Affinage

CXCR4

C-X-C chemokine receptor type 4 · UniProt P61073

Length
352 aa
Mass
39.7 kDa
Annotated
2026-06-09
100 papers in source corpus 26 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CXCR4 is a leukocyte-expressed, Gαi-coupled seven-transmembrane chemokine receptor that converts the chemokine CXCL12/SDF-1 into chemotaxis, calcium mobilization, and pro-survival kinase signaling, and that doubles as an HIV-1 entry coreceptor (PMID:8752280, PMID:8752281, PMID:8276799, PMID:8970955). CXCL12 engages the receptor N-terminus for binding and the second extracellular loop for activation, with signaling requiring the DRY motif of the second intracellular loop and being pertussis-toxin-sensitive, whereas coreceptor function for HIV-1 is genetically separable from chemokine signaling (PMID:10074122). Downstream, CXCR4 drives ERK and Akt phosphorylation to promote chemotaxis and protect cells from apoptosis (PMID:12388552, PMID:24629239), and in T cells it physically associates with the TCR to recruit ZAP-70 through ITAM domains, prolonging ERK activation and licensing AP-1-dependent cytokine responses (PMID:16919488). Receptor output is shaped by partner receptors and ligand identity: CXCR7 constitutively heterodimerizes with CXCR4 and dampens Gαi activation and calcium responses (PMID:19380869), while CD74/CXCR4 complexes transduce the non-cognate ligand MIF to activate Akt (PMID:19665027, PMID:19066630). Signal termination depends on C-terminal serine phosphorylation by GRK6 and PKC, which directs AIP4-mediated ubiquitination and lysosomal degradation; C-tail truncating gain-of-function mutations impair this desensitization and cause prolonged signaling in WHIM syndrome and Waldenström macroglobulinemia (PMID:9718374, PMID:15661033, PMID:30936203, PMID:26490317). Genetically, CXCR4 is essential in vivo for hematopoietic and cardiac development, cerebellar granule cell migration, cortical interneuron motility and lamination via Gαi/o, and plasma cell homing to bone marrow niches (PMID:9634238, PMID:21220099, PMID:27681431). Cryo-EM structures show CXCL12 inserting its N-terminus into the orthosteric pocket and CXCR4 assembling into trimers and tetramers whose distinct conformations can allosterically tune activity (PMID:39313635), a pocket also exploited by the endogenous albumin-derived antagonist EPI-X4 and by biased antagonists that block G-protein signaling while permitting β-arrestin recruitment (PMID:25921529, PMID:30327409).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1994 Medium

    Establishing CXCR4 as a leukocyte seven-transmembrane GPCR defined the receptor scaffold before its ligand was known, framing the search for its activating signal.

    Evidence cDNA cloning from a monocyte library with radiolabeled ligand binding and RT-PCR expression profiling

    PMID:8276799

    Open questions at the time
    • Natural ligand unidentified at the time
    • No signaling pathway assigned
  2. 1996 High

    Identifying CXCL12/SDF-1 as the natural ligand connected the orphan receptor to calcium mobilization and chemotaxis, and showed it gates HIV-1 entry.

    Evidence Receptor transfection with calcium and chemotaxis assays plus HIV-1 infection inhibition; dual-tropic coreceptor assays in CD4 cells

    PMID:8752280 PMID:8752281 PMID:8970955

    Open questions at the time
    • Receptor domains required for binding versus signaling not yet mapped
    • G-protein coupling not directly demonstrated here
  3. 1998 High

    Knockout mice established CXCR4 as the sole in vivo SDF-1 receptor and revealed essential developmental roles, moving the receptor from a chemotaxis effector to a master patterning gene.

    Evidence Genetic knockout mouse with phenotypic analysis of hematopoiesis, cardiac, and cerebellar development; parallel endocytic and promoter mapping studies

    PMID:9599023 PMID:9634238 PMID:9718374

    Open questions at the time
    • Cell-autonomous versus niche contributions not resolved
    • Molecular basis of distinct endocytic signals not yet linked to ubiquitination machinery
  4. 1999 High

    Domain mutagenesis separated ligand binding (N-terminus), activation (ECL2, DRY motif, Gi-coupling) and HIV coreceptor function, defining the structural logic of the receptor.

