CXCR3 (CD183) is a class A seven-transmembrane G protein-coupled chemokine receptor of the plasma membrane. Its canonical product, isoform A, is the receptor for the interferon-inducible C-X-C chemokines CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC). Ligand binding requires sulfated tyrosines 27 and 29 in the extracellular N terminus, and receptor activation through pertussis-toxin-sensitive Gi proteins drives cytosolic calcium mobilization and directed cell migration; an arginine in the second extracellular loop is needed for signaling but not for binding. CXCR3 is induced on activated and memory T lymphocytes of the Th1 and cytotoxic types and also occurs on NK cells, some B cells, eosinophils and cytokine-stimulated haematopoietic progenitors, where it directs effector cells to sites of interferon-driven inflammation and modulates integrin-dependent adhesion. CXCL4/PF4 and CXCL13 act as additional, context-dependent agonists. Alternative splicing yields CXCR3-B, an isoform with an extended N terminus expressed on microvascular endothelium, which binds CXCL4 with high affinity, signals with raised cAMP, and mediates angiostatic, anti-proliferative and pro-apoptotic responses to CXCR3 ligands, and CXCR3-alt, a truncated exon-skipping variant. Human CXCR3 does not respond to CC chemokines; unlike the mouse receptor it is not activated by CCL21. The receptor can form heteromers with CXCR4 and with the atypical receptor ACKR4, which alter its ligand binding and chemotactic output.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001937 negative regulation of endothelial cell proliferation | IDA P49682-2 PMID:12782716 An alternatively spliced variant of CXCR3 mediates the inhib... | KEEP AS NON CORE | Summary: CXCR3-B (isoform 2) expression and ligation inhibit endothelial cell DNA synthesis and growth. Reason: Direct isoform-specific experiment in HMEC-1 transfectants and primary microvascular endothelial cells. This is a genuine isoform-dependent role of the CXCR3 gene product (CXCR3-B) as an angiostatic receptor, but it is peripheral to the principal leukocyte chemotaxis function of the canonical CXCR3-A product. Supporting Evidence: PMID:12782716 overexpression of CXCR3-B dramatically reduced DNA synthesis and up-regulated apoptotic HMEC-1 death through activation of distinct signal transduction pathways PMID:12782716 mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4 |
| GO:0002685 regulation of leukocyte migration | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping from the chemokine receptor signature to regulation of leukocyte migration. Reason: CXCR3 is not a regulator acting on a migration process carried out by others; as the chemoattractant receptor it is a direct participant in directed leukocyte chemotaxis. The more precise participation term already carried by this gene is T cell chemotaxis. Proposed replacements: T cell chemotaxis Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:9064356 the IP10/Mig receptor is involved in the selective recruitment of effector T cells |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000120 | MODIFY | Summary: G protein-coupled receptor activity, from combined automated methods. Reason: Correct but general. CXCR3 is a rhodopsin-family 7TM receptor coupling to pertussis-toxin-sensitive Gi; the specific activity supported by ligand-binding and signaling experiments is C-X-C chemokine receptor activity, a descendant term this review accepts on another row. Proposed replacements: C-X-C chemokine receptor activity Supporting Evidence: PMID:9064356 The sequence includes seven putative transmembrane segments characteristic of PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:18174362 CXCL4-induced chemotaxis of T lymphocytes was inhibited by a CXCR3 antagonist and pretreatment of cells with pertussis toxin (PTX), suggestive of CXCR3-mediated G-protein signaling via |
| GO:0004950 chemokine receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Chemokine receptor activity from the InterPro chemokine-receptor signature. Reason: Correct but general; the ligand class is established experimentally as C-X-C (CXCL9, CXCL10, CXCL11, and CXCL4 or CXCL13 