Affinage

CXCL12

Stromal cell-derived factor 1 · UniProt P48061

Length
93 aa
Mass
10.7 kDa
Annotated
2026-06-09
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CXCL12 (SDF-1/PBSF) is a constitutively secreted chemokine that orchestrates cell migration, survival, and tissue development, established by germline knockout mice that die perinatally with defective B-cell lymphopoiesis, bone-marrow myelopoiesis, and cardiac ventricular septation (PMID:8757135). Its signaling output is determined by two receptors: the G-protein-coupled receptor CXCR4 transduces directional and proliferative signals, while the atypical receptor CXCR7/ACKR3 shapes ligand availability—it constitutively internalizes and degrades CXCL12 without ligand saturation (PMID:20161793), regulates circulating plasma CXCL12 levels through venular endothelium (PMID:24116850), and heterodimerizes with CXCR4 to impair Gαi activation and calcium responses, dampening chemotaxis (PMID:19380869). Through CXCR4, CXCL12 engages context-dependent intracellular cascades that converge on cytoskeletal and survival machinery: a PAK1/2→p38α→MAPKAP-K2→HSP27 axis required for migration (PMID:16574378), Rac1/PAK-driven actin polymerization controlling dendritic spine plasticity (PMID:31971513), ABL2(Arg)-mediated cortactin Y421 phosphorylation driving invadopodia and invasion (PMID:32035133), PI3K/AKT/mTOR signaling promoting neurite regeneration and mTORC2-dependent angiogenesis (PMID:23578489, PMID:27106789), ERK1/2 supporting cancer-stem-cell invasion and lymphangiogenesis (PMID:28193907, PMID:22932666), JAK/Gi-dependent immunological synapse formation in T cells (PMID:25917087), and Btk-driven integrin αIIbβ3 activation underlying platelet aggregation and arterial thrombosis (PMID:35313337). CXCL12 activity is further tuned by structural and transcriptional regulation: distinct, non-overlapping receptor-binding and glycosaminoglycan-binding surfaces allow GAGs to anchor haptotactic gradients in tissue while leaving the receptor epitope free (PMID:18334249), an Asn44/Asn45–RFFESH 'hot spot' governs binding to both CXCR4 and CXCR7 (PMID:23812669), promoter DNA methylation and STAT3-p300-driven histone acetylation control its expression (PMID:21753787, PMID:28072604), and it can form a chemotactic heterocomplex with reduced HMGB1 that signals through CXCR4 (PMID:31418171). In disease contexts these mechanisms drive rheumatoid synovial MMP expression (PMID:21753787), atherosclerotic suppression of macrophage cholesterol efflux (PMID:31662443), chemotherapy-induced nociception (PMID:28072604), and senescent-fibroblast-mediated tumor immunosuppression (PMID:39251867).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1996 High

    Established that CXCL12 is non-redundantly required for development, defining its core physiological roles before its receptors and signaling were dissected.

    Evidence Germline knockout mouse with histological and progenitor analyses

    PMID:8757135

    Open questions at the time
    • Did not identify the receptor mediating each phenotype
    • Cell-autonomous versus niche contributions not resolved
    • Downstream signaling cascades undefined
  2. 2008 Medium

    Resolved how CXCL12 is positioned in tissue versus how it engages its receptor, showing receptor-binding and glycosaminoglycan-binding surfaces are structurally separable.

    Evidence NMR epitope mapping and isoform-specific GAG-binding assays

    PMID:18334249

    Open questions at the time
    • In vivo contribution of GAG anchoring to gradient formation not directly tested here
    • Functional consequence of isoform-specific GAG affinity differences incomplete
  3. 2006 High

    Defined a discrete kinase cascade linking CXCL12 stimulation to the actin/migration machinery, moving beyond Gαi/calcium readouts.

    Evidence p38α knockout mice, RNAi of MAPKAP-K2/HSP27, and pharmacological inhibition in migration assays

    PMID:16574378

    Open questions at the time
    • Receptor (CXCR4 vs CXCR7) upstream of PAK not specified
    • Direct HSP27 effector targets on the cytoskeleton not mapped
  4. 2009 High

    Explained how CXCR7 modulates CXCR4 output, demonstrating constitutive heterodimerization that conformationally suppresses Gαi activation and chemotaxis.

    Evidence BRET/FRET, calcium flux, and chemotaxis assays in T cells and transfected lines

    PMID:19380869

    Open questions at the time
    • Stoichiometry of heterodimers in native cells unclear
    • In vivo relevance of dimer-mediated dampening not established here
  5. 2010 High

    Reframed CXCR7 as a scavenger that controls CXCL12 abundance, distinguishing ligand availability regulation from classical signaling.

