution:  2.9Å
Species:  Human
References:  68
Natural/Endogenous Ligands Click here for help
CXCL12γ {Sp: Human}
CXCL12δ {Sp: Human}
CXCL12ε {Sp: Human}
CXCL12φ {Sp: Human}
CXCL12β {Sp: Human}
CXCL12α {Sp: Human}
CXCL12 {Sp: Mouse}
Comments: SDF1α and SDF1β are the active isomers of CXCL12

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CXCL12α {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Immunopharmacology Ligand Hs Full agonist 7.7 – 8.2 pKd 26,42
⤷ pKd 7.7 – 8.2 [26,42]
[125I]CXCL12α (human) Peptide Ligand is labelled Ligand is radioactive Hs Full agonist 7.4 – 8.4 pKd 14,26,67
⤷ pKd 8.1 – 8.4 (Kd 7.94x10-9 – 3.98x10-9 M) [14,26]
pKd 7.4 (Kd 3.58x10-8 M) [67]
[125I]CXCL12β (human) Peptide Ligand is labelled Ligand is radioactive Hs Full agonist 7.9 pKd 26
⤷ pKd 7.9 [26]
CXCL12β {Sp: Human} Peptide Ligand is endogenous in the given species Immunopharmacology Ligand Hs Full agonist 7.9 pKd 26
⤷ pKd 7.9 (Kd 1.37x10-8 M) [26]
CXCL12H25R (monomer) Peptide Hs Agonist 7.8 pKd 15
⤷ pKd 7.8 (Kd 1.5x10-8 M) [15]
CXCL122 (dimer) Peptide Hs Partial agonist <6.0 pKd 15
⤷ pKd <6.0 (Kd >1x10-6 M) [15]
CXCL12-(1-17) Peptide Hs Full agonist 6.1 pKi 42
⤷ pKi 6.1 [42]
CXCL12-(1-9) dimer Peptide Hs Full agonist 6.1 pKi 42
⤷ pKi 6.1 [42]
CXCL12-(1-9) Peptide Hs Full agonist 4.9 pKi 42
⤷ pKi 4.9 [42]
CXCL12α {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Immunopharmacology Ligand Hs Agonist 9.3 pIC50 1
⤷ pIC50 9.3 (IC50 5x10-10 M) [1]
Description: Measuring CXCL12-induced displacement of CXCR4-bound 125I-CXCL12 from membranes prepared from HEK293T cells expressing human CXCR4.
ALX40-4C Peptide Click here for species-specific activity table Hs Partial agonist 6.1 pIC50 73
⤷ pIC50 6.1 (IC50 7.94x10-7 M) [73]
CXCL12γ {Sp: Human} Peptide Ligand is endogenous in the given species Immunopharmacology Ligand Hs Agonist - - 53,70
⤷ [53,70]
CXCL12δ {Sp: Human} Peptide Ligand is endogenous in the given species Immunopharmacology Ligand Hs Agonist - - 70
⤷ [70]
CXCL12ε {Sp: Human} Peptide Ligand is endogenous in the given species Immunopharmacology Ligand Hs Agonist - - 70
⤷ [70]
CXCL12φ {Sp: Human} Peptide Ligand is endogenous in the given species Immunopharmacology Ligand Hs Agonist - - 70
⤷ [70]
Agonist Comments
SDF-1α and SDF-1β are both referred to as CXCL12 and they have equivalent binding affinity and potency [26].
The CXCL12 isoforms (δ, γ, ε and φ) identified by Yu et al. (2006) were shown to stimulate cell migration in a CXCR4-dependent fashion [70].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SDF1 P2G Peptide Hs Antagonist 8.1 pKd 11
⤷ pKd 8.1 (Kd 9x10-9 M) [11]
mavorixafor Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 8.0 pKi 67
⤷ pKi 8.0 (Ki 1.1x10-8 M) [67]
Description: Assay using 125I-SDF-1α as tracer, in Cf2Th cells expressing hCXCR4.
plerixafor Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 6.7 – 7.0 pKi 1,73
⤷ pKi 7.0 (Ki 1x10-7 M) [73]
pKi 6.7 (Ki 1.99x10-7 M) [1]
SDF-1, 1-9[P2G] dimer Peptide Hs Antagonist 5.6 pKi 42
⤷ pKi 5.6 [42]
isothiourea-1t Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Antagonist 9.0 pEC50 62
⤷ pEC50 9.0 [62]
isothiourea-1a Small molecule or natural product Hs Antagonist 8.0 pEC50 62
⤷ pEC50 8.0 [62]
motixafortide Peptide Immunopharmacology Ligand Hs Antagonist 9.0 pIC50 60
⤷ pIC50 9.0 (IC50 9.1x10-10 M) [60]
Description: Inhibition of binding of 125I-SDF-1α (CXCL12) to CXCR4.
