CXCR4 is a seven-transmembrane chemokine receptor that recognizes CXCL12 and activates heterotrimeric G-protein signaling, principally through Gi. This axis directs cell migration, including hematopoietic cell homing, and contributes to immune-cell positioning and developmental programs. Pathogenic CXCR4 variants cause WHIM syndrome, characterized by peripheral neutropenia despite retention of mature myeloid cells in bone marrow. The receptor signals at the plasma membrane and undergoes regulated internalization and endosomal sorting. Intracellular interactions with arrestins, cytoskeletal regulators and ubiquitin-system proteins control its signaling and trafficking. CXCR4 also participates in MIF signaling with CD74 and serves as a CD4-associated entry coreceptor for susceptible HIV strains. Alternative N-terminal products differ in expression and ligand responses.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001618 virus receptor activity | TAS PMID:10228019 Down-regulation of CXCR4 by human herpesvirus 6 (HHV-6) and ... | KEEP AS NON CORE | Summary: CXCR4 is a viral entry receptor in defined HIV contexts. Reason: The cited abstract and independent structural work support CXCR4 engagement during HIV entry. This is a genuine host receptor role, distinct from its normal CXCL12 signaling function. HIV-2 structural data do not establish an experimental high-resolution HIV-1 complex, nor do these sources make CXCR4 a general herpesvirus receptor. |
| GO:0001666 response to hypoxia | IEP PMID:15174142 Modulation of gene expression by hypoxia in human umbilical ... | KEEP AS NON CORE | Summary: Hypoxia increases CXCR4 transcript expression in human endothelial cells. Reason: The cited abstract identifies CXCR4 among transcripts upregulated in hypoxic HUVEC. This fits the response term, which includes gene-expression changes, without requiring intrinsic oxygen sensing. Retain the existing contextual IEP assertion; the full original and CXCR4-specific protein or RT-PCR measurements were not verified, and receptor-mediated angiogenesis or protection is not inferred. Supporting Evidence: |
| GO:0002407 dendritic cell chemotaxis | TAS PMID:16621978 The multiple personalities of the chemokine receptor CCR7 in... | UNDECIDED | Summary: The cited review does not yet provide verified CXCR4-specific dendritic-cell chemotaxis evidence. Reason: PMID:16621978 is a review article whose accessible abstract discusses CCR7. Its full discussion and cited primary evidence for CXCR4-dependent dendritic-cell chemotaxis were not recovered. General CXCL12 chemotaxis in other cells does not independently settle this cell-specific assertion. Preserve uncertainty without concluding that the curator confused receptors or that CXCR4 cannot guide dendritic cells. Supporting Evidence: |
| GO:0003779 actin binding | IDA PMID:12421915 Cutting edge: association of the motor protein nonmuscle myo... | KEEP AS NON CORE | Summary: CXCR4 associates with actin in a receptorβactomyosin complex. Reason: GST-CXCR4-tail pull-downs from human T-cell lysates yielded actin identified by peptide fingerprinting and MS/MS; microscopy also placed CXCR4 and actin at the migrating front. These positive biochemical and cellular observations support retaining the existing contextual actin-binding annotation. They do not resolve an isolated receptor-actin contact or assign motor activity to CXCR4. Supporting Evidence: PMID:12421915 together with filamentous actin and myosin L chain |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000120 | MODIFY | Summary: The combined GPCR rule can be refined to the demonstrated CXCL12 receptor activity. Reason: The literal InterPro mapping and current ARBA00029151 branch 0 support GPCR identity. Human CXCL12 agonism and receptorβGi work identify the more informative performed molecular function. This refines the broad source assertion and overlaps existing specific receptor annotations; it does not manufacture a new activity. Proposed replacements: C-X-C motif chemokine 12 receptor activity |
| GO:0004930 G protein-coupled receptor activity | TAS PMID:8276799 Cloning of a human seven-transmembrane domain receptor, LEST... | MODIFY | Summary: The initially cloned receptor is now established as a CXCL12 receptor. Reason: The historical cloning source supports GPCR identity but predates the decisive ligand assignment. Later direct receptor experiments justify replacing the broad GPCR label with CXCL12 receptor activity while retaining the original citation and evidence code. Proposed replacements: C-X-C motif chemokine 12 receptor activity |
| GO:0004950 chemokine receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: The chemokine-receptor family mapping can be refined to CXCL12 receptor activity. Reason: IPR000355 supplies a valid family-level inference. The independently established ligand-specific activity is more informative and already represented by other source tuples; the refinement does not imply that CXCL12 is the only molecule capable of binding CXCR4. Proposed replacements: C-X-C motif chemokine 12 receptor activity |
| GO:0005515 protein binding | IPI PMID:10644702 beta-arrestin differentially regulates the chemokine recepto... | MODIFY | Summary: The interaction can be specified as arrestin family protein binding. Reason: The complete abstract reports beta-arrestin cross-linking to CXCR4 and binding to its third intracellular loop and C-terminal tail. This supports the ARRB2 partner-class refinement. The full original was not recovered; exact construct and assay details beyond the abstract remain unverified. Proposed replacements: arrestin family protein binding Supporting Evidence: PMID:10644702 beta-arrestin was able to bind |
| GO:0005515 protein binding | IPI PMID:12421915 Cutting edge: association of the motor protein nonmuscle myo... | MODIFY | Summary: CXCR4 associates with a myosin II heavy chain. Reason: The original identifies MYH9 by mass spectrometry of CXCR4-tail pull-downs and confirms endogenous association in human T cells. Refine the generic term to the measured partner class; lysate co-association does not establish isolated binary binding or receptor motor activity. Proposed replacements: myosin II heavy chain binding Supporting Evidence: PMID:12421915 the motor protein nonmuscle myosin H chain-IIA |
| GO:0005515 protein binding | IPI PMID:15660419 Constitutive association of cell surface CCR5 and CXCR4 in t... | MODIFY | Summary: CXCR4 associates with the CCR5 chemokine receptor. Reason: The original abstract explicitly reports CCR5/CXCR4 co-immunoprecipitation in CD4-expressing NIH 3T3 transfectants, absent without CD4. CCR5 identity supports a specific receptor-binding refinement. This is context-dependent co-complex evidence, not a purified binary binding or CXCR4 agonism assay. Proposed replacements: CCR5 chemokine receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17077324 Endolyn (CD164) modulates the CXCL12-mediated migration of u... | MODIFY | Summary: CXCR4 associates with the adhesion molecule CD164. Reason: The original abstract identifies CD164 association with CXCR4 during CXCL12 presentation on fibronectin. Independently inspected reciprocal co-immunoprecipitation in the later ovarian-cell study corroborates this pair. CD164 is an adhesion sialomucin; the refinement names the bound partner class without assigning adhesion catalysis or nuclear CD164 activities to CXCR4. Proposed replacements: cell adhesion molecule binding |