    Evidence CXCR4 chimeras and point mutants assayed for SDF-1 binding, calcium signaling, HIV infection, and pertussis toxin sensitivity

    PMID:10074122

    Open questions at the time
    • Atomic-resolution ligand engagement not visualized
    • C-tail role in trafficking not addressed here
  5. 2002 Medium

    Linking CXCR4 to ERK and Akt activation and apoptosis protection established it as a pro-survival and invasion signal in cancer cells.

    Evidence Western blotting for ERK/Akt phosphorylation, serum-withdrawal apoptosis assay, and chemotaxis across glioma lines

    PMID:12388552

    Open questions at the time
    • Branch-specific contributions of ERK versus Akt not dissected
    • Single cancer context
  6. 2006 High

    Discovery of physical TCR association and ZAP-70/ITAM usage showed CXCR4 can route chemokine input into antigen-receptor signaling, explaining costimulation of T cells.

    Evidence Reciprocal co-IP of CXCR4 and TCR with ZAP-70 kinase, calcium, AP-1 reporter, and cytokine secretion assays; promoter-driven transcriptional upregulation studies

    PMID:16840440 PMID:16919488

    Open questions at the time
    • Stoichiometry of the CXCR4–TCR complex unknown
    • Generality beyond T cells not established
  7. 2009 High

    Defining CXCR7 and CD74 as heteromeric partners showed receptor output is set by partner identity, with CXCR7 dampening Gαi and CD74 enabling MIF-driven Akt signaling.

    Evidence BRET dimerization with Gi activation and calcium assays (CXCR7); reciprocal co-IP and Akt phosphorylation with antibody/inhibitor blocking (CD74)

    PMID:19380869 PMID:19665027

    Open questions at the time
    • Structural basis of heterodimer-induced conformational change not resolved
    • Relative abundance of heteromers in vivo unclear
  8. 2011 High

    Genetic and pharmacological dissection in brain established that CXCR4 controls interneuron migration through Gαi/o, distinct from CXCR7-mediated MAPK signaling.

    Evidence Cxcr4-/- and Cxcr7-/- mice with live imaging, in vivo pertussis toxin Gαi/o inhibition, and MAPK assays; in vivo MIF co-IP from tissue

    PMID:19066630 PMID:21220099

    Open questions at the time
    • Downstream cytoskeletal effectors of leading-process morphology not identified
    • Physiological MIF/CXCR4 role versus SDF-1 not quantified
  9. 2016 High

    WHIM-mimicking knockin and patient sequencing established that C-tail truncation is a gain-of-function lesion impairing desensitization, with disease-relevant consequences for plasma cell homing and B-cell malignancy.

    Evidence WHIM knockin mouse immunization and bone marrow analysis; deep sequencing of Waldenström macroglobulinemia patient samples; reviewed chemotaxis assays of truncation mutants

    PMID:15661033 PMID:26490317 PMID:27681431

    Open questions at the time
    • Quantitative link between residual desensitization and clonal expansion not defined
    • Interaction with MYD88 L265P not mechanistically resolved
  10. 2019 High

    Mapping GRK6- and PKC-driven C-tail phosphorylation to AIP4-mediated ubiquitination clarified the molecular machinery that terminates CXCR4 signaling and degrades it in lysosomes.

    Evidence Phorbol ester and heterologous CXCR5 activation of PKC, GRK6 siRNA, and ubiquitination/phosphorylation/lysosomal trafficking assays

    PMID:30936203

    Open questions at the time
    • Specific GRK6 phosphosites not all mapped
    • How truncation mutants escape this machinery not directly tested here
  11. 2024 High

    Cryo-EM structures resolved how CXCL12, AMD3100, and antibodies engage the orthosteric pocket and revealed higher-order oligomers, providing a structural framework for biased and endogenous antagonism.