T134 Peptide Hs Antagonist 8.4 pIC50 61
⤷ pIC50 8.4 (IC50 3.98x10-9 M) [61]
T140 Peptide Hs Inverse agonist 7.8 – 8.6 pIC50 61,73
⤷ pIC50 7.8 – 8.6 [61,73]
viral macrophage inflammatory protein-II Peptide Click here for species-specific activity table Hs Antagonist 8.2 pIC50 35
⤷ pIC50 8.2 [35]
TIQ-15 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.2 pIC50 46
⤷ pIC50 8.2 (IC50 6.25x10-9 M) [46]
Description: Measuring antagonist-mediated inhibition of CXCL12-induced calcium flux in human T lymphoblast CCRF-CEM cells.
isothiourea-1t Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Antagonist 8.0 – 8.1 pIC50 1,62
⤷ pIC50 8.0 – 8.1 (IC50 1x10-8 – 7.9x10-9 M) [1,62]
compound 46c [PMID: 29350534] Small molecule or natural product Mm Antagonist 8.0 pIC50 46
⤷ pIC50 8.0 (IC50 9.24x10-9 M) [46]
isothiourea-1t Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Rn Antagonist 8.0 pIC50 62
⤷ pIC50 8.0 [62]
mavorixafor Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Antagonist 7.9 pIC50 57
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [57]
Description: Displacement of [125I]SDF-1α binding from CXCR4 in human CEM-CCRF cells by liquid scintillation counting.
compound 46c [PMID: 29350534] Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.8 pIC50 46
⤷ pIC50 7.8 (IC50 1.55x10-8 M) [46]
Description: Measuring antagonist-mediated inhibition of CXCL12-induced calcium flux in human T lymphoblast CCRF-CEM cells.
isothiourea-1a Small molecule or natural product Hs Antagonist 7.3 pIC50 62
⤷ pIC50 7.3 [62]
T22 Peptide Hs Antagonist 7.3 pIC50 61
⤷ pIC50 7.3 [61]
CX549 Small molecule or natural product Immunopharmacology Ligand Hs Antagonist ~7.3 pIC50 69
⤷ pIC50 ~7.3 (IC50 ~5x10-8 M) [69]
isothiourea-1a Small molecule or natural product Rn Antagonist 7.3 pIC50 62
⤷ pIC50 7.3 [62]
CXCR4 antagonist 22 Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 6.3 pIC50 1
⤷ pIC50 6.3 (IC50 5x10-7 M) [1]
Description: Displacement of CXCR4-bound 125I-CXCL12 from membranes prepared from HEK293T cells expressing human CXCR4.
plerixafor Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 6.2 pIC50 19
⤷ pIC50 6.2 (IC50 6.51x10-7 M) [19]
Description: Antagonism of SDF-1/CXCL12 ligand binding to CXCR4 expressed by CCRF–CEM T-cells.
View species-specific antagonist tables
Antagonist Comments
AMD3100 (plerixafor, Mozobil®) was approved by the US FDA in December 2008 for hematopoietic progenitor cell mobilisation [39].
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
ulocuplumab Peptide Primary target of this compound Immunopharmacology Ligand Hs Binding 8.6 pEC50 37
⤷ pEC50 8.6 (EC50 2.26x10-9 M) [37]
Description: Measuring displacement of iodinated SDF-1 from exogenously expressed CXCR4 in vitro.
Antibody Comments
Using their i-body platform, AdAlta have identified an anti-CXCR4 antibody (AD-114) that has proven effective as an anti-fibrotic agent in preclinical testing, in animal models of idiopathic pulmonary fibrosis (IPF) [18] and retinal fibrosis associated with age-related macular degeneration. AD-114 represents a novel mechanism of action for IPF, and a "first in class" therapy for this indication.