    Evidence Internalization, degradation, and cycling assays across cell lines, mouse tissue, and zebrafish

    PMID:20161793

    Open questions at the time
    • Trafficking adaptors mediating CXCR7 cycling not identified
    • Quantitative impact on tissue gradients not measured
  6. 2011 Medium

    Demonstrated promoter DNA hypomethylation as a transcriptional driver of pathological CXCL12 expression and assigned a CXCR7-dependent downstream effect.

    Evidence Bisulfite sequencing, demethylation treatment, and receptor-specific siRNA in rheumatoid synovial fibroblasts

    PMID:21753787

    Open questions at the time
    • Methyltransferase/demethylase responsible not identified
    • CXCR7-to-MMP signaling intermediates undefined
  7. 2011 Medium

    Established the molecular basis of CXCL12 paralog/receptor selectivity, showing a single residue tunes affinity to direct germ cell migration.

    Evidence Zebrafish genetics, site-directed mutagenesis, and PGC migration/affinity assays

    PMID:21693511

    Open questions at the time
    • Generalizability of the affinity rule to mammalian isoforms not tested
    • Structural basis of the affinity shift not resolved
  8. 2013 High

    Identified the shared CXCL12 surface engaging both receptors, locating Asn44/Asn45 and RFFESH as the binding hot spot.

    Evidence X-ray crystallography of a Fab/CXCL12α complex with mutagenesis and binding/migration assays

    PMID:23812669

    Open questions at the time
    • Does not explain receptor selectivity since the site is shared
    • Conformational differences between CXCR4 and CXCR7 engagement unresolved
  9. 2013 Medium

    Linked CXCL12/CXCR4 to neuronal regeneration through a specific PI3K/AKT/mTOR route, excluding JAK/STAT3.

    Evidence RGC neurite assays on myelin, receptor and pathway inhibitors, and an in vivo optic nerve crush model

    PMID:23578489

    Open questions at the time
    • mTOR complex specificity not distinguished here
    • Disinhibition mechanism toward myelin not molecularly defined
  10. 2015 Medium

    Showed CXCL12/CXCR4 shapes the T cell immunological synapse via Gi/JAK-dependent actin and MTOC organization, connecting the chemokine to adaptive immune activation.

    Evidence CXCR4 siRNA/blockade, confocal imaging, flow cytometry, and JAK inhibition in T cells

    PMID:25917087

    Open questions at the time
    • Direct JAK substrates at the synapse not identified
    • Physiological in vivo consequence for T cell responses not tested
  11. 2015 Medium

    Connected CXCL12/CXCR4 signaling to a tetraspanin (CD9) program promoting myoblast migration and fusion in muscle regeneration.

    Evidence Muscle injury models, receptor-specific siRNA, and migration/fusion assays across stem cell types

    PMID:25890097

    Open questions at the time
    • Signaling steps linking CXCR4 to CD9 transcription unmapped
    • Whether CD9 is necessary for the in vivo regenerative phenotype unclear
  12. 2016 Medium

    Defined the mTOR complex specificity of CXCL12-driven angiogenesis, showing mTORC2/PFKFB3 glycolytic control of sprouting.

    Evidence Complex-specific siRNA, pharmacology, Akt-Ser473 readout, and 3D/in vivo angiogenesis models

    PMID:27106789

    Open questions at the time
    • Link between mTORC2 and PFKFB3 induction not mechanistically detailed
    • Endothelial versus tumor cell source of signal not separated
  13. 2016 Medium

    Showed oncogenic JAK2 amplifies CXCL12/CXCR4 chemotaxis via PI3K, providing a disease context for enhanced responsiveness in myeloproliferative neoplasms.

    Evidence MPL-W515L expression, JAK2 knockdown/inhibition, and chemotaxis of patient CD34+ cells

    PMID:28903325

    Open questions at the time
    • Direct biochemical interaction between JAK2 and CXCR4 signaling not demonstrated
    • Receptor-level mechanism of sensitization unresolved
  14. 2017 High

    Uncovered transcriptional induction of CXCL12 by chemotherapy through STAT3-p300 histone acetylation, linking it to neuropathic pain via CXCR4-potentiated synaptic transmission.

    Evidence CoIP, ChIP, STAT3 genetics/inhibition, CXCL12 knockout, and electrophysiology in spinal neurons

    PMID:28072604

    Open questions at the time
    • CXCR4 downstream effectors potentiating mEPSCs not detailed
    • Generalizability beyond antitubulin agents untested
  15. 2017 Medium

    Established autocrine CXCL12/CXCR4/ERK1/2 signaling as a driver of cancer-stem-cell invasion and metastasis.