    Evidence Cryo-EM of CXCR4 with CXCL12, AMD3100, and REGN7663, plus oligomer analysis; endogenous EPI-X4 antagonist characterization and biased X4-2-6 ternary-complex studies

    PMID:25921529 PMID:30327409 PMID:39313635

    Open questions at the time
    • Functional consequence of trimer/tetramer states in vivo not established
    • Dynamics of conformational transitions during activation not captured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct CXCR4 conformational states, oligomer stoichiometries, and partner-receptor heteromers are coordinated to produce context-specific signaling outputs in vivo remains unresolved.
  • No in vivo readout linking oligomeric state to physiology
  • Quantitative interplay between CXCR7/CD74/TCR heteromers in native cells unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
AIP4CD74CXCL12CXCR7GRK6MIFZAP-70
Complex memberships
CD74/CXCR4 complexCXCR4/CXCR7 heterodimerCXCR4/TCR complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 SDF-1 (CXCL12) is the natural ligand for CXCR4 (LESTR/fusin); SDF-1 signals through CXCR4 to induce intracellular Ca2+ increase and chemotaxis in CXCR4-transfected cells, and blocks T-tropic HIV-1 infection of CD4+ cells expressing CXCR4. Receptor transfection assays, Ca2+ mobilization assay, chemotaxis assay, HIV-1 infection inhibition assay Nature High 8752280 8752281
1994 CXCR4 (LESTR) was cloned as a novel seven-transmembrane, GTP-binding protein-coupled receptor highly expressed in leukocytes; transfected cells expressing LESTR did not bind IL-8, NPY, or a panel of other chemotactic ligands, leaving its natural ligand unidentified at that time. cDNA cloning from monocyte library, radiolabeled ligand binding assays, RT-PCR expression profiling The Journal of biological chemistry Medium 8276799
1998 CXCR4-knockout mice exhibit haematopoietic and cardiac defects identical to those of SDF-1-deficient mice, indicating CXCR4 is the sole receptor for SDF-1 in vivo; CXCR4 loss also causes cerebellar granule cell migration defects, establishing CXCR4 as required for neuronal cell migration and patterning. Genetic knockout mouse model, phenotypic analysis of haematopoiesis, cardiac development, and cerebellar development Nature High 9634238
1996 Primary syncytium-inducing HIV-1 strains are dual-tropic and can use either CXCR4 (LESTR/fusin) or CCR5 as co-receptors for entry into CD4+ cells. Infection assays using cat CCC/CD4 cells transiently expressing LESTR or CCR5 Journal of virology Medium 8970955
1999 SDF-1 requires the CXCR4 N-terminus for binding and activates downstream signaling through the second extracellular loop; activation requires the Asp-Arg-Tyr motif in the second intracellular loop and is pertussis-toxin sensitive (Gi-coupled). The C-terminal tail is dispensable for signaling. Several CXCR4 mutants unable to bind SDF-1 or signal still support HIV-1 infection, indicating that coreceptor function is independent of chemokine signaling. CXCR4 chimeras and point mutants, SDF-1 binding assays, calcium signaling assays, HIV-1 infection assays, pertussis toxin treatment Journal of virology High 10074122
1998 CXCR4 endocytosis is mediated by two distinct signals: a C-terminal serine-rich domain is required for ligand-induced but not phorbol ester-induced internalization, while a Ser/IleLeu motif mediates phorbol ester-induced but not ligand-induced endocytosis. CXCR4 deletion/mutation constructs, internalization assays in T cells, phorbol ester and SDF-1 stimulation Journal of cell science High 9718374
2001 CXCR4 exists in antigenically distinct conformational states on primary T and B cells; conformational heterogeneity is not due to glycosylation, sulfation of the N-terminal domain, or pertussis toxin-sensitive G-protein coupling. The commonly used anti-CXCR4 antibody 12G5 recognizes only a subpopulation of CXCR4 molecules on primary cells. Monoclonal antibody panel, flow cytometry, chemotaxis assay, HIV-1 infection inhibition, pertussis toxin treatment, glycosylation and sulfation analysis Journal of virology Medium 11533159
2002 CXCR4 activation by SDF-1 (CXCL12) in glioma cells induces rapid phosphorylation of MAP kinases (ERK) and Akt (PKB), and protects glioma cells from serum withdrawal-induced apoptosis; CXCR4 also mediates glioma cell chemotaxis. Western blotting for ERK and Akt phosphorylation, apoptosis assay (serum withdrawal), Boyden chamber chemotaxis assay, receptor expression profiling across 16 glioma lines The Journal of biological chemistry Medium 12388552
