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FLASH GENE
Symbol CXCR4 contributors: mct/pgu - updated : 12-09-2016
HGNC name chemokine (C-X-C motif) receptor 4
HGNC id 2561
DNA
TYPE functioning gene
STRUCTURE 3.81 kb     2 Exon(s)    1 Copie(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status confirmed
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
2 - 1691 - 352 - 2006 16948134
isoform b
1 - 1912 - 356 - 2006 16948134
isoform a
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Cardiovascularheart    
Digestivestomach    
Endocrineneuroendocrinepituitary  highly
Lymphoid/Immunelymph node   highly
 spleen   highly
Nervousbrainforebraincerebral cortex  
 spinal cord    
Respiratorylung    
Visualeyeretina    Rattus norvegicus
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Epithelialbarrier/liningretinal pigment epithelium (RPE)  
Nervouscentral   
cells
SystemCellPubmedSpeciesStageRna symbol
Blood/Hematopoieticleukocyte
Lymphoid/Immunedendritic cell
Lymphoid/Immunemacrophage
Visualepithelial cell
cell lineage the more immature CD34+ hematopoietic stem cells, in platelets
cell lines breast cancer cell lines
fluid/secretion
at STAGE
physiological period embryo
Text developping vascular endothelial cells
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • seven transmembrane segments (7TM), with only five transmembrane domain chemokine receptors
  • two potential N-glycosylation sites
  • three intracellular loop (ICL1, ICL2, ICL3), ICL2 and ICL3 are involved in JAK2 and STAT3 phosphorylation
  • secondary structure intracellular loop 1 (ICL1, AAs 65 to 71) linking helices I and II; ICL2 (AAs 140 to 144) linking helices III and IV; ICL3 (AAs 225 to 230) linking helices V and VI; and the C terminus (ICL3 also contains T4L inserted between Ser229 and Lys230 and flanked by short linkers (GS-T4L-GS))
    HOMOLOGY
    Homologene
    FAMILY
  • G protein coupled receptor 1 family
  • CATEGORY signaling , receptor membrane G
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    basic FUNCTION
  • regulates hematopoietic and tumor cell homing to bone
  • mediating migration of resting leukocytes and hematopoietic progenitors in response to SDF
  • required for entry of T cell line-tropic strains HIV-1 into CD4 cells
  • playing a role of receptor for SDF1 to directing the primordial germ cell migration
  • allows cells to migrate in response to a gradient of chemokine ligands
  • playing also an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodelling processes in endothelial cells
  • important for maturation and survival of dendritic cells to initiate acquired immune response
  • may be involved in a general mechanism in the regulation of hematopoiesis, linking lineage-specific transcription factors, miRNAs and key mRNA targets, particularly growth factor/chemokine receptors
  • during human T cell activation by antigen-presenting cells, recruited into the immunological synapse, where they deliver costimulatory signals
  • activation of CXCR4 results in a direct negative inotropic modulation of cardiac myocyte function
  • promotes metastasis by preventing anoikis in cancer cells
  • may be involved in the maturation of bone marrow-derived dendritic cells, which is regulated by notch signaling
  • forms functional complexes with CD74 that mediate MIF-specific signaling
  • fucntional receptor for extracellular ubiquitin
  • critical regulator of oligodendrocyte precursor cells (OPCs) remyelination within damaged white matter of the adult CNS
  • CXCR4 and the related CCR5 serve as co-receptors for HIV-1 viral particles, facilitating their entry into cells
  • CXCL12/CXCR4 system is involved in modulation of nociceptive signalling
  • its signaling regulates radial glial morphology and cell fate during embryonic spinal cord development
  • prevents dispersion of granule neuron precursors in the adult dentate gyrus
  • CXCL12/CXCR4 signal axis plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal stem cells
  • CXCR4 signaling also modulates synaptic function and neuronal survival in the mature brain, through direct and indirect effects on neurons and glia
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • CXCL12/CXCR4 signaling pathway is involved in the development of numerous neuronal and non-neuronal structures
  • a component
  • SDF1/CXCR4 signaling playing a role in the development of migrating muscle progenitors and a threshold number of progenitor cells is required to generate muscle of appropriate size
  • part of AIP4.arrestin-2 complex that functions on endosomes to regulate sorting of CXCR4 into the degradative pathway
  • crucial regulatory axis for the ventral axonal trajectory of developing spinal MNs, consisting of the ISL1-LHX3 complex, STAM1 and CXCR4
  • INTERACTION
    DNA
    RNA
    small molecule other,
  • dietary antioncogene cumin repressing CXCR4 expression
  • protein
  • ligand of CXCL12 (to transduce CXCL12 -mediated chemotaxis)
  • interaction between CXCR4 and CCR5 to exert specific biological functions and modulate T lymphocyte responses, and cooperation between receptors represents one key strategy for the functional plasticity of chemokines
  • SYT3 is essential for CXCR4 recycling in T cells and thereby for the maintenance of high CXCR4 surface levels required for migration)
  • interact with PLEC (PLEC plays an important role in CXCR4 signaling and trafficking and HIV-1 infection)