    Evidence Loss- and gain-of-function with ERK readout in vitro and in vivo metastasis model

    PMID:28193907

    Open questions at the time
    • ERK downstream invasion effectors not identified
    • Contribution of CXCR7 not assessed
  16. 2019 High

    Defined a platelet-intrinsic CXCL12/CXCR4/Btk→integrin αIIbβ3 cascade controlling thrombosis without affecting hemostasis.

    Evidence Platelet-specific CXCL12 knockout, Btk phosphorylation, aggregation under flow, and carotid injury model

    PMID:35313337

    Open questions at the time
    • Source of CXCL12 acting in trans versus cis not fully resolved
    • Coupling between Btk and integrin inside-out signaling not detailed
  17. 2019 Medium

    Showed CXCL12/CXCR4 suppresses macrophage cholesterol efflux through a GSK3β/β-catenin/TCF21→ABCA1 transcriptional axis, implicating it in atherosclerosis.

    Evidence Luciferase, ChIP, phospho-immunoblotting, receptor knockdown, and Apoe-/- in vivo overexpression

    PMID:31662443

    Open questions at the time
    • Direct CXCR4-to-GSK3β coupling mechanism not shown
    • Relative contribution to plaque burden quantitatively limited
  18. 2019 High

    Demonstrated CXCL12 forms a functional heterocomplex with reduced HMGB1 that enhances CXCR4-dependent inflammatory recruitment, defining a druggable composite chemoattractant.

    Evidence NMR binding, chemotaxis, and in vivo recruitment with diflunisal disruption

    PMID:31418171

    Open questions at the time
    • Structural basis of heterocomplex-CXCR4 engagement not resolved
    • Endogenous regulation of the complex in vivo unclear
  19. 2020 Medium

    Linked CXCL12/CXCR4 to synaptic plasticity via Rac1/PAK actin polymerization, showing it restores dendritic spines and cognitive flexibility.

    Evidence Neuroinflammation model, intracranial CXCL12, CXCR4 antagonism, pathway inhibition, and spine imaging

    PMID:31971513

    Open questions at the time
    • Molecular link from CXCR4 to Rac1 activation not detailed
    • Specificity for thin spines mechanistically unexplained
  20. 2020 Medium

    Identified ABL2(Arg)-mediated cortactin Y421 phosphorylation as the mechanism for CXCL12/CXCR4-driven invadopodia formation in glioma.

    Evidence Arg siRNA, cortactin phosphorylation, CoIP, and invadopodia/invasion assays

    PMID:32035133

    Open questions at the time
    • How CXCR4 activates Arg kinase not defined
    • In vivo invasion contribution not tested here
  21. 2024 Medium

    Connected senescent-fibroblast-derived CXCL12 to tumor immunosuppression, showing it blocks CD8 T cell differentiation and recruits MDSCs.

    Evidence p16-reporter mice, scRNA-seq, senescent-cell elimination, CXCL12 inhibition, and bispecific anti-CXCL12/PD1 antibody