Immunopharmacology Comments
CXCR4 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. Due to its role in cancer cell homing and metastasis the CXCR4-CXCL12 axis is a potential target for cancer therapy [52,55,63-64]. This is exemplified by the development of ulocuplumab as an anti-cancer biologic therapy. Targeting the CXCR4-CXCL12 axis also offers the possibility of modulating the immune response in non-cancer indications [40,51,72].
Immuno Process Associations
Immuno Process:  Barrier integrity
GO Annotations:  Associated to 2 GO processes
GO:0019064 fusion of virus membrane with host plasma membrane TAS
click arrow to show/hide IEA associations
GO:0001618 virus receptor activity IEA
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0002407 dendritic cell chemotaxis TAS
GO:0006954 inflammatory response TAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 6 GO processes
GO:0016493 C-C chemokine receptor activity IBA
GO:0016494 C-X-C chemokine receptor activity NAS
GO:0038147 C-X-C motif chemokine 12 receptor activity IDA
GO:0038160 CXCL12-activated CXCR4 signaling pathway IDA
GO:0071345 cellular response to cytokine stimulus IDA
GO:2000448 positive regulation of macrophage migration inhibitory factor signaling pathway IMP
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 5 GO processes
GO:0002407 dendritic cell chemotaxis TAS
GO:0016493 C-C chemokine receptor activity IBA
GO:0016494 C-X-C chemokine receptor activity NAS
GO:0038147 C-X-C motif chemokine 12 receptor activity IDA
GO:0038160 CXCL12-activated CXCR4 signaling pathway IDA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0042098 T cell proliferation IMP
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0042098 T cell proliferation IMP
Immuno Disease Associations
Disease Name:  WHIM syndrome
Disease Synonyms:  no synonynms
Comment:  Mutations in CXCR4 that augment its activity have been identified in patients with WHIM syndrome. Such mutations can impair CXCR4/β-arrestin interaction and β-arrestin-mediated signal attenuation. This effect leads to defective desensitization and internalization of CXCR4 in response to ligand (CXCL12; SDF1) activation; in effect, increased CXCR4 activity.
Disease X-refs:  OMIM: 193670
Orphanet: ORPHA51636
References:  5,38
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Calcium channel
References:  47,50
Tissue Distribution Click here for help
CD4 lymphocytes in normal intestinal mucosa.
Species:  Human
Technique:  Flow cytometry.
References:  3
CNS: Frontal lobe, temporal lobe, spinal cord.
Species:  Human
Technique:  Northern blotting.
References:  56
Basophils.
Species:  Human
Technique:  RT-PCR and flow cytometry.
References:  30
Glomerular podocytes.
Species:  Human
Technique:  RT-PCR.
References:  28
Bone marrow stromal cells (BMSCs).
Species:  Human
Technique:  Flow cytometry and RT-PCR.
References:  27
Testes.
Species:  Human
Technique:  RT-PCR.
References:  22
Blood dendritic cells.
Species:  Human
Technique:  RT-PCR.
References:  4
Microglia.
Species:  Human
Technique:  Flow cytometry.
References:  2,17
Colon.
Species:  Human
Technique:  RT-PCR and Immunohistochemistry.
References:  33
Natural killer (NK) cells.
Species:  Human
Technique:  Flow cytometric and RNase protection assay.
References:  31
Precursor and mature megakaryocyte cells, and platelets.
Species:  Human
Technique:  RT-PCR and flow cytometry.
References:  36
CD34+ hematopoietic progenitor cells.
Species:  Human
Technique:  RT-PCR and Southern blotting.
References:  12
Fetal thymocytes.
Species:  Human
Technique:  Flow cytometry.
References:  34
Developing CNS: retina, olfactory epithelium, olfactory bulb, hippocampus, cerebellum, spinal cord.
Species:  Human
Technique:  in situ hybridisation.
References:  74
Thymus > spleen.
Species:  Mouse
Technique:  Northern blotting.
References:  23
Primordial germ cells.
Species:  Mouse
Technique:  RT-PCR
References:  48
Developing neocortex and hippocampus.
Species:  Mouse
Technique:  in situ hybridisation.
References:  43
Testicular macrophages.
Species:  Rat
Technique:  Northern blotting.
References:  22
Hippocampal neurons.
Species:  Rat
Technique:  RT-PCR.
References:  45
Brain: choroid plexus > olfactory nucleus, cortex, pituitary.
Species:  Rat
Technique:  Radioligand binding.