2006 CXCR4 physically associates with the T cell receptor (TCR) upon SDF-1α stimulation, and utilizes ITAM domains of the TCR to activate ZAP-70 tyrosine kinase, leading to prolonged ERK MAP kinase activation, increased intracellular calcium, robust AP-1 transcriptional activity, and SDF-1α costimulation of cytokine secretion in T cells. Co-immunoprecipitation of CXCR4 and TCR, ZAP-70 kinase assays, ERK phosphorylation assays, calcium flux assays, AP-1 reporter assay, cytokine secretion assay Immunity High 16919488
2009 CXCR7 constitutively heterodimerizes with CXCR4 as efficiently as homodimerization; CXCR7 expression induces conformational rearrangements within preassembled CXCR4/Gαi protein complexes and impairs CXCR4-promoted Gαi-protein activation and calcium responses to CXCL12. BRET/energy transfer dimerization assays, G protein activation assays, calcium mobilization assays, primary T cell chemotaxis with CXCR4 pharmacological blockade Blood High 19380869
2009 CD74 forms functional heteromeric complexes with CXCR4 at the cell surface; these CD74/CXCR4 complexes mediate MIF-specific AKT activation that is blocked by anti-CXCR4 antibodies and AMD3100, while CXCL12-stimulated AKT activation is not reduced by anti-CD74. Co-immunoprecipitation from HEK293 cells and from primary monocytes, AKT phosphorylation assays, antibody/inhibitor blocking experiments FEBS letters Medium 19665027
2011 CXCR4 and CXCR7 have distinct roles in cortical interneuron migration: CXCR4 loss leads to interneuron motility defects and altered leading process morphology, and in vivo inhibition of Gαi/o signaling phenocopies Cxcr4-knockout lamination defects, whereas CXCL12 stimulation of CXCR7 (but not CXCR4) promotes MAP kinase signaling. Cxcr4-/- and Cxcr7-/- knockout mice, live imaging of migrating interneurons, pharmacological CXCR4 blockade, in vivo pertussis toxin-mediated Gαi/o inhibition, MAPK signaling assays Neuron High 21220099
2005 WHIM syndrome mutations in CXCR4 truncate the cytoplasmic tail, impairing receptor downregulation/desensitization and causing enhanced (gain-of-function) chemotaxis in response to CXCL12, establishing that CXCR4 C-tail truncation leads to aberrant prolonged signaling. Analysis of patient-derived CXCR4 mutations, chemotaxis assays with mutant receptor, biochemical studies of receptor desensitization Immunological reviews Medium 15661033
2016 Fine-tuning of CXCR4 desensitization is required for efficient plasma cell (PC) differentiation, trafficking, and bone marrow maintenance; a gain-of-function CXCR4 knockin mutation (phenocopying WHIM syndrome) intrinsically promotes germinal center response and PC differentiation but prevents antigen-specific PCs from homing to bone marrow survival niches, correlating with early accumulation of immature plasmablasts. WHIM syndrome knockin mouse model, immunization experiments, flow cytometry, antibody titer measurement, bone marrow analysis Cell reports High 27681431
2006 HGF upregulates CXCR4 transcription in MCF-7 breast cancer cells via Ets1 (activated by MAPK1/ERK1/2) and NF-κB cooperating at the CXCR4 promoter; blocking these transcription factors with dominant negatives or inhibitors prevented CXCR4 induction and CXCL12-directed chemoinvasion. Hypoxia upregulates CXCR4 via HIF-1 and NF-κB. Dominant negative transcription factor constructs, pharmacological inhibitors, CXCR4 promoter-reporter assay, Boyden chamber chemoinvasion assay, Western blotting Carcinogenesis Medium 16840440
2008 CXCR4-MIF (macrophage migration inhibitory factor) complexes occur in vivo in rat bladder urothelium and are detected by co-immunoprecipitation; cyclophosphamide-induced cystitis increases CXCR4 expression and CXCR4-MIF associations, and MIF-stimulated signaling through CXCR4 represents an alternative, non-cognate ligand pathway distinct from SDF-1/CXCR4 signaling. Co-immunoprecipitation from bladder tissue, immunohistochemistry, Western blotting, ELISA, real-time RT-PCR PloS one Medium 19066630
2014 In kidney fibrosis (unilateral ureteral obstruction model), CXCR4 expression is upregulated in tubular cells and correlates with increased TGF-β1, PDGF-α, and decreased BMP7; genetic ablation of CXCR4 from tubular cells or macrophages attenuates fibrosis, Smad activation, and α-smooth muscle actin levels, revealing a CXCR4–TGF-β1–BMP7 pathway cross-talk in renal fibrosis. Cell-type-specific CXCR4 genetic knockout, unilateral ureteral obstruction model, Western blotting for TGF-β1/PDGF-α/BMP7/Smad/α-SMA, histology American journal of physiology. Renal physiology Medium 25537742