    PMID:39251867

    Open questions at the time
    • Receptor (CXCR4 vs CXCR7) on T cells/MDSCs not specified
    • Direct signaling pathway in target immune cells undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the shared Asn44/Asn45-RFFESH binding hot spot produces distinct signaling versus scavenging outcomes at CXCR4 versus CXCR7, and how post-translational modifications and GAG anchoring quantitatively shape gradients in vivo, remain unresolved.
  • No structural model distinguishing CXCR4 versus CXCR7 engagement of the shared epitope
  • Quantitative in vivo contribution of GAG binding and proteolytic/citrullination modifications to gradient formation not established
  • Receptor identity unassigned in several disease contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 4 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-109582 Hemostasis 1
Partners
CXCR4CXCR7/ACKR3HMGB1
Complex memberships
CXCL12–CXCR4 (heterodimer with CXCR7/ACKR3)CXCL12–HMGB1 heterocomplex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Targeted disruption of PBSF/SDF-1 (CXCL12) in mice resulted in perinatal lethality with severe reduction of B-cell progenitors in fetal liver and bone marrow, reduction of myeloid progenitors specifically in bone marrow but not fetal liver, and cardiac ventricular septal defect, establishing CXCL12 as essential for B-cell lymphopoiesis, bone-marrow myelopoiesis, and cardiogenesis. Targeted gene disruption (knockout mouse), histological and progenitor cell analyses Nature High 8757135
2009 CXCR7 constitutively heterodimerizes with CXCR4 as efficiently as homodimerization; CXCR7 expression induces conformational rearrangements within preassembled CXCR4/Gαi complexes and impairs CXCR4-promoted Gαi-protein activation and calcium responses to CXCL12, thereby modulating CXCL12-mediated chemotaxis in T cells. BRET/FRET energy transfer assays, calcium flux assays, chemotaxis assays in primary T cells and transfected cell lines, CXCL12/CXCR7 blocking experiments Blood High 19380869
2010 CXCR7 acts as a specific scavenger receptor for CXCL12 (and CXCL11), mediating constitutive ligand internalization and targeting chemokine cargo for degradation; CXCR7 continuously cycles between the plasma membrane and intracellular compartments independently of ligand, and CXCR7-dependent chemokine degradation is not saturated with increasing ligand concentrations. Ligand internalization assays, degradation assays in mammalian cells and zebrafish, live cell imaging, in situ studies in mouse heart valves and human umbilical vein endothelium PloS one High 20161793
2006 CXCL12-induced cell migration requires a PAK1/2 → p38α MAPK → MAPKAP-K2 → HSP27 signaling pathway; pharmacological inhibition or genetic ablation of p38α, RNAi against MAPKAP-K2, or RNAi against HSP27 each blocked CXCL12-induced cell migration. Pharmacological inhibition (SB203580, BIRB0796), genetic p38α knockout mice, RNA interference (MAPKAP-K2, HSP27), macrophage migration assay, HeLa cell migration assay Cellular signalling High 16574378
2011 DNA hypomethylation of the CXCL12 promoter in rheumatoid arthritis synovial fibroblasts (RASFs) drives increased CXCL12 expression relative to osteoarthritis SFs; CXCL12 stimulation of RASFs increases MMP expression via CXCR7 (not CXCR4), as demonstrated by CXCR7 siRNA knockdown. Bisulfite sequencing, McrBC methylation assay, 5-azacytidine demethylation, ELISA, CXCR7 siRNA transfection, real-time PCR for MMPs Genes and immunity Medium 21753787
2012 CXCL12 promotes lymphangiogenesis and lymphatic endothelial cell (LEC) migration and tube formation via CXCR4, activating intracellular Akt and Erk phosphorylation; the CXCL12-CXCR4 axis promotes lymphangiogenesis independently of the VEGFR-3 pathway in vivo. In vitro LEC migration and tubule formation assays, phosphorylation assays (Akt, Erk), specific antagonist treatment, in vivo lymphangiogenesis model, orthotopic breast cancer model with anti-CXCL12 antibody treatment Clinical cancer research Medium 22932666
2014 CXCR7/ACKR3 expressed on venule endothelium regulates circulating CXCL12 plasma levels; genetic deletion or pharmacological inhibition of CXCR7 caused pronounced increases in plasma CXCL12 levels and impaired leucocyte migration toward CXCL12. Genetic CXCR7 deletion, pharmacological CXCR7 inhibition, plasma CXCL12 ELISA, leucocyte migration assay, immunohistochemistry, complementary protein detection techniques in human and mouse tissues Immunology Medium 24116850