| GO:0005515 protein binding | IPI PMID:18632580 CXCR4-CCR5: a couple modulating T cell functions. | MODIFY | Summary: CCR5/CXCR4 association has a chemokine-receptor partner. Reason: The abstract explicitly reports physical association of CCR5 and CXCR4 in a signaling complex during human T-cell responses. The positive pair also has independent co-immunoprecipitation support. The more precise binding term does not claim purified direct contact or make CXCR4 itself a CCR5 ligand agonist. Proposed replacements: CCR5 chemokine receptor binding |
| GO:0005515 protein binding | IPI PMID:18765807 Pathogen induction of CXCR4/TLR2 cross-talk impairs host def... | MODIFY | Summary: CXCR4 associates with the signaling receptor TLR2. Reason: The original human-monocyte FRET experiments show fimbria-induced TLR2/CXCR4 proximity in lipid rafts with expression and negative-receptor controls. Receptor binding describes the partner class; it does not require CXCR4 to occupy a ligand-binding site or act as a TLR2 agonist. The assay establishes cellular association rather than purified contact. Proposed replacements: signaling receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19106094 Deubiquitination of CXCR4 by USP14 is critical for both CXCL... | MODIFY | Summary: CXCR4 binds the ubiquitin-specific protease USP14. Reason: Co-immunoprecipitation and CXCR4-tail pull-downs support selective USP14 association in the inspected original. The pull-down uses USP14-containing cell lysate rather than two purified proteins. The replacement describes the partner class, not deubiquitinase activity by the receptor. Proposed replacements: ubiquitin-specific protease binding Supporting Evidence: PMID:19106094 association of USP14 with CXCR4, or its C terminus |
| GO:0005515 protein binding | IPI PMID:19380869 CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediat... | MODIFY | Summary: The CXCR4 partner is the atypical chemokine receptor ACKR3. Reason: The original abstract describes receptor heteromer formation and altered Gi signaling, and later independently inspected human-cell proximity/co-immunoprecipitation assays corroborate the same pair. Chemokine receptor binding is more informative than generic protein binding. ACKR3-dependent signaling and fixed native stoichiometry are not transferred to CXCR4. Proposed replacements: chemokine receptor binding |
| GO:0005515 protein binding | IPI PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | MODIFY | Summary: CXCR4 associates with the MIF receptor CD74. Reason: The original co-immunoprecipitation and antibody/inhibitor experiments support a functional CXCR4βCD74 receptor complex in MIF signaling. CD74 includes an engineered retention-motif deletion construct in the assay, and the study does not resolve purified binary contact or universal stoichiometry. The receptor-binding refinement preserves these limits. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:19665027 endogenous CD74/CXCR4 complexes were isolated by co-immunoprecipitation from monocytes |
| GO:0005515 protein binding | IPI PMID:20215400 F-actin-binding protein drebrin regulates CXCR4 recruitment ... | MODIFY | Summary: The recorded rat drebrin-A interaction supports cytoskeletal regulatory protein binding. Reason: Preserve the literal Q07266-1 rat partner. The original tests drebrin constructs and separately demonstrates endogenous human drebrinβCXCR4 association. Drebrin regulates actin organization and receptor recruitment; its partner class supports this refinement. The sequence backbone does not establish which fragment was tested. Proposed replacements: cytoskeletal regulatory protein binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:20215400 F-actin-binding protein drebrin regulates CXCR4 recruitment ... | MODIFY | Summary: Human drebrin association supports cytoskeletal regulatory protein binding. Reason: The original reports CXCR4-tail pull-downs, endogenous co-immunoprecipitation and proximity measurements in human T cells. These support binding to the actin regulator drebrin. Construct-based mapping and endogenous interaction are distinct evidence; neither makes CXCR4 an actin-polymerizing enzyme. Proposed replacements: cytoskeletal regulatory protein binding Supporting Evidence: PMID:20215400 Drebrin interacts with the cytoplasmic tail of CXCR4 |
| GO:0005515 protein binding | IPI PMID:20802527 Pancreatic adenocarcinoma upregulated factor promotes metast... | MODIFY | Summary: The PAUF study supports CXCR4 association with TLR2. Reason: Reciprocal co-immunoprecipitation of the human receptors in HEK293T cells supports the positive interaction. TLR2 is a signaling receptor, so its partner class is a useful refinement. This does not make CXCR4 a TLR2 agonist; the reported cAMP-related reporter is also distinct from a direct cAMP measurement. Proposed replacements: signaling receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21730065 CXCR7/CXCR4 heterodimer constitutively recruits beta-arresti... | MODIFY | Summary: CXCR4 associates with the chemokine receptor ACKR3. Reason: The original abstract describes a CXCR4/ACKR3 complex with beta-arrestin recruitment and altered signaling; independent primary receptor-association assays corroborate this pair. Refine by the partner class without asserting all receptor assemblies share a fixed stoichiometry or identical signaling. Proposed replacements: chemokine receptor binding |
| GO:0005515 protein binding | IPI PMID:23170857 Identification and profiling of CXCR3-CXCR4 chemokine recept... | MODIFY | Summary: CXCR3 is the specific receptor partner in this heteromer study. Reason: The original abstract explicitly describes CXCR3/CXCR4 co-immunoprecipitation, time-resolved FRET, BRET and heteromer assays in HEK293T cells. CXCR3 receptor binding therefore refines the generic pair. Membrane binding cooperativity differed from intact-cell behavior, so neither a universal native assembly nor agonism by CXCR4 is inferred. Proposed replacements: CXCR3 chemokine receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:23773523 Differential G protein subunit expression by prostate cancer... | MODIFY | Summary: CXCR4 associates with CXCR5 in the prostate-cell study. Reason: The inspected Results and co-immunoprecipitation Methods identify CXCR4 in CXCR5 complexes under the tested CXCL13 conditions. CXCR5 receptor binding specifies that partner, without assigning CXCR5-driven Gq/G13 activity to CXCR4 or claiming purified direct contact. Proposed replacements: CXCR5 chemokine receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:23926103 Actin-binding protein drebrin regulates HIV-1-triggered acti... | MODIFY | Summary: CXCR4 associates with the actin regulator drebrin during HIV exposure. Reason: The original target Results and Figure 1 describe drebrin immunoprecipitates containing CXCR4 in J77 cells exposed to HIV-1, with isotype and bead controls. This supports the partner-class refinement. Drebrin-mediated inhibition of viral entry is not assigned to CXCR4. Proposed replacements: cytoskeletal regulatory protein binding Supporting Evidence: PMID:23926103 drebrin associates with CXCR4 before and during HIV infection |