2019 PKC and GRK6 contribute to CXCR4 lysosomal trafficking and degradation via distinct mechanisms: PKC (activated heterologously by CXCR5/CXCL13 or phorbol ester) phosphorylates serine residues in the CXCR4 C-tail required for AIP4 (E3 ubiquitin ligase) binding and ubiquitination; GRK6 depletion by siRNA reduces CXCR4 degradation and ubiquitination. PKC inhibition does not alter CXCL12-mediated ubiquitination, indicating that GRK6 acts through a separate mechanism. PKC activation by phorbol ester (PMA) and heterologous CXCR5/CXCL13 stimulation, siRNA depletion of GRK6, ubiquitination assays, phosphorylation assays, lysosomal trafficking assays The Journal of biological chemistry High 30936203
2015 EPI-X4, a 16-amino-acid fragment of serum albumin generated by pH-regulated proteases, is an endogenous CXCR4 antagonist; it adopts a lasso-like structure, antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells in mice, and suppresses inflammatory responses. Blood-derived peptide library screen against CXCR4-tropic HIV-1, structural characterization, CXCL12-induced migration assays, in vivo stem cell mobilization assays Cell reports High 25921529
2018 Biased antagonism of CXCR4 by peptide X4-2-6 forms a ternary complex with the receptor and CXCL12, blocking G protein-mediated signaling and chemotaxis while permitting β-arrestin recruitment and receptor endocytosis; this avoids CXCR4 surface accumulation and antagonist tolerance, in contrast to AMD3100 which displaces all CXCL12 components. Ternary complex assays, G protein signaling assays, β-arrestin recruitment assays, receptor internalization/surface expression assays, chemotaxis assays, small-molecule biased antagonist identification Science signaling High 30327409
2024 Cryo-EM structures of human CXCR4 reveal that CXCL12 activates CXCR4 by inserting its N-terminus deep into the orthosteric pocket; AMD3100 binding is stabilized by electrostatic interactions with acidic residues in the seven-transmembrane-helix bundle; antibody REGN7663 inserts its CDR H3 loop into the orthosteric pocket; CXCR4 forms trimeric and tetrameric assemblies with distinct subunit conformations, suggesting that oligomerization can allosterically regulate receptor function. Cryo-electron microscopy of CXCR4 in complex with CXCL12, AMD3100, and REGN7663 antibody; structural analysis of oligomeric assemblies Nature structural & molecular biology High 39313635
2014 CXCR4 inhibition in colon cancer cells reduces CXCL12-induced Akt phosphorylation but not ERK activation, while CXCR7 knockdown does not affect Akt or ERK; hypoxia upregulates CXCR4 (but not CXCR7) at the transcript and membrane protein level via HIF-1α, and CXCR4 expression remains stable at the membrane for up to 48 hours after return to normoxia. siRNA knockdown of CXCR4 and CXCR7, Western blotting for Akt and ERK phosphorylation, flow cytometry for membrane CXCR4, HIF-1α inhibition, hypoxia/normoxia conditions Molecular cancer Medium 24629239
2014 CXCR4 mutations in Waldenström macroglobulinemia are heterozygous, somatic, located exclusively in the C-terminal domain, and produce a truncated receptor with higher cell-surface CXCR4 expression; these mutations are activating (gain-of-function) and occur in the same clone as MYD88 L265P mutations. Deep next-generation sequencing and Sanger sequencing of CXCR4 in patient samples; protein expression analysis; clone analysis Clinical cancer research Medium 26490317
2010 Chronic morphine treatment upregulates CXCL12/SDF-1 in dorsal root ganglion sensory neurons and increases functional CXCR4 expression in those neurons; intraperitoneal administration of the CXCR4 antagonist AMD3100 completely reverses opioid-induced hyperalgesia in rats. RT-PCR, immunohistochemistry, functional assays in F11 neuroblastoma-sensory hybrid cells, in vivo pharmacological rescue with AMD3100 Brain, behavior, and immunity Medium 21193025
1998 The human CXCR4 gene has a two-exon structure; a 2.6 kb 5'-flanking region contains a TATA box, transcription start site, and consensus binding sequences for transcription factors associated with hematopoiesis and lymphocyte development. Genomic cloning, promoter characterization, identification of transcription start site and transcription factor binding sites FEBS letters Medium 9599023