References:  6
Primary cultures of rat astrocytes and microglia.
Species:  Rat
Technique:  Northern blotting.
References:  32
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Detection of neutrophil morphological change (activation) by light microscopy.
Species:  Human
Tissue:  Neutrophils.
Response measured:  Activation.
References:  20
Measurement of chemotaxis of thymocyte cells endogenously expressing the CXCR4 receptor.
Species:  Human
Tissue:  Thymocytes.
Response measured:  Chemotaxis.
References:  71
Measurement of Ca2+ levels in thymocytes endogenously expressing the CXCR4 receptor.
Species:  Human
Tissue:  Thymocytes.
Response measured:  Stimulation of Ca2+ influx.
References:  71
Detection of HIV-1 entry into human U87MG cells transfected with human HA-tagged CXCR4 receptors and human CD4.
Species:  Human
Tissue:  Human astroglioma cell line U87MG.
Response measured:  HIV-1 entry.
References:  8
Measurement of Ca2+ levels in the human colonic epithelial cell line HT-29 endogenously expressing the CXCR4 receptor.
Species:  Human
Tissue:  HT-29 cells.
Response measured:  Increase in intracellular Ca2+ concentration.
References:  33
Measurement of ERK and p38 MAPK activity in HEK 293 cells transfected with the human CXCR4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Activation of ERK and p38 MAPK via β-arrestin2
References:  59
Measurement of chemotaxis of HEK 293 cells transfected with the human CXCR4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Chemotaxis involving β-arrstin2 and p38 MAPK activation.
References:  59
Measurement of Ca2+ currents in HEK 293 cells stably expressing N-type calcium channels and the rat CXCR4 receptor, using Ba2+ as the charge carrier (IBa).
Species:  Rat
Tissue:  HEK 293 cells.
Response measured:  IBa inhibition.
References:  50
Physiological Functions Click here for help
HIV coreceptor.
Species:  Human
Tissue:  Intestinal cell line HT-29.
References:  13
Chemotaxis.
Species:  Human
Tissue:  Neutrophils.
References:  20
Lymphopoiesis.
Species:  Human
Tissue:  Thymocytes.
References:  34
Haematopoiesis.
Species:  Mouse
Tissue:  In vivo.
References:  74
Cell migration and survival.
Species:  Mouse
Tissue:  Primordial germ cells.
References:  48
Interneuron migration.
Species:  Mouse
Tissue:  Neocortex.
References:  58
Neovascularisation (angiogenesis).
Species:  Rat
Tissue:  Aorta.
References:  54
Physiological Consequences of Altering Gene Expression Click here for help
CXCR4 receptor knockout mice exhibit defective haematopoiesis and cardiac development.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  74
CXCR4 receptor knockout mice exhibit small and malformed dorsal root ganglia as well as delayed migration of sensory neuron progenitors to the dorsal root ganglion.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  7
CXCR4 receptor knockout mice embryos exhibit defects in primordial germ cell migration and survival.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  48
CXCR4 receptor knockout mice exhibit fewer interneurons in the superficial layers of the neocortex, these interneurons instead being located in the deep layers of the neocortex.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  58
CXCR4 receptor knockout mice exhibit abnormal development of the dorsal root ganglia with major defects in cell migration in the developing cerebellar cortex.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  43
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0000260 abnormal angiogenesis PMID: 9634237 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0002144 abnormal B cell differentiation PMID: 9634237 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0002144 abnormal B cell differentiation PMID: 15520246 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000872 abnormal cerebellum external granule cell layer morphology PMID: 9634238 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000849 abnormal cerebellum morphology PMID: 9689100 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000849 abnormal cerebellum morphology PMID: 9634238 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000788 abnormal cerebral cortex morphology PMID: 11983855 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000812 abnormal dentate gyrus morphology PMID: 11983855  12183377 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0000281 abnormal interventricular septum morphology PMID: 9634238 
Cxcr4tm1Yiw|Tg(Lck-cre)1Jtak Cxcr4tm1Yiw/Cxcr4tm1Yiw,Tg(Lck-cre)1Jtak/0