| GO:0005515 protein binding | IPI PMID:24094005 CD164 regulates the tumorigenesis of ovarian surface epithel... | MODIFY | Summary: The ovarian-cell experiment supports CD164 association. Reason: Reciprocal CD164/CXCR4 co-immunoprecipitation supports a positive interaction with this adhesion sialomucin. Nuclear localization and promoter regulation in the study concern CD164, not a demonstrated nuclear activity of CXCR4. The binding refinement names the partner class, not those downstream activities. Proposed replacements: cell adhesion molecule binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25775528 Heteromerization of chemokine (C-X-C motif) receptor 4 with ... | MODIFY | Summary: ACKR3 is an explicitly tested positive CXCR4 partner. Reason: Despite the adrenergic-receptor title, the original Results test ACKR3 as a positive control: human vascular smooth-muscle proximity assays and tagged HeLa co-immunoprecipitation support CXCR4/ACKR3 association. Refine to chemokine receptor binding, with no purified-contact or universal stoichiometry claim. Proposed replacements: chemokine receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:27331810 New Insights into Mechanisms and Functions of Chemokine (C-X... | MODIFY | Summary: The human vascular-cell experiments support CXCR4/ACKR3 association. Reason: The selected Results and Methods measure endogenous receptor proximity and selective peptide effects, with surface-expression controls. This supports chemokine receptor binding. The proposed higher-order assembly is modeled, and mouse knockdown results are a separate condition. Proposed replacements: chemokine receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28862946 Ξ±(1)-Adrenergic Receptors Function Within Hetero-Oligomeric ... | MODIFY | Summary: ACKR3/CXCR4 proximity is positive in the tested vascular cells. Reason: The human-cell proximity assays, recombinant controls and ACKR3 knockdown support this receptor pair. Refine by the chemokine-receptor partner class without converting the cellular association into purified binary binding or assigning every adrenergic-response effect to CXCR4. Proposed replacements: chemokine receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28978524 RING finger protein 113A regulates C-X-C chemokine receptor ... | MODIFY | Summary: RNF113A is an E3 ubiquitin ligase that binds CXCR4. Reason: The original binding Methods and Figure 3 use immunoprecipitated HeLa protein with in-vitro translated deletion/mutation constructs to map the association. This supports ubiquitin-ligase binding, not ligase activity by the receptor. The later corrigendum replaces a duplicated Figure 4 loading control and states that conclusions are unchanged; it does not withdraw the Figure 3 interaction. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:29386406 Identification and functional characterization of arginine v... | MODIFY | Summary: The seeded partner is ACKR3, a chemokine receptor. Reason: The inspected original includes positive endogenous ACKR3/CXCR4 proximity in human vascular smooth-muscle cells. Its additional AVPR1A experiments concern another pair and do not replace the literal P25106 source partner. Refine to chemokine receptor binding with the cellular-association scope retained. Proposed replacements: chemokine receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:34927784 ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activato... | MODIFY | Summary: The tested ITCH product retains its E3-ligase partner class. Reason: The actual experiment associates a CXCR4 tail phosphomimetic with catalytically inactive ITCH and maps WW-domain requirements. Official Q96J02-2 lacks residues 159β200 of the displayed product but retains the WW and HECT regions; its literal sequence backbone is verified. Refine to E3-ligase binding without claiming receptor ubiquitination catalysis, intact wild-type binary binding or equal activity of all products. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:34927784 CXCR4 with ITCH and enhances ITCH-mediated ubiquitination of CXCR4 |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | KEEP AS NON CORE | Summary: The RAMP screen contains a positive CXCR4βRAMP3 result. Reason: Original Tables S6/S7 contain positive CXCR4-RAMP3 membrane-complex capture, including two passing CXCR4 antibodies and two epitope schemes. This supports the existing interaction. No narrower partner-specific molecular function or RAMP-dependent CXCR4 transport/signaling activity is established by those measurements, so the positive generic association is retained as non-core under the standing project policy. Supporting Evidence: |
| GO:0005737 cytoplasm | TAS PMID:10415069 Chemokine receptor expression and signaling in macaque and h... | KEEP AS NON CORE | Summary: Intracellular CXCR4 pools are compatible with broad cytoplasmic localization. Reason: The cited neural-cell abstract does not independently resolve the precise cytoplasmic staining pattern. Retain the curator assertion with corroboration from directly inspected endosomal/lysosomal trafficking experiments. Cytoplasm here does not mean soluble cytosol or establish a separate cytoplasmic receptor activity. |
| GO:0005764 lysosome | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | KEEP AS NON CORE | Summary: Internalized CXCR4 reaches LAMP-1-positive lysosomes. Reason: The original HA-CXCR4 control experiments in HEK293 cells explicitly report lysosomal localization after receptor trafficking. This is a valid contextual compartment even without a demonstrated receptor signaling function inside lysosomes. Tagged expression and the unassigned construct accession limit product specificity. Supporting Evidence: |
| GO:0005764 lysosome | IDA PMID:24790097 The ubiquitin ligase deltex-3l regulates endosomal sorting o... | KEEP AS NON CORE | Summary: Endogenous CXCR4 is detected in the lysosomal trafficking route. Reason: The inspected HeLa experiments measure CXCR4 relative to LAMP2 after CXCL12 stimulation. This is the receptor itself, not merely localization of the DTX3L regulator. Retain the observed degradation-associated location outside the principal surface-receptor core. Supporting Evidence: |
| GO:0005764 lysosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The UniProt lysosome mapping agrees with direct trafficking observations. Reason: The literal SL-0158 mapping is supported by the inspected HA-CXCR4 lysosomal experiments. Preserve it as a contextual location, without assuming signaling in the degradative compartment. |
| GO:0005769 early endosome | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | KEEP AS NON CORE | Summary: HA-CXCR4 enters EEA-1-positive early endosomes. Reason: The original comparator experiments explicitly describe CXCR4 in early endosomes. GPER subsequently follows a different route; that does not invalidate the CXCR4 control. Retain the compartment as trafficking context, not evidence of a distinct endosomal molecular function. Supporting Evidence: |
| GO:0005769 early endosome | IDA PMID:24790097 The ubiquitin ligase deltex-3l regulates endosomal sorting o... | KEEP AS NON CORE | Summary: CXCR4 endosomal distribution responds to sorting-regulator perturbation. Reason: The inspected HeLa target experiments assess CXCR4 relative to EEA1 and LAMP2, including DTX3L knockdown. The positive early-endosomal pool is retained as a contextual localization without assigning DTX3L activity to CXCR4. Supporting Evidence: |
| GO:0005769 early endosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The early-endosome location mapping has direct target corroboration. Reason: SL-0094 maps to the compartment directly observed for CXCR4 in the trafficking study. Keep the mapping and its original source, while treating this as receptor trafficking rather than an additional core activity. |
| GO:0005770 late endosome | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | KEEP AS NON CORE | Summary: CXCR4 reaches Rab7-positive late endosomes. Reason: The original Results explicitly distinguish CXCR4-positive Rab7 late endosomes and LAMP-1 lysosomes from the GPER recycling/TGN route. Retain the actual late-endosome assertion; it is not a recycling-endosome annotation. Supporting Evidence: |