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1994 9634238
1996 The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 1664 8752280
1996 The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 1431 8752281
2010 CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 1211 20484021
2014 The intricate role of CXCR4 in cancer. Advances in cancer research 538 25287686
2012 A review on CXCR4/CXCL12 axis in oncology: no place to hide. European journal of cancer (Oxford, England : 1990) 532 22683307
2006 Regulation of CXCR4 signaling. Biochimica et biophysica acta 519 17169327
2009 CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood 507 19380869
2008 CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 391 18987663
1994 Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. The Journal of biological chemistry 359 8276799
1996 Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry. Journal of virology 347 8970955
2002 CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. The Journal of biological chemistry 317 12388552
2010 CXCR4 and cancer. Pathology international 239 20594270
2005 Functions of CXCL12 and CXCR4 in breast cancer. Cancer letters 235 16046252
2011 CXCR4 and CXCR7 have distinct functions in regulating interneuron migration. Neuron 232 21220099
2000 CXCR4: chemokine receptor extraordinaire. Immunological reviews 218 11138774
2013 Small molecule inhibitors of CXCR4. Theranostics 217 23382786
2002 CXCR4/CXCL12 expression and signalling in kidney cancer. British journal of cancer 214 11953881
2016 CXCR4 signaling in health and disease. Immunology letters 206 27363619
2009 A functional heteromeric MIF receptor formed by CD74 and CXCR4. FEBS letters 202 19665027
2006 CXCR4 physically associates with the T cell receptor to signal in T cells. Immunity 202 16919488
2008 CXCR7, CXCR4 and CXCL12: an eccentric trio? Journal of neuroimmunology 199 18533280
1999 Identification of CXCR4 domains that support coreceptor and chemokine receptor functions. Journal of virology 192 10074122
2015 CXCR4 in breast cancer: oncogenic role and therapeutic targeting. Drug design, development and therapy 183 26356032
2015 Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging. Theranostics 167 25825601
2012 Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12. Cytokine & growth factor reviews 165 22989616
2009 The biology of CCR5 and CXCR4. Current opinion in HIV and AIDS 163 19339947
2006 CXCR4 expression mediates glioma cell invasiveness. Oncogene 157 16407848
2001 Antigenically distinct conformations of CXCR4. Journal of virology 137 11533159
2017 CXCR4 Ligands: The Next Big Hit? Journal of nuclear medicine : official publication, Society of Nuclear Medicine 125 28864616
2019 Involvement of CXCR4 in Normal and Abnormal Development. Cells 122 30791675
1998 Differential regulation of CXCR4 and CCR5 endocytosis. Journal of cell science 117 9718374
2006 Human melanoma metastases express functional CXCR4. Clinical cancer research : an official journal of the American Association for Cancer Research 114 16638848
2018 CXCR4-directed theranostics in oncology and inflammation. Annals of nuclear medicine 111 30105558
1998 Chemokine receptor CXCR4 expression in endothelium. Biochemical and biophysical research communications 111 9439607
1997 Expression of the human immunodeficiency virus type-1 coreceptors CXCR-4 (fusin, LESTR) and CKR-5 in CD34+ hematopoietic progenitor cells. Blood 107 9160656