2016 CXCL12 regulates angiogenesis through CXCR4 via mTORC2 (but not mTORC1); CXCR4 signaling activates mTORC2 through a G-protein- and PI3K-dependent pathway as indicated by Akt Ser473 phosphorylation; mTORC2-dependent glycolytic regulator PFKFB3 is required for microvascular sprouting. mTOR complex-specific siRNA knockdown, pharmacological inhibition, Akt phosphorylation assays, 3D in vitro angiogenesis model, mouse tumor angiogenesis model Angiogenesis Medium 27106789
2013 Crystal structure of hu30D8 Fab/CXCL12α complex combined with mutational analysis revealed that residues Asn44/Asn45 of CXCL12α and part of the RFFESH region are a 'hot spot' required for CXCL12α binding to both CXCR4 and CXCR7. X-ray crystallography (Fab/CXCL12α complex), site-directed mutagenesis, cell surface binding assay, cell migration assay Clinical cancer research High 23812669
2017 Antitubulin chemotherapeutics (paclitaxel/vincristine) increase CXCL12 expression in spinal dorsal horn neurons via STAT3-p300 interaction: STAT3 phosphorylation increases its binding to the CXCL12 gene promoter and interaction with acetyltransferase p300, leading to enhanced histone H4 acetylation at the CXCL12 promoter and increased transcription; CXCL12 then signals via CXCR4 (not CXCR7) to potentiate nociceptive synaptic transmission. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), adeno-associated virus Cre-mediated STAT3 knockout, STAT3 inhibitor, siRNA, transgenic CXCL12 knockout mice, neutralizing antibody, electrophysiology (mEPSC recording), behavioral assays Pain High 28072604
2019 CXCL12 acts via CXCR4 to activate the GSK3β/β-catenin(Thr120)/TCF21 signaling pathway, reducing TCF21-dependent transcription of ABCA1 and inhibiting ABCA1-mediated cholesterol efflux from macrophages; CXCR4 knockdown/inhibition blocked these effects. Luciferase reporter assay, chromatin immunoprecipitation, Western blotting (phospho-GSK3β, phospho-β-catenin), CXCR4 siRNA/inhibitor, cholesterol efflux assay, lentivirus CXCL12 overexpression in Apoe-/- mice Journal of lipid research Medium 31662443
2019 Platelet-derived CXCL12 activates CXCR4 on platelets to trigger a signaling cascade involving Bruton's tyrosine kinase (Btk), leading to integrin αIIbβ3 activation, platelet aggregation, and granule release; platelet-specific CXCL12 deficiency in mice limits arterial thrombosis and neointimal lesion formation without increasing bleeding time. Platelet-specific CXCL12 knockout mice, CXCR4 inhibition, Btk phosphorylation assays, platelet aggregation assays under static and arterial flow conditions, carotid artery injury model, tail bleeding time assay, peptide (i[VREY]4) inhibition Blood High 35313337
2015 CXCL12 signaling through CXCR4 regulates the formation of productive immunological synapses in T cells; CXCR4 downregulation or blockade impairs actin polymerization at the T cell–APC contact site, alters MTOC polarization and IS structure, reduces T cell/APC contact duration and T cell activation (CD25, CD69, IL-2); this effect is mediated through Gi and JAK1/JAK2 kinases. CXCR4 siRNA knockdown, CXCR4 blocking antibody, confocal microscopy of actin and MTOC, flow cytometry (CD25, CD69), IL-2 mRNA measurement, pharmacological JAK1/2 inhibition Journal of immunology Medium 25917087
2019 HMGB1 forms a heterocomplex with CXCL12 (reduced/all-thiol form) that signals via CXCR4 to recruit inflammatory cells; diflunisal binds directly to both HMGB1 and CXCL12 and disrupts this heterocomplex, specifically inhibiting the chemotactic activity of HMGB1 in vitro and in vivo without inhibiting TLR4-dependent (disulfide-HMGB1) responses. NMR binding assays, in vitro chemotaxis assays, in vivo inflammatory recruitment models, direct binding assays between diflunisal, HMGB1, and CXCL12 EMBO reports High 31418171
2020 CXCL12 rescues synaptodendritic spine density and cognitive flexibility via CXCR4-dependent stimulation of the Rac1/PAK actin polymerization pathway in layer II/III pyramidal neurons of the medial prefrontal cortex; CXCL12 preferentially regulates plastic thin spines. Rodent model of neuroinflammation (HAND), intracranial CXCL12 administration, CXCR4 antagonist treatment, confocal imaging of dendritic spines, Rac1/PAK pathway inhibition, behavioral cognitive flexibility assays eLife Medium 31971513