  • interacting with MIF and CD74 (CD74 forms functional complexes with CXCR4 that mediate MIF-specific signaling)
  • molecular link between UBE2I and the metastasis genes such as CDC42 and CXCR4, and thus provide new insight into the mechanism by which UBE2I9 promotes tumor invasion and metastasis
  • CCL18 is an important modulator of CXCR4-dependent responses in pre-B ALL cells via interactions with GPR30 (PMIDS:
  • both ACKR3 and CXCR4 are important for endothelial progenitor cells (EPCs) in response to CXCL12
  • ACKR3 may interact with CXCR4 at the intracellular level, possibly affecting CXCR4 trafficking and/or coupling to other proteins
  • PLG regulates MMP9-dependent CXCR4 expression to facilitate hematopoietic progenitor and stem cell (HPSC) mobilization in response to CSF3
  • coordinated changes in CXCR4 and S1PR5 responsiveness govern NK-cell trafficking
  • HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4
  • KLF11 regulates the expression of CXCR4 at a specific KLF11 binding site
  • CXCL12 protects neural progenitor cells (hNPCs) from apoptotic challenges through CXCR7- and CXCR4-mediated endocytotic signaling
  • NOTCH1 signaling regulates CXCR4 expression and the migration of mesenchymal stem cells
  • DEFB103B can both antagonize CXCR4 function on T cells and promote receptor internalization in the absence of activation
  • CXCL14 represents, along with CXCR7, molecules that co-evolved with the CXCL12-CXCR4 axis to modulate important physiological processes in development, stem cell maintenance, and immune responses
  • ACKR3 potentiates CXCR4 response and may contribute to the maintenance of leukemia by initiating cell recruitment to bone marrow niches that were once occupied by normal hematopoietic stem cells
  • MIF promotes the migration of B cells through a ZAP70-dependent pathway mediated by cooperative engagement of CXCR4 and CD74
  • novel role for the really interesting new gene-domain E3 ubiquitin ligase deltex-3-like (DTX3L) in regulating CXCR4 sorting from endosomes to lysosomes
  • addition of CXCL12 leads to the dissociation of EIF2S2 from CXCR4 suggesting that stimulation of the receptor may trigger the local protein synthesis required for efficient cell movement
  • RGS1 desensitizes the chemokine receptors CCR7 and CXCR4 that are critical to the localization of T and B cells in lymphoid organs
  • GNG4 is an inhibitor of CXCL12/CXCR4-dependent signaling
  • link between the ECM protein MATN4 and cytokine receptor CXCR4 involved in the regulation of hematopoietic stem cells (HSCs) proliferation and expansion under acute stress
  • ARRB1 and STAM cooperate to promote focal adhesion kinase autophosphorylation and chemotaxis via the chemokine receptor CXCR4
  • NRF1 regulates likely the expression of CXCR4 in normal retinal development and in pathologic processes of retinal hypoxia and neovascularization
  • HCLS1 is important for the activation of GTPases and integrins, and mediates signaling downstream of many receptors including BCR, TCR, and CXCR4
  • cell & other
    REGULATION
    activated by ZBTB16 in megakaryopoiesis
    induced by NFKB to promoting breast cancer cell migration and metastasis
    CXCL12 (increased the mRNA and surface expression of CXCR4 receptor in synovial fibroblasts)
    inhibited by VHL
    Other regulated by YY1
    USP8 is a positive regulator of CXCR4 trafficking for degradation
    ASSOCIATED DISORDERS
    corresponding disease(s) WHIM
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in breast cancer cells, malignant breast tumor and metastases
    tumoral     --over  
    in metastatic renal clear cell carcinoma
    constitutional     --other  
    aberrantly expressed in pathological specimens of vitreoretinal membranes
    tumoral     --over  
    in melanoma cells in primary lesions, significantly associated with the presence of ulceration, increased tumor thickness, a greater risk of developing regional and distant metastases and a higher mortality rate
    constitutional       loss of function
    enhances osteoclastogenesis, and may enhance established skeletal tumor burden by increasing osteoclasts activity
    constitutional     --over  
    with CXCL12 in patients with heart failure
    constitutional       gain of function
    CXCR4 activation, by promoting the differentiation of oligodendrocyte precursor cells into oligodendrocytes, is critical for remyelination of the injured adult CNS
    tumoral     --over  
    significantly associated with lymph node status and distant metastasis and indicated poor overall and disease free survival
    Susceptibility to leukocyte telomere length
    Variant & Polymorphism SNP rs4452212 associated with variation of leukocyte telomere length
    Candidate gene
  • use of CXCR4 inhibitors, particularly in patients with bone metastases
  • presence of functional CXCR4 on cardiac myocytes introduces a new target for treating cardiac dysfunction
  • useful prognostic factor for patients with metastatic prostate cancer treated with androgen-withdrawal therapy
  • Marker
    Therapy target
    SystemTypeDisorderPubmed
    miscelleaneoushypertension 
    CXCR4 and ACKR3 as new pharmacological targets to control vasoreactivity and blood pressure
    ANIMAL & CELL MODELS
  • diminished Cxcr4 alters interneuron migration in Large Deletion (LgDel) 22q11.2DS mice