2015 Genomic Landscape of CXCR4 Mutations in Waldenström Macroglobulinemia. Clinical cancer research : an official journal of the American Association for Cancer Research 105 26490317
1998 Genomic organization and promoter characterization of human CXCR4 gene. FEBS letters 100 9599023
2022 CXCR4-targeted theranostics in oncology. European journal of nuclear medicine and molecular imaging 99 35674738
2010 CXCL12 and CXCR4 in bone marrow physiology. Expert review of hematology 93 21082982
2009 The chemokine receptors CXCR4 and CXCR3 in cancer. Current oncology reports 93 19216844
2008 CXCL12/CXCR4 signalling in neuronal cell migration. Current opinion in neurobiology 93 18644448
2012 An infernal trio: the chemokine CXCL12 and its receptors CXCR4 and CXCR7 in tumor biology. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft 87 23279723
2020 Targeting CXCR4 in AML and ALL. Frontiers in oncology 85 33014834
2006 HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappaB. Carcinogenesis 85 16840440
2018 Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine 81 29903571
2010 CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain, behavior, and immunity 79 21193025
2015 Discovery and characterization of an endogenous CXCR4 antagonist. Cell reports 77 25921529
2018 CXCR4 involvement in neurodegenerative diseases. Translational psychiatry 75 29636460
2012 Development of novel CXCR4-based therapeutics. Expert opinion on investigational drugs 75 22283809
2013 Molecular imaging of chemokine receptor CXCR4. Theranostics 73 23382787
2020 CXCR4 in Waldenström's Macroglobulinema: chances and challenges. Leukemia 72 33273682
2009 CXCL12, CXCR4 and CXCR7 expression in brain metastases. Cancer biology & therapy 72 19625779
2004 SDF-1 and CXCR4 in normal and malignant hematopoiesis. Histology and histopathology 72 14702198
2017 The good and bad faces of the CXCR4 chemokine receptor. The international journal of biochemistry & cell biology 70 29288743
2012 Imaging agents for the chemokine receptor 4 (CXCR4). Chemical Society reviews 70 22743644
2014 Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer. Molecular cancer 68 24629239
2007 Tissue microenvironment modulates CXCR4 expression and tumor metastasis in neuroblastoma. Neoplasia (New York, N.Y.) 65 17325742
2016 CXCL12/CXCR4 axis: an emerging neuromodulator in pathological pain. Reviews in the neurosciences 59 26353174
2018 Multisystem multitasking by CXCL12 and its receptors CXCR4 and ACKR3. Cytokine 58 29398278
2010 The role of chemokine receptor CXCR4 in lung cancer. Cancer biology & therapy 58 20147779
2009 CXCR4 chemokine receptor antagonists: perspectives in SCLC. Expert opinion on investigational drugs 58 19335276
2005 CXCR4 mutations in WHIM syndrome: a misguided immune system? Immunological reviews 58 15661033
2019 CXCR4-Directed Imaging in Solid Tumors. Frontiers in oncology 57 31475113
2024 SPP1+ TAM Regulates the Metastatic Colonization of CXCR4+ Metastasis-Associated Tumor Cells by Remodeling the Lymph Node Microenvironment. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 53 39236316
2014 Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors. American journal of physiology. Renal physiology 52 25537742
2011 Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia. Blood 52 22186993
2009 Bioluminescent CXCL12 fusion protein for cellular studies of CXCR4 and CXCR7. BioTechniques 52 19594447
2018 CXCR4-targeting nanobodies differentially inhibit CXCR4 function and HIV entry. Biochemical pharmacology 51 30342024