2013 CXCL12/SDF-1 facilitates optic nerve regeneration in mature retinal ganglion cells (RGCs) via CXCR4-dependent stimulation of the PI3K/AKT/mTOR pathway (not JAK/STAT3); CXCL12 exerts disinhibitory effects toward myelin that are blocked by a CXCR4 antagonist or PI3K/mTOR inhibition. In vitro RGC neurite growth assay on laminin and myelin, CXCR4 antagonist treatment, PI3K/mTOR pathway inhibitors, JAK/STAT3 inhibitors, intravitreal CXCL12 injection, in vivo optic nerve crush model, mTOR activity assay Neurobiology of disease Medium 23578489
2017 CXCL12/CXCR4 autocrine signaling in esophageal cancer stem cells activates the ERK1/2 pathway to maintain high invasion and metastasis capacity; loss-of-function (shRNA, inhibitors) and gain-of-function strategies both confirmed CXCL12's role. CXCR4 shRNA knockdown, CXCR4 inhibitors, CXCL12 loss-of-function and gain-of-function, ERK1/2 phosphorylation assay, in vitro invasion/migration assays, in vivo metastasis model Oncotarget Medium 28193907
2020 CXCL12/CXCR4 axis induces glioma cell invadopodia formation and invasion by stimulating Arg kinase (ABL2)-mediated phosphorylation of cortactin at Y421; Arg silencing blocked CXCL12-induced cortactin phosphorylation and invadopodium formation, and CXCL12 could not induce invasion in Arg-knockdown cells. Arg siRNA knockdown, cortactin phosphorylation assay, co-immunoprecipitation of Arg and cortactin, invadopodia formation assay, invasion assay Experimental cell research Medium 32035133
2011 In zebrafish, a single amino acid exchange distinguishes two Cxcl12 paralogs by determining their differential affinity for duplicated Cxcr4 receptors, establishing the molecular basis for primordial germ cell (PGC) preferential migration toward one paralog; this represents protein subfunctionalization via receptor-ligand affinity. Zebrafish genetics, site-directed mutagenesis of CXCL12 paralogs, PGC migration assays, receptor binding/affinity measurements Development (Cambridge, England) Medium 21693511
2016 Oncogenic JAK2 cooperates with CXCL12/CXCR4 signaling to enhance chemotactic responses in hematopoietic cells through increased PI3K signaling; JAK2 inhibition reduces CXCL12/CXCR4-induced chemotaxis, and primary myelofibrosis patient cells show increased CXCL12-induced chemotaxis compared to controls. MPL-W515L expression, JAK2 siRNA knockdown, JAK2 chemical inhibitors, chemotaxis assays with human cell lines and primary CD34+ cells from MPN patients, PI3K pathway readouts Oncotarget Medium 28903325
2015 CXCL12 (SDF-1) induces CD9 tetraspanin expression in satellite cell-derived myoblasts, bone marrow-derived mesenchymal stem cells, and embryonic stem cells through CXCR4 (not CXCR7); CXCR4 silencing blocked the CD9 upregulation effect, and CD9 upregulation enhances cell migration and fusion with myoblasts during muscle regeneration. In vivo skeletal muscle injury model (rat and Pax7-/- mice), CXCR4/CXCR7 siRNA knockdown, flow cytometry for CD9, in vitro migration and fusion assays with multiple stem cell types Stem cell research & therapy Medium 25890097
2024 CXCL12-secreting senescent fibroblasts (p16high) in aged bladder accumulate as cancer-associated fibroblasts and promote tumor growth; CXCL12 secreted by these cells inhibits CD8+ naïve T cell differentiation into cytotoxic T cells and attracts MDSCs, creating an immunosuppressive tumor microenvironment; elimination of p16high cells or CXCL12 inhibition suppressed tumor growth in vivo. Genetically modified mouse models (p16-reporter), single-cell RNA sequencing, p16high cell elimination, CXCL12 signaling inhibition, humanized mouse HCC model, bispecific antibody (anti-CXCL12/PD1) Nature aging Medium 39251867
2008 CXCL12 has structurally distinct binding sites for its receptor CXCR4 and for glycosaminoglycans (heparan sulfate); these sites do not overlap, and different CXCL12 isoforms display different GAG-binding abilities, suggesting GAG binding positions CXCL12 in tissues to maintain haptotactic gradients while leaving the receptor-binding domain free. Structural analysis, NMR mapping of GAG-binding and receptor-binding epitopes, isoform-specific binding assays Carbohydrate research Medium 18334249