| GO:0005770 late endosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The late-endosome mapping is consistent with the target experiment. Reason: The literal SL-0152 mapping agrees with the inspected Rab7-positive CXCR4 trafficking observation. The compartment is retained without an inference about local receptor signaling. |
| GO:0005886 plasma membrane | EXP PMID:10452968 Cutting edge: CXCR4-Lo: molecular cloning and functional exp... | ACCEPT | Summary: CXCR4 is an experimentally established plasma-membrane receptor. Reason: The historical human CXCR4-LO abstract reports functional expression, and independent directly inspected surface-labeling assays establish receptor localization. The original full assay was not recovered; acceptance defers to its curator for that experiment. Historical construct/start-site nomenclature is not silently equated with every modern splice product. |
| GO:0005886 plasma membrane | EXP PMID:14602072 The E3 ubiquitin ligase AIP4 mediates ubiquitination and sor... | ACCEPT | Summary: CXCR4 acts at the plasma membrane before endosomal sorting. Reason: The cited abstract places AIP4-mediated ubiquitination of CXCR4 at the plasma membrane. Retain this established receptor location, independently supported by the trafficking studies; the original detailed panels for this citation were not recovered. CXCR4 is the ubiquitination substrate, not its catalyst. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | ACCEPT | Summary: The MIF/CD74 experiments identify surface CXCR4. Reason: The inspected human-cell receptor localization and functional inhibition experiments support the plasma-membrane receptor pool in the MIF/CD74 setting. Engineered constructs and cellular association do not establish equal abundance or function of the two official products. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | ACCEPT | Summary: Surface labeling directly establishes plasma-membrane CXCR4. Reason: The original study follows anti-HA-labeled surface CXCR4 in stable HEK293 transfectants before and after SDF-1 stimulation. The surface pool is direct evidence for the principal receptor location, independent of the GPER-centered title. Supporting Evidence: |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The cell-membrane mapping identifies the principal receptor location. Reason: The official SL-0039 entry and direct surface-labeling experiments agree on plasma-membrane CXCR4. Preserve the source mapping without confusing cell membrane with soluble cytoplasm. |
| GO:0005886 plasma membrane | TAS PMID:10393923 Five-transmembrane domains appear sufficient for a G protein... | ACCEPT | Summary: The historical transmembrane-deletion study includes surface CXCR4. Reason: Its abstract explicitly reports surface expression and functional trafficking of engineered five-transmembrane CXCR4 constructs in HEK293 cells. The normal plasma-membrane location is independently established, so retain the gene-level location while distinguishing those mutants from official splice products. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164500 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-164500 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164507 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-164507 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164508 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-164508 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164515 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-164515 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164521 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-164521 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-164524 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-164524 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-374214 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-374214 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-380073 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-749454 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-749456 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8986258 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual Reactome path links the event through its receptor-containing entities to human CXCR4, physical entity 2980772, reference P61073, explicitly in plasma membrane. Set membership does not mean CXCR4 performs every other component activity. Supporting Evidence: Reactome:R-HSA-8986258 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9823950 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual expression event produces CXCR4 physical entity 2980772, whose reference is human P61073 and compartment is plasma membrane. This supports the location annotation. CXCR4 is the expression output, not the transcriptional performer; no transcription or germ-cell/endoderm process is inferred from that role. Supporting Evidence: Reactome:R-HSA-9823950 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9828028 | ACCEPT | Summary: The Reactome source explicitly places CXCR4 at the plasma membrane. Reason: The actual expression event produces CXCR4 physical entity 2980772, whose reference is human P61073 and compartment is plasma membrane. This supports the location annotation. CXCR4 is the expression output, not the transcriptional performer; no transcription or germ-cell/endoderm process is inferred from that role. Supporting Evidence: Reactome:R-HSA-9828028 |
| GO:0006915 apoptotic process | TAS PMID:10942389 HIV-1 gp120- and gp160-induced apoptosis in cultured endothe... | KEEP AS NON CORE | Summary: CXCR4 contributes to envelope-induced endothelial apoptosis. Reason: The inspected publisher Methods and Results test recombinant HIV-1 IIIB gp120/gp160 in serum-starved human endothelial cells. CXCR4-neutralizing 12G5 reduces nucleosome-ELISA apoptosis relative to class-matched IgG, with TUNEL and downstream caspase evidence. Retain this context-dependent receptor contribution without making apoptosis a universal physiological output or assigning caspase catalysis to CXCR4. Supporting Evidence: |
| GO:0006935 chemotaxis | IEA GO_REF:0000002 | ACCEPT | Summary: Chemotaxis is a performed output of the CXCL12 receptor. Reason: The chemokine-receptor family mapping is consistent with direct CXCR4-dependent chemotactic signaling. The receptor transduces the external cue rather than acting merely as a transported substrate, so the broad existing chemotaxis assertion is retained. |
| GO:0006954 inflammatory response | TAS PMID:8276799 Cloning of a human seven-transmembrane domain receptor, LEST... | KEEP AS NON CORE | Summary: CXCR4 participates in inflammatory signaling in defined contexts. Reason: The old cloning source alone does not resolve the inflammatory mechanism, but the inspected MIF/CD74 and microbial TLR2 cross-talk experiments establish receptor-mediated modulation of inflammatory responses. Retain this broad contextual process without treating inflammatory activity as exclusive to CXCR4 or assuming a single direction of effect. |