Not Specified		 MGI:109563  MGI:3655253  MP:0003156 abnormal leukocyte migration PMID: 20939892 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0005460 abnormal leukopoiesis PMID: 9634238 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0002401 abnormal lymphopoiesis PMID: 9634238 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
B6.129X-Cxcr4/J		 MGI:109563  MP:0003090 abnormal muscle progenitor cell migration PMID: 16166380 
Cxcr4tm1Qma|Gab1tm1Wbm Cxcr4tm1Qma/Cxcr4tm1Qma,Gab1tm1Wbm/Gab1tm1Wbm
involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6		 MGI:108088  MGI:109563  MP:0003090 abnormal muscle progenitor cell migration PMID: 16166380 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
B6.129X-Cxcr4/J		 MGI:109563  MP:0000729 abnormal myogenesis PMID: 16166380 
Cxcr4tm1Qma|Gab1tm1Wbm Cxcr4tm1Qma/Cxcr4tm1Qma,Gab1tm1Wbm/Gab1tm1Wbm
involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6		 MGI:108088  MGI:109563  MP:0000729 abnormal myogenesis PMID: 16166380 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0002389 abnormal Peyer's patch follicle morphology PMID: 15520246 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0002982 abnormal primordial germ cell migration PMID: 12900445 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
B6.Cg-Cxcr4		 MGI:109563  MP:0002982 abnormal primordial germ cell migration PMID: 12684531 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
B6.Cg-Cxcr4		 MGI:109563  MP:0002145 abnormal T cell differentiation PMID: 12707343 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000853 absent cerebellar foliation PMID: 9689100 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0001177 atelectasis PMID: 9689100 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0004978 decreased B-1 B cell number PMID: 15520246 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0008207 decreased B-2 B cell number PMID: 15520246 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0001265 decreased body size PMID: 9689100 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000333 decreased bone marrow cell number PMID: 9689100 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
B6.Cg-Cxcr4		 MGI:109563  MP:0005092 decreased double-positive T cell number PMID: 12707343 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0004200 decreased fetal size PMID: 9634238 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0002460 decreased immunoglobulin level PMID: 15520246 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0008211 decreased mature B cell number PMID: 15520246 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm2Yzo Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm2Yzo/Cxcr4tm2Yzo
involves: 129P2/OlaHsd		 MGI:109563  MGI:88319  MP:0008098 decreased plasma cell number PMID: 15520246 
Cd19+|Cd19tm1(cre)Cgn|Cxcr4tm1Tng|Cxcr4tm2Tng Cd19tm1(cre)Cgn/Cd19+,Cxcr4tm1Tng/Cxcr4tm2Tng
involves: 129P2/OlaHsd * C57BL/6		 MGI:109563  MGI:88319  MP:0008098 decreased plasma cell number PMID: 15189736 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0008392 decreased primordial germ cell number PMID: 12900445 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0008208 decreased pro-B cell number PMID: 9689100 
Cxcr4tm1Yiw|Tg(Lck-cre)1Jtak Cxcr4tm1Yiw/Cxcr4tm1Yiw,Tg(Lck-cre)1Jtak/0
Not Specified		 MGI:109563  MGI:3655253  MP:0003436 decreased susceptibility to induced arthritis PMID: 20939892 
Cxcr4tm1Yiw|Tg(Lck-cre)1Jtak Cxcr4tm1Yiw/Cxcr4tm1Yiw,Tg(Lck-cre)1Jtak/0
Not Specified		 MGI:109563  MGI:3655253  MP:0000715 decreased thymocyte number PMID: 20939892 
Cxcr4tm1Qma|Gab1tm1Wbm Cxcr4tm1Qma/Cxcr4tm1Qma,Gab1tm1Wbm/Gab1tm1Wbm
involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6		 MGI:108088  MGI:109563  MP:0009907 decreased tongue size PMID: 16166380 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000885 ectopic Purkinje cell PMID: 9689100 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0001603 failure of myelopoiesis PMID: 9634237 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0000465 gastrointestinal hemorrhage PMID: 9634237 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0002192 hydrops fetalis PMID: 9634238 
Cxcr4tm1Qma|Gab1tm1Wbm Cxcr4tm1Qma/Cxcr4tm1Qma,Gab1tm1Wbm/Gab1tm1Wbm
involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6		 MGI:108088  MGI:109563  MP:0003359 hypaxial muscle hypoplasia PMID: 16166380 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0001602 impaired myelopoiesis PMID: 9689100 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0001602 impaired myelopoiesis PMID: 9634238 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000533 kidney hemorrhage PMID: 9689100 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000532 kidney vascular congestion PMID: 9689100 
Cxcr4tm1Yzo Cxcr4tm1Yzo/Cxcr4tm1Yzo
Not Specified		 MGI:109563  MP:0006208 lethality throughout fetal growth and development PMID: 9634238 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0002058 neonatal lethality PMID: 9634237 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0010418 perimembraneous ventricular septal defect PMID: 9634237 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0002081 perinatal lethality PMID: 9689100 
Cxcr4tm1Tng Cxcr4tm1Tng/Cxcr4tm1Tng
involves: 129P2/OlaHsd		 MGI:109563  MP:0002081 perinatal lethality PMID: 9634237 
Cxcr4tm1Qma Cxcr4tm1Qma/Cxcr4tm1Qma
involves: 129X1/SvJ		 MGI:109563  MP:0000873 thin external granule cell layer PMID: 9689100 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Waldenstrom macroglobulinemia
Description: A malignant B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and hypersecretion of monoclonal immunoglobulin M (IgM) protein
Synonyms: lymphoplasmacytic lymphoma [Disease Ontology: DOID:0050747]
Macroglobulinemia, Waldenstrom, somatic included [OMIM: 153600]
Macroglobulinemia, Waldenstrom, susceptibility to, 1 [OMIM: 153600]
WM
Disease Ontology: DOID:0050747
OMIM: 153600
Orphanet: ORPHA33226
Comments:  Gene mutations that cause truncation of the cytoplasmic tail domain of the CXCR4 protein are associated with Waldenstrom macroglobulinemia.
References:  29
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Truncation, loss of function Human S338STOP G>C 29
Truncation, loss of function Human S338STOP G>T 29
Truncation, loss of function Human S339Frameshift AGATdeleted 29
Truncation, loss of function Human S344Frameshift GAAGACTCAG>AC 29
Disease:  WHIM syndrome
Description: WHIM syndrome is an extremely rare congenital autosomal dominant immune deficiency characterized by abnormal retention of mature neutrophils in the bone marrow (myelokathexis) and occasional hypogammaglobulinemia, associated with an increased risk for bacterial infections and a susceptibility to human papillomavirus (HPV) induced lesions (cutaneous warts, genital dysplasia and invasive mucosal carcinoma) (from orphanet).
Synonyms: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM)
Warts-Infections-Leukopenia-Myelokatexis (WILM)
OMIM: 193670
Orphanet: ORPHA51636
Comments:  Mutations in the CXCR4 gene that result in truncation of the cytoplasmic tail domain of the receptor have been identified in almost all cases of WHIM syndrome. The mutations result in receptor gain of function (i.e. prolonged agonist-dependent signalling).
References:  25,29
Clinically-Relevant Mutations and Pathophysiology Comments
CXCR4 haploinsufficiency promotes hematopoietic stem cell engraftment, suggesting a useful strategy to promote hematopoietic stem cell engraftment in transplantation [44].
Biologically Significant Variants Click here for help
Type:  Splice variant
Species:  Human
Description:  An unspliced version of the human CXCR4 receptor, called CXCR4-Lo, has been found, with a 9 amino acid extension at the N-terminus. This receptor may be a functional backup to CXCR4 during embryogenesis.
References:  21
Type:  Splice variant
Species:  Mouse
Description:  A fully functioning splice variant of the mouse CXCR4 receptor, CXCR4-B, has been found with a different expression pattern from CXCR4.
References:  24,47
General Comments
CXCR4 is a receptor for stromal cell-derived factor-1 (SDF1; CXCL12) [9,49]. When co-expressed alongside CD4, CXCR4 is involved in HIV-1 infection. It is the major T cell-tropic coreceptor for HIV-1. In contrast, CCR5 serves as the principal macrophage-tropic coreceptor for viral entry. SDF1 inhibits HIV-1 infection by lymphocyte-tropic HIV-1 strains [9,49].

Cancer cells overexpress CXCR4 when compared to normal cells, and it is the most common chemokine receptor found on cancer cells. Its ligand CXCL12 is also found in the tumour micorenvironment [46]. Expression of CXCR4 correlates with cancer cell metastasis, angiogenesis, and tumour growth [10]. CXCR4 antagonists are predicted to exhibit anti-tumour activity via inhibition of CXCL12-CXCR4-mediated pro-survival signaling and chemotaxis [46,65].

References

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