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1875 8757135
2010 CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 1211 20484021
2010 CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer metastasis reviews 608 20839032
2012 A review on CXCR4/CXCL12 axis in oncology: no place to hide. European journal of cancer (Oxford, England : 1990) 532 22683307
2009 CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood 507 19380869
2010 CXCR7 functions as a scavenger for CXCL12 and CXCL11. PloS one 391 20161793
2011 CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clinical cancer research : an official journal of the American Association for Cancer Research 343 21349998
2017 The unique structural and functional features of CXCL12. Cellular & molecular immunology 306 29082918
2010 The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood 260 20930067
2020 The Role of the CXCL12/CXCR4/CXCR7 Chemokine Axis in Cancer. Frontiers in pharmacology 243 33363463
2005 Functions of CXCL12 and CXCR4 in breast cancer. Cancer letters 235 16046252
2002 CXCR4/CXCL12 expression and signalling in kidney cancer. British journal of cancer 214 11953881
2019 Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy. Current medicinal chemistry 208 28875842
2008 CXCR7, CXCR4 and CXCL12: an eccentric trio? Journal of neuroimmunology 199 18533280
1998 A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection. Seminars in immunology 191 9653044
2023 CXCL12-CXCR4/CXCR7 Axis in Cancer: from Mechanisms to Clinical Applications. International journal of biological sciences 175 37497001
2012 CXCR7 impact on CXCL12 biology and disease. Trends in molecular medicine 175 23153575
2010 CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization. Current pharmaceutical design 173 21158728
2012 Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12. Cytokine & growth factor reviews 165 22989616
2018 Pathological roles of the homeostatic chemokine CXCL12. Cytokine & growth factor reviews 153 30396776
2014 CXC chemokine ligand 12 (CXCL12) and its receptor CXCR4. Journal of molecular medicine (Berlin, Germany) 138 24722947
2019 The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases. Frontiers in endocrinology 136 31507535
2017 The role of CXCL12 in tumor microenvironment. Gene 124 29017963
2006 CXCL12 and C5a trigger cell migration via a PAK1/2-p38alpha MAPK-MAPKAP-K2-HSP27 pathway. Cellular signalling 103 16574378
2012 The CXCL12-CXCR4 chemokine pathway: a novel axis regulates lymphangiogenesis. Clinical cancer research : an official journal of the American Association for Cancer Research 101 22932666
2010 CXCL12 is a constitutive and inflammatory chemokine in the intestinal immune system. Inflammatory bowel diseases 101 19774645
2008 CXCL12 and CXCR4 in adenocarcinoma of the lung: association with metastasis and survival. The Journal of thoracic and cardiovascular surgery 100 19258077
2022 CXCR4/CXCL12 Activities in the Tumor Microenvironment and Implications for Tumor Immunotherapy. Cancers 99 35565443
2013 Involvement of CXCR4/CXCR7/CXCL12 Interactions in Inflammatory bowel disease. Theranostics 98 23382785
2012 Roles of chemokine CXCL12 and its receptors in ischemic stroke. Current drug targets 94 22204316
2010 CXCL12 and CXCR4 in bone marrow physiology. Expert review of hematology 93 21082982
2008 CXCL12/CXCR4 signalling in neuronal cell migration. Current opinion in neurobiology 93 18644448
2011 DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes and immunity 92 21753787
2013 Platelet-derived CXCL12 (SDF-1α): basic mechanisms and clinical implications. Journal of thrombosis and haemostasis : JTH 91 24024928
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
2000 A chemokine, SDF-1/PBSF, and its receptor, CXC chemokine receptor 4, as mediators of hematopoiesis. International journal of hematology 83 11197205
2014 Insights on the CXCL12-CXCR4 axis in hepatocellular carcinoma carcinogenesis. American journal of translational research 82 25075251
2018 Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine 81 29903571
2022 CXCL12/CXCR4: An amazing challenge and opportunity in the fight against fibrosis. Ageing research reviews 79 36442720
2014 Endothelial expression of CXCR7 and the regulation of systemic CXCL12 levels. Immunology 77 24116850
2009 CXCL12, CXCR4 and CXCR7 expression in brain metastases. Cancer biology & therapy 72 19625779
2020 The Signaling Duo CXCL12 and CXCR4: Chemokine Fuel for Breast Cancer Tumorigenesis. Cancers 69 33096815
2017 Epigenetic upregulation of CXCL12 expression mediates antitubulin chemotherapeutics-induced neuropathic pain. Pain 63 28072604
2016 CXCL12/CXCR4 axis: an emerging neuromodulator in pathological pain. Reviews in the neurosciences 59 26353174
1998 Interleukin-8 and hIRH (SDF1-alpha/PBSF) mRNA expression and histological activity index in patients with chronic hepatitis C. Hepatology (Baltimore, Md.) 59 9657103
2018 Multisystem multitasking by CXCL12 and its receptors CXCR4 and ACKR3. Cytokine 58 29398278
2009 Targeting the CXCR4/CXCL12 axis in systemic lupus erythematosus. Expert opinion on therapeutic targets 57 19670960
2008 Relationships between glycosaminoglycan and receptor binding sites in chemokines-the CXCL12 example. Carbohydrate research 57 18334249
2012 CXCL12 signaling in the development of the nervous system. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 56 22270883
2005 CXCL12 and CXCR4 expression by human gingival fibroblasts in periodontal disease. Clinical and experimental immunology 56 16045736
2016 mTORC2 mediates CXCL12-induced angiogenesis. Angiogenesis 55 27106789
2021 CXCL12 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 54 34286441