| GO:0006955 immune response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited immune-response role is compatible with CXCR4 biology. Reason: The actual PTHR10489 tree places CXCR4 below the asserted PTN001628461 node, with a literal on-path IBD and experimental descendant evidence. Direct human receptor studies support immune-cell signaling; broad immune response is retained as contextual rather than a separate molecular core. Short donor lists or target self-evidence are not defects. |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:10644702 beta-arrestin differentially regulates the chemokine recepto... | ACCEPT | Summary: CXCR4 transduces chemokine signals through heterotrimeric G proteins. Reason: The cited abstract reports chemokine-stimulated G-protein activation and inhibition of cAMP production in CXCR4-expressing HEK293 cells, modulated by beta-arrestin. This is a performed receptor signaling function. Original experiments beyond the abstract were not independently inspected. Supporting Evidence: |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: The GPCR pathway mapping agrees with receptor-mediated signaling. Reason: Both literal InterPro domains support the receptor class, and CXCL12-triggered signaling is directly established. Retain the pathway rather than adding a redundant signaling assertion. |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IDA PMID:39093700 Cryo-EM structure of monomeric CXCL12-bound CXCR4 in the act... | ACCEPT | Summary: CXCR4 couples CXCL12 recognition to inhibitory G-protein signaling. Reason: The source abstract and structural report identify an active CXCL12βCXCR4βGi complex; the current GO-CAM also models CXCR4 activation of GNAI1 and downstream adenylate cyclase inhibition. The detailed original cyclase assay was not inspected, so its specific IDA is retained with curator deference and independent pathway support. |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IBA GO_REF:0000033 | ACCEPT | Summary: Calcium mobilization is an established CXCR4 signaling output. Reason: The literal on-path IBD and complete donor joins support the inherited assertion. Human CXCL12 agonism and inspected cellular signaling assays corroborate cytosolic calcium responses. This does not assign calcium-channel activity or universal Gq coupling to the receptor. |
| GO:0007420 brain development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CXCR4 has a conserved developmental role in the nervous system. Reason: The actual target path includes PTN002573776; mouse Cxcr4 has an experimental brain-development annotation and rat/zebrafish sources are traced separately. Retain the broad developmental inference as contextual. This is not an assertion that every human product has been tested in brain-development experiments. |
| GO:0009615 response to virus | TAS PMID:10583963 Use of chemokine receptors by poxviruses. | KEEP AS NON CORE | Summary: Human CXCR4 expression can alter viral permissiveness. Reason: The cited abstract explicitly reports that expression of human CXCR4 permits myxoma infection in otherwise resistant rodent fibroblasts. Retain the contextual response-to-virus assertion without importing the CCR5-specific antagonist results as CXCR4 measurements or claiming a universal poxvirus entry mechanism. Supporting Evidence: |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The ligand-accessible CXCR4 pool is at the external cell surface. Reason: The actual broad-node IBD is on the target lineage, and receptor topology plus direct surface antibody/ligand experiments support extracellular exposure. This does not mean that the entire multipass protein is soluble on the extracellular side. |
| GO:0009986 cell surface | IDA PMID:10521508 Trafficking of the HIV coreceptor CXCR4. Role of arrestins a... | ACCEPT | Summary: The original trafficking study directly identifies surface CXCR4. Reason: Its complete abstract describes surface-receptor assays and agonist-induced internalization in COS-1 and HEK293 cells. Surface localization is independently corroborated by the inspected later trafficking source; the detailed original mutant panels remain uninspected. |
| GO:0009986 cell surface | IDA PMID:10644702 beta-arrestin differentially regulates the chemokine recepto... | ACCEPT | Summary: CXCR4 is present at the cell surface and undergoes regulated internalization. Reason: The cited abstract describes agonist-dependent receptor internalization and its regulation by beta-arrestin. Retain the established cell-surface location with curator deference for the uninspected original surface measurements; independent surface and trafficking experiments corroborate the location. Supporting Evidence: |
| GO:0009986 cell surface | IDA PMID:18308860 CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhe... | ACCEPT | Summary: Cell-surface CXCR4 is biologically well established. Reason: The source abstract studies human lymphocyte adhesion and CXCL12-dependent motility but does not display the exact CXCR4 localization panel. Retain this established gene-level location with explicit curator deference, supported independently by receptor surface-labeling assays. |
| GO:0009986 cell surface | IDA PMID:19106094 Deubiquitination of CXCR4 by USP14 is critical for both CXCL... | ACCEPT | Summary: The USP14 study directly monitors cell-surface CXCR4. Reason: The inspected original uses tagged CXCR4 and confocal imaging to follow receptor localization in HEK293 cells. EGFP-CXCR4 and immunostained HA-USP14 colocalize at the cell surface and in internal membrane compartments after CXCL12 stimulation. Retain the surface localization without treating the tagged constructs as evidence that both official splice products behave identically. Supporting Evidence: |
| GO:0009986 cell surface | IDA PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | ACCEPT | Summary: Surface CXCR4 participates in the MIF receptor complex. Reason: The inspected original assays establish surface receptor detection and CXCR4-dependent MIF signaling in the CD74 context. Neither CD74 retention-motif constructs nor co-immunoprecipitation imply equal behavior of every CXCR4 isoform. Supporting Evidence: |
| GO:0009986 cell surface | IDA PMID:23620790 CBAP functions as a novel component in chemokine-induced ZAP... | ACCEPT | Summary: Endogenous human T-cell CXCR4 is measured at the surface. Reason: The original Jurkat control experiment measures surface CXCR4 by flow cytometry in control and CBAP-knockdown cells. This target-specific localization observation is distinct from the separate mouse T-cell experiments and does not establish CBAP binding. Supporting Evidence: |
| GO:0015026 coreceptor activity | TAS PMID:10754293 Engagement of CD28 modulates CXC chemokine receptor 4 surfac... | KEEP AS NON CORE | Summary: CXCR4 has an established viral coreceptor role. Reason: Retain the HIV-context coreceptor activity supported by the cited abstract and independent receptor-complex evidence. This term is contextual to viral entry, rather than evidence that CXCR4 serves as a generic TCR/CD28 or herpesvirus coreceptor. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The membrane-domain mapping can be refined to plasma membrane. Reason: The literal InterPro membrane/GPCR signatures are correct but broader than the experimentally established principal location. Refine to plasma membrane without denying internal endosomal receptor pools. This overlaps independent plasma-membrane annotations rather than adding new localization biology. Proposed replacements: plasma membrane |
| GO:0016477 cell migration | IEA GO_REF:0000117 | ACCEPT | Summary: CXCR4 signaling participates in cell migration. Reason: The current ARBA00028795 branch 4 genuinely matches the target FunFam/taxon predicates. Direct receptor signaling and migration experiments support the broad existing process; the rule match alone is not used as experimental evidence. |