2017 Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia. Journal of hematology & oncology 51 28526063
2012 CXCR4 inhibitors: tumor vasculature and therapeutic challenges. Recent patents on anti-cancer drug discovery 51 22376154
2019 Modulators of CXCR4 and CXCR7/ACKR3 Function. Molecular pharmacology 50 31548340
2014 CXCR4 blockade induces atherosclerosis by affecting neutrophil function. Journal of molecular and cellular cardiology 49 24816217
2006 Expression of chemokine receptor CXCR4 in esophageal squamous cell and adenocarcinoma. BMC cancer 49 17176471
2016 CXCR4 and Glioblastoma. Anti-cancer agents in medicinal chemistry 48 26299663
2011 CXCR4-based imaging agents. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 46 22045705
2016 Efficient Plasma Cell Differentiation and Trafficking Require Cxcr4 Desensitization. Cell reports 45 27681431
2013 Chemokine receptor CXCR4: role in gastrointestinal cancer. Critical reviews in oncology/hematology 45 24120239
2005 WHIM syndrome: a defect in CXCR4 signaling. Current allergy and asthma reports 42 16091205
2020 CXCR4 Inhibition Counteracts Immunosuppressive Properties of Metastatic NSCLC Stem Cells. Frontiers in immunology 40 33123122
2019 Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3. Molecular pharmacology 40 31481460
2010 CXCR4-mediated glutamate exocytosis from astrocytes. Journal of neuroimmunology 40 20580441
2008 Cyclophosphamide-induced cystitis increases bladder CXCR4 expression and CXCR4-macrophage migration inhibitory factor association. PloS one 40 19066630
2016 Drug Design Targeting the CXCR4/CXCR7/CXCL12 Pathway. Current topics in medicinal chemistry 39 26369824
2014 CXCL14 antagonizes the CXCL12-CXCR4 signaling axis. Biomolecular concepts 39 25372750
2022 Colorectal Cancer: The Contribution of CXCL12 and Its Receptors CXCR4 and CXCR7. Cancers 38 35406582
2015 Role of chemokine receptors CXCR4 and CXCR7 for platelet function. Biochemical Society transactions 38 26551719
2021 In Vivo Targeting of CXCR4-New Horizons. Cancers 37 34885030
2023 CXC chemokine receptor 4 (CXCR4) blockade in cancer treatment. Journal of cancer research and clinical oncology 36 36905421
2022 Demystifying the CXCR4 conundrum in cancer biology: Beyond the surface signaling paradigm. Biochimica et biophysica acta. Reviews on cancer 36 36058380
2011 The expression of CXCR4, CXCL12 and CXCR7 in malignant pleural mesothelioma. The Journal of pathology 36 21294125
2018 Biased antagonism of CXCR4 avoids antagonist tolerance. Science signaling 35 30327409
2024 Structural insights into CXCR4 modulation and oligomerization. Nature structural & molecular biology 34 39313635
2017 A Role for CXCR4 in Peritoneal and Hematogenous Ovarian Cancer Dissemination. Molecular cancer therapeutics 34 29146630
2014 CXCL14 is no direct modulator of CXCR4. FEBS letters 32 25451233
2022 Zedoarondiol inhibits atherosclerosis by regulating monocyte migration and adhesion via CXCL12/CXCR4 pathway. Pharmacological research 30 35772647
2008 CXCR4, inhibitors and mechanisms of action. Chemical biology & drug design 29 18624812
2015 Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells. Journal of cellular and molecular medicine 28 26082201
2019 Heterologous regulation of CXCR4 lysosomal trafficking. The Journal of biological chemistry 27 30936203
2014 The CXCR4/CXCL12 axis in cutaneous malignancies with an emphasis on melanoma. Histology and histopathology 27 24879309

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