2019 Stromal cell-derived factor-1 (CXCL12) and its role in bone and muscle biology. Cytokine 54 31336263
2017 Misbalanced CXCL12 and CCL5 Chemotactic Signals in Vitiligo Onset and Progression. The Journal of investigative dermatology 54 28132854
2019 CXCL12 promotes atherosclerosis by downregulating ABCA1 expression via the CXCR4/GSK3β/β-cateninT120/TCF21 pathway. Journal of lipid research 52 31662443
2009 Bioluminescent CXCL12 fusion protein for cellular studies of CXCR4 and CXCR7. BioTechniques 52 19594447
2015 MIF and CXCL12 in Cardiovascular Diseases: Functional Differences and Similarities. Frontiers in immunology 50 26257740
2021 The CXCL12 Crossroads in Cancer Stem Cells and Their Niche. Cancers 49 33530455
2016 Expression and function of CXCL12/CXCR4/CXCR7 in thyroid cancer. International journal of oncology 49 27082011
2024 CXCL12+ tumor-associated endothelial cells promote immune resistance in hepatocellular carcinoma. Journal of hepatology 47 39393439
2017 Stem cell autocrine CXCL12/CXCR4 stimulates invasion and metastasis of esophageal cancer. Oncotarget 47 28193907
2013 CXCL12/SDF-1 facilitates optic nerve regeneration. Neurobiology of disease 46 23578489
2018 Expression and Cellular Localization of CXCR4 and CXCL12 in Human Carotid Atherosclerotic Plaques. Thrombosis and haemostasis 45 29304539
2011 Expression of the new CXCL12 receptor, CXCR7, in gliomas. Cancer biology & therapy 42 21084856
2007 The role of the chemokine CXCL12 in osteoclastogenesis. Trends in endocrinology and metabolism: TEM 42 17320408
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
2023 An emerging paradigm of CXCL12 involvement in the metastatic cascade. Cytokine & growth factor reviews 38 37949685
2022 Colorectal Cancer: The Contribution of CXCL12 and Its Receptors CXCR4 and CXCR7. Cancers 38 35406582
2019 CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer? Journal of oncology 38 31275385
2019 CXC chemokine ligand 12 (CXCL12) in atherosclerosis: An underlying therapeutic target. Clinica chimica acta; international journal of clinical chemistry 36 31145896
2013 The role of CXCL12-CXCR4 signaling pathway in pancreatic development. Theranostics 36 23382781
2013 Development and preclinical characterization of a humanized antibody targeting CXCL12. Clinical cancer research : an official journal of the American Association for Cancer Research 36 23812669
2011 The expression of CXCR4, CXCL12 and CXCR7 in malignant pleural mesothelioma. The Journal of pathology 36 21294125
2019 Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment. EMBO reports 35 31418171
2020 CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility. eLife 33 31971513
2022 Targeting platelet-derived CXCL12 impedes arterial thrombosis. Blood 32 35313337
2015 Sdf-1 (CXCL12) induces CD9 expression in stem cells engaged in muscle regeneration. Stem cell research & therapy 32 25890097
2011 Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 32 22173290
2020 NLRP3 Regulated CXCL12 Expression in Acute Neutrophilic Lung Injury. Journal of inflammation research 31 32801831
2022 Zedoarondiol inhibits atherosclerosis by regulating monocyte migration and adhesion via CXCL12/CXCR4 pathway. Pharmacological research 30 35772647
2021 miR-126-3p is essential for CXCL12-induced angiogenesis. Journal of cellular and molecular medicine 30 34117709
2016 CXCL12/CXCR4 pathway is activated by oncogenic JAK2 in a PI3K-dependent manner. Oncotarget 30 28903325
2020 CXCL12 in normal and pathological pregnancies: A review. American journal of reproductive immunology (New York, N.Y. : 1989) 29 32485053
2015 CXCL12 Regulates through JAK1 and JAK2 Formation of Productive Immunological Synapses. Journal of immunology (Baltimore, Md. : 1950) 29 25917087
2014 Emerging Targets in Pituitary Adenomas: Role of the CXCL12/CXCR4-R7 System. International journal of endocrinology 29 25484899
2011 SDF-1/CXCL12: its role in spinal cord injury. The international journal of biochemistry & cell biology 29 22172378
2021 The multifaceted roles of the chemokines CCL2 and CXCL12 in osteophilic metastatic cancers. Cancer metastasis reviews 28 33973098
2012 CXCL12 in control of neuroinflammation. Immunologic research 28 22392052
2014 CXCL12 chemokine and GABA neurotransmitter systems crosstalk and their putative roles. Frontiers in cellular neuroscience 27 24808825
2014 The CXCR4/CXCL12 axis in cutaneous malignancies with an emphasis on melanoma. Histology and histopathology 27 24879309
2011 Cxcl12 evolution--subfunctionalization of a ligand through altered interaction with the chemokine receptor. Development (Cambridge, England) 27 21693511
2024 Preexisting senescent fibroblasts in the aged bladder create a tumor-permissive niche through CXCL12 secretion. Nature aging 26 39251867
2014 Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma. International journal of cancer 26 25400097
2024 Crosstalk between CXCL12/CXCR4/ACKR3 and the STAT3 Pathway. Cells 25 38920657
2021 The Role of CXCL12 in Kidney Diseases: A Friend or Foe? Kidney diseases (Basel, Switzerland) 24 34179113
2020 Functions of the CXCL12 Receptor ACKR3/CXCR7-What Has Been Perceived and What Has Been Overlooked. Molecular pharmacology 24 32883765
2001 Role of chemokine SDF-1/PBSF and its receptor CXCR4 in blood vessel development. Annals of the New York Academy of Sciences 24 11795258
2020 Arg kinase mediates CXCL12/CXCR4-induced invadopodia formation and invasion of glioma cells. Experimental cell research 23 32035133
1999 Reduced expression of the CXCR4 receptor mRNA in hepatocellular carcinoma and lack of inducibility of its ligand alpha-chemokine hIRH/SDF1alpha/PBSF in vitro. International journal of oncology 23 10200343

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