| GO:0016493 C-C chemokine receptor activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: The CC-agonist receptor assertion extends beyond the demonstrated target ligand class. Reason: The actual PTN001628461 IBD is a broad Euteleostomi duplication-node assertion and is genuinely ancestral to CXCR4. Its CC-receptor descendants do not resolve the target-specific ligand distinction: GO:0016493 requires CC-chemokine-triggered transmembrane signaling, whereas the directly tested viral CC ligand vMIP-II is an antagonist. The CXCL12 receptor activity and positive CC binding remain intact. This is a ligand-class overextension, not a false-ancestry, donor-count, or universal inability to bind CC chemokines argument. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001628461 Β· PTN001628461 SUPPORTS SOURCE BUT NOT TARGET The literal GO:0016493 IBD lies on the real target ancestry at the broad Euteleostomi duplication node. CC-receptor descendant evidence supports the ancestral assertion, but does not establish CC-agonist signaling by CXCR4; the directly tested vMIP-II interaction is antagonistic. Positive CC binding and CXCL12 receptor signaling remain supported. Supporting Evidence: GO_REF:0000033 PMID:25612609 vMIP-II functions as a broad-spectrum antagonist of many human CKRs |
| GO:0016494 C-X-C chemokine receptor activity | IDA PMID:8752281 The CXC chemokine SDF-1 is the ligand for LESTR/fusin and pr... | MODIFY | Summary: The directly identified CXC ligand is CXCL12. Reason: The original human agonism result identifies CXCL12/SDF-1 and supports the existing specific receptor activity. Refine this broader CXC-receptor label to that established molecular function; the limited inactive human CC chemokines tested in the paper do not establish universal CC nonbinding. Proposed replacements: C-X-C motif chemokine 12 receptor activity Supporting Evidence: |
| GO:0016494 C-X-C chemokine receptor activity | NAS PMID:9468539 Genomic organization and functional characterization of the ... | MODIFY | Summary: CXCL12 receptor activity gives the informative ligand-specific assignment. Reason: The historical nomenclature source supports CXCR4 identity, while direct CXCL12 agonism establishes the refined activity. Preserve its NAS provenance and do not imply that the nomenclature paper independently performed the ligand assay. Proposed replacements: C-X-C motif chemokine 12 receptor activity |
| GO:0019722 calcium-mediated signaling | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited calcium-signaling role has target experimental grounding. Reason: The on-path IBD includes human CXCR4 experimental evidence alongside other descendants; that self-evidence is legitimate, not circular. Retain calcium-mediated signaling, distinguishing the receptor from the channels or second-messenger enzymes that execute downstream steps. |
| GO:0019722 calcium-mediated signaling | IMP PMID:19064997 Secreted trefoil factor 2 activates the CXCR4 receptor in ep... | ACCEPT | Summary: CXCR4-dependent calcium signaling is well established. Reason: The cited source is available only at abstract level after bounded recovery, so the exact mutant assay is not independently verified. The gene-level assertion is nevertheless directly corroborated by independent CXCR4 ligand-response studies and is retained with curator deference, without assigning all mutant or splice products equal activity. |
| GO:0019955 cytokine binding | IEA GO_REF:0000002 | MODIFY | Summary: C-X-C chemokine binding captures the directly established CXCL12 ligand class. Reason: CXCL12 recognition directly supports C-X-C chemokine binding, which is more informative than the InterPro-derived cytokine-binding term. The inspected PMID:19665027 experiments establish CXCR4/CD74 association and MIF-dependent signaling; they do not independently measure MIF-CXCR4 ligand contact. This refinement preserves that positive MIF receptor-complex biology and does not classify MIF as a CXC chemokine or deny its signaling role. Proposed replacements: C-X-C chemokine binding |
| GO:0019957 C-C chemokine binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CXCR4 has direct positive CC-chemokine binding evidence. Reason: The actual IBD is on the target path and includes legitimate human target evidence. The structural source directly binds viral vMIP-II, a CC chemokine antagonist. Retain contextual binding separately from the overextended CC-agonist receptor assertion; no universal physiological CC agonism is inferred. |
| GO:0019957 C-C chemokine binding | IPI PMID:25612609 Structural biology. Crystal structure of the chemokine recep... | KEEP AS NON CORE | Summary: The viral CC chemokine vMIP-II binds CXCR4. Reason: The original structure uses an engineered D187C/W5C disulfide-trapped receptorβligand complex and characterizes vMIP-II as an antagonist. The positive CC binding assertion is sound within that scope, but does not demonstrate CC-induced receptor signaling or native fixed stoichiometry. Supporting Evidence: PMID:25612609 viral chemokine antagonist vMIP-II |
| GO:0022008 neurogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The lineage-supported neurogenesis role is contextual. Reason: The actual PTN002573776 placement includes CXCR4 and the literal experimental rat donor has the same neurogenesis term. Retain the conserved developmental assertion without inferring a new molecular function, every-human-isoform equivalence, or absence of evidence from a short donor list. |
| GO:0030155 regulation of cell adhesion | IDA PMID:19703720 Adhesion of human haematopoietic (CD34+) stem cells to human... | UNDECIDED | Summary: The accessible evidence does not resolve the CXCR4-specific adhesion experiment. Reason: The abstract describes human CD34-positive populations and KG1a adhesion to liver cells: pertussis toxin reduces adhesion, while CXCR3/CXCR4 ligands induce migration. It does not isolate a CXCR4-directed intervention in the adhesion assay, and the full original was not recovered. Preserve uncertainty without inferring that the curator used the wrong gene or that CXCR4 cannot affect adhesion. Supporting Evidence: PMID:19703720 Pertussis toxin was shown to decrease binding |
| GO:0030334 regulation of cell migration | IEA GO_REF:0000117 | ACCEPT | Summary: CXCR4 signaling regulates cell migration. Reason: The current ARBA00028900 branch 12 matches the actual FunFam and Eutheria predicates. Receptor-mediated migration evidence supports the broad process; context can determine direction and magnitude, so no universal pro-migratory response is inferred. |
| GO:0030335 positive regulation of cell migration | IMP PMID:20023705 Ubc9 promotes breast cell invasion and metastasis in a sumoy... | KEEP AS NON CORE | Summary: CXCR4 promotes migration in the tested breast-cancer context. Reason: The inspected experiments use human breast-cancer cells and CXCR4 shRNAs with migration/invasion endpoints. The CDC42 and CXCR4 expression interplay limits an isolated mechanistic interpretation, but supports a positive contextual contribution rather than a universal outcome across cell types. Supporting Evidence: |
| GO:0031252 cell leading edge | IDA PMID:12421915 Cutting edge: association of the motor protein nonmuscle myo... | KEEP AS NON CORE | Summary: CXCR4 concentrates at the leading edge of migrating T lymphocytes. Reason: The original confocal experiments show CXCR4 and myosin IIA at the leading edge, with actin and myosin light chain in the polarized actomyosin organization. Retain this cell-state-specific localization. Supporting Evidence: |
| GO:0031410 cytoplasmic vesicle | IDA PMID:10521508 Trafficking of the HIV coreceptor CXCR4. Role of arrestins a... | KEEP AS NON CORE | Summary: CXCR4 undergoes vesicular internalization. Reason: The original abstract explicitly reports internalization of surface CXCR4 in COS-1 and HEK293 cells and distinguishes ligand- and phorbol-ester responses. Retain the broad vesicular location as contextual trafficking, independently supported by the inspected later study. |
| GO:0031410 cytoplasmic vesicle | IDA PMID:19106094 Deubiquitination of CXCR4 by USP14 is critical for both CXCL... | KEEP AS NON CORE | Summary: Internalized CXCR4 occupies intracellular vesicular compartments. Reason: The inspected USP14 study follows internalized CXCR4 in membrane-bound intracellular compartments. Retain this trafficking location. The paper mentions additional Rab7/Rab11 observations as data not shown, so those statements are not used to assign a more specific compartment here. Supporting Evidence: |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19116316 The E3 ubiquitin ligase atrophin interacting protein 4 binds... | KEEP AS NON CORE | Summary: CXCR4 binds the E3 ubiquitin ligase AIP4/ITCH during receptor sorting. Reason: The original abstract and Figure 1 caption report direct binding of purified His-tagged AIP4 to the GST-fused CXCR4 tail, alongside cell-lysate assays. This is a regulatory substrateβligase interaction. Retain it as contextual binding, without assigning ubiquitin-ligase activity to CXCR4; the complete original main text was not recovered. Supporting Evidence: PMID:19116316 interact directly with CXCR4 via a novel noncanonical WW domain-mediated interaction |
| GO:0032027 myosin light chain binding | IDA PMID:12421915 Cutting edge: association of the motor protein nonmuscle myo... | KEEP AS NON CORE | Summary: Myosin light chain occurs in the CXCR4-associated actomyosin complex. Reason: Figure 2 reports myosin-light-chain co-immunoprecipitation with endogenous CXCR4 in human T cells, with receptor and control-antibody conditions. Retain this positive contextual association. The assay does not resolve whether the contact is mediated by other components of the actomyosin complex. Supporting Evidence: PMID:12421915 myosin L chain was also associated with CXCR4 |
| GO:0032991 protein-containing complex | IDA PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | MODIFY | Summary: The MIF-responsive CXCR4βCD74 assembly is a signaling receptor complex. Reason: The original association and functional blocking experiments support a receptor complex acting in MIF signaling. The current specific complex term is more informative than generic protein-containing complex. Co-immunoprecipitation and engineered CD74 do not establish a universal stoichiometry. Proposed replacements: signaling receptor complex Supporting Evidence: |
| GO:0032991 protein-containing complex | IMP PMID:25612609 Structural biology. Crystal structure of the chemokine recep... | TOO GENERAL | Summary: The broad complex term adds no specificity beyond established receptor-complex membership. Reason: The engineered D187C-CXCR4/W5C-vMIP-II structure is positive complex evidence. Protein-containing complex is nevertheless uninformative at gene level because the signaling-receptor-complex refinement supported independently by PMID:19665027 already entails it. This does not recast the antagonist-trapped structure as an agonist assembly or reject its measured association; its construct and stoichiometry limits remain explicit. Supporting Evidence: PMID:25612609 a 1:1 stoichiometry |
| GO:0038147 C-X-C motif chemokine 12 receptor activity | IDA PMID:28978524 RING finger protein 113A regulates C-X-C chemokine receptor ... | ACCEPT | Summary: The RNF113A study includes CXCL12-dependent CXCR4 signaling. Reason: The inspected original shows ligand-dependent receptor turnover and altered downstream Akt/ERK responses when the E3 ligase is manipulated. Independent human agonism establishes the performed receptor activity. The corrected Figure 4 loading control is disclosed without claiming that the conclusions or receptor-binding data were withdrawn. |
| GO:0038147 C-X-C motif chemokine 12 receptor activity | IDA PMID:39093700 Cryo-EM structure of monomeric CXCL12-bound CXCR4 in the act... | ACCEPT | Summary: CXCL12 recognition is the principal demonstrated CXCR4 activity. Reason: The source abstract and active receptorβGi structural report support CXCL12 receptor function, with independent earlier human agonism. The detailed modern construct and assay were not recovered in full, so their precision is not invented or generalized to both official products. |
| GO:0038160 CXCL12-activated CXCR4 signaling pathway | IDA PMID:28978524 RING finger protein 113A regulates C-X-C chemokine receptor ... | ACCEPT | Summary: CXCR4 performs the receptor step in CXCL12 signaling. Reason: The actual original Results assess CXCL12-dependent receptor stability and downstream signaling under RNF113A perturbation. CXCR4 is the receptor, whereas RNF113A performs ubiquitination; the pathway assertion does not assign ubiquitin-ligase catalysis to CXCR4. Supporting Evidence: |
| GO:0038160 CXCL12-activated CXCR4 signaling pathway | IDA PMID:39093700 Cryo-EM structure of monomeric CXCL12-bound CXCR4 in the act... | ACCEPT | Summary: CXCL12-activated CXCR4 signaling is directly supported. Reason: The cited active receptorβGi report and independent human ligand-response evidence establish this pathway. Preserve the IDA assertion while acknowledging that the complete modern experimental Methods were not inspected. |
| GO:0038160 CXCL12-activated CXCR4 signaling pathway | IGI PMID:27693460 Vascular mimicry formation is promoted by paracrine TGF-Ξ² an... | ACCEPT | Summary: The CXCL12/CXCR4 pathway is established independently of the tumor endpoint. Reason: The source abstract describes the chemokineβreceptor axis in hepatocellular carcinoma, but its exact IGI assay was not recovered. Retain the established receptor pathway with curator deference and independent direct ligand evidence; this does not automatically establish normal endothelial vasculature development. |
| GO:0038160 CXCL12-activated CXCR4 signaling pathway | IMP PMID:24912431 The WHIM-like CXCR4(S338X) somatic mutation activates AKT an... | ACCEPT | Summary: The WHIM-like truncation experiments retain CXCL12 receptor signaling. Reason: The original abstract explicitly compares CXCR4 S338X with wild type under SDF-1 stimulation and reports prolonged signaling with reduced internalization. Preserve the pathway assertion without treating enhanced mutant responses as the normal behavior of either official splice product. Supporting Evidence: |
| GO:0043130 ubiquitin binding | IDA PMID:20228059 CXC chemokine receptor 4 is a cell surface receptor for extr... | KEEP AS NON CORE | Summary: CXCR4 recognizes extracellular ubiquitin in the tested systems. Reason: The inspected study combines ligand binding, human receptor overexpression/knockdown and antagonist/Gi-sensitive signaling in THP1 and transfected cells. This supports contextual ubiquitin binding. It is distinct from covalent ubiquitination of CXCR4 and does not make the receptor an intracellular ubiquitin enzyme. Supporting Evidence: |
| GO:0043217 myelin maintenance | ISS GO_REF:0000024 | UNDECIDED | Summary: Remyelination evidence does not settle mature-myelin maintenance. Reason: The exact mouse donor assertion cites CXCR4 inhibition/silencing during repair after cuprizone injury. The independently read source supports OPC differentiation and remyelination, whereas GO:0043217 specifically preserves mature myelin. Whether that distinct maintenance role is established remains uncertain; this is a term-to-assay boundary, not inaccessible evidence or a claim that the donor gene is wrong. Supporting Evidence: GO_REF:0000024 PMID:20534485 critical for remyelination of the injured adult CNS |
| GO:0046718 symbiont entry into host cell | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Viral entry follows from the established receptor role. Reason: The literal logical inference from virus receptor activity is compatible with CXCR4-mediated HIV entry. Retain the contextual host role without inferring entry by every symbiont or transferring envelope fusion catalysis to CXCR4. |
| GO:0048714 positive regulation of oligodendrocyte differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse CXCR4 supports oligodendrocyte differentiation during repair. Reason: The actual mouse donor study measures OPC differentiation and remyelination after CXCR4 inhibition or local silencing. Preserve the human ISS inference as a contextual developmental/repair role, with no claim that a human isoform was experimentally tested. |
| GO:0060326 cell chemotaxis | IBA GO_REF:0000033 | ACCEPT | Summary: Inherited cell chemotaxis is directly relevant to CXCR4 function. Reason: The actual target lineage and literal IBD support the assertion, including human experimental grounding that is not circular. CXCR4 transduces chemotactic signals; neither donor count nor a need for downstream motility machinery invalidates its performed signaling contribution. |
| GO:0060326 cell chemotaxis | IMP PMID:19106094 Deubiquitination of CXCR4 by USP14 is critical for both CXCL... | ACCEPT | Summary: CXCR4 performs the receptor step in CXCL12-directed chemotaxis. Reason: The inspected original measures CXCL12-directed migration of CXCR4-expressing HEK293 cells and tests receptor ubiquitination-site mutants and USP14 perturbations. These experiments support receptor-mediated chemotaxis while separating chemotactic output from ERK signaling. Supporting Evidence: |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | UNDECIDED | Summary: The original exosome target assignment remains unverified. Reason: The cited B-cell study reports mass-spectrometric exosome proteomics, and secondary curated records list CXCR4. The original target-level supplemental table could not be inspected after bounded publisher attempts. Preserve the positive HDA assertion without claiming absence or demanding receptor activity inside exosomes; the exact source detection remains uncertain. Supporting Evidence: |
| GO:0070161 anchoring junction | EXP PMID:20215400 F-actin-binding protein drebrin regulates CXCR4 recruitment ... | MODIFY | Summary: The measured junctional site is the immunological synapse. Reason: The original follows CXCR4 recruitment to contacts between human T cells and superantigen-loaded antigen-presenting cells, including confocal and live-cell measurements. The specific immunological-synapse term describes this observed location more accurately than generic anchoring junction; it does not assign structural adhesion activity to the receptor. Proposed replacements: immunological synapse Supporting Evidence: PMID:20215400 both proteins redistribute to the immune synapse with similar kinetics |
| GO:0070161 anchoring junction | IEA GO_REF:0000044 | MODIFY | Summary: The UniProt junction mapping is specifically grounded in immunological-synapse localization. Reason: The literal SL-0038 mapping is supported by the UniProt location note citing PMID:20215400: antigen-dependent recruitment to the T-cell-antigen-presenting-cell contact. The same observed site is refined to immunological synapse in the experimental row. Apply that location specificity here while preserving the IEA provenance and without assigning structural anchoring activity to CXCR4. Proposed replacements: immunological synapse |
| GO:0071345 cellular response to cytokine stimulus | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | ACCEPT | Summary: CXCR4 responds to the cytokine CXCL12 in the actual control experiment. Reason: The original HA-CXCR4 experiments quantify SDF-1-dependent surface loss/internalization relative to vehicle. This supports cellular response to cytokine stimulus, the exact seeded term. It does not assert cytokine production or substitute the separate cytokine-mediated signaling term. Supporting Evidence: |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:25016030 Deficiency in adipocyte chemokine receptor CXCR4 exacerbates... | KEEP AS NON CORE | Summary: Mouse adipose CXCR4 contributes to cold-induced thermogenic responses. Reason: The original Fabp4-Cre/high-fat-diet and cold-exposure experiments support the contextual mouse donor phenotype. Preserve human ISS provenance, the normalization-dependent physiological endpoints and the authors' unresolved signaling mechanism; no direct human experiment or CXCR4βUCP1 mechanism is inferred. Supporting Evidence: |
| GO:1904018 positive regulation of vasculature development | IMP PMID:27693460 Vascular mimicry formation is promoted by paracrine TGF-Ξ² an... | UNDECIDED | Summary: The tumor vasculogenic-mimicry experiment does not yet settle this broad developmental assertion. Reason: The accessible abstract describes CXCL12/CXCR4-dependent vasculogenic mimicry in hepatocellular carcinoma. The complete target experiments and the relationship of that endpoint to normal vasculature development were not verified. Retain uncertainty without rejecting the source because its title or abstract foregrounds tumor cells. Supporting Evidence: PMID:27693460 tumor cells but not endothelial cells form vascular-like channels |
| GO:2000448 positive regulation of macrophage migration inhibitory factor signaling pathway | IMP PMID:19665027 A functional heteromeric MIF receptor formed by CD74 and CXC... | KEEP AS NON CORE | Summary: CXCR4 positively participates in MIF signaling with CD74. Reason: The inspected human-cell experiments show MIF-induced AKT responses sensitive to CXCR4 antagonism and to CD74-directed inhibition, with receptor association. This is a real contextual signaling contribution. It does not establish a universal complex stoichiometry, MIF production by CXCR4, or MIF as a CC/CXC chemokine. Supporting Evidence: |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: How do the two official N-terminal CXCR4 products differ in endogenous cell-surface abundance, ligand recognition and signaling when alternative initiation and expression level are controlled?
Q: Does CXCR4 directly maintain mature myelin independently of its established effects on oligodendrocyte differentiation and remyelination?
Q: Which molecular contacts determine the relative contributions of CD74, CXCR4 and other receptors to MIF responses in distinct human cell types?
Q: Under which cellular conditions do CXCR4 complexes with other chemokine receptors or RAMP3 alter ligand selectivity and signaling?
Experiment: Use inducible, lineage-restricted Cxcr4 perturbation after normal myelination and without a demyelinating insult. Compare myelin ultrastructure and long-term stability with matched controls and rescue, separately from OPC differentiation and remyelination readouts.
Hypothesis: CXCR4 has a maintenance role in mature myelin separable from its role in repair-associated oligodendrocyte differentiation.
Type: Post-developmental conditional perturbation and ultrastructural analysis
Experiment: Combine orthogonal vesicle purification, receptor-specific detection and protease-protection analysis with plasma-membrane contamination controls. Resolve receptor detection and membrane orientation without requiring signaling activity inside the vesicles.
Hypothesis: Endogenous CXCR4 is present in purified B-cell extracellular vesicles under the conditions of the original proteomic report.
Type: Extracellular-vesicle localization and topology assay
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Download this section (compressed HTML)Loading supporting contentβ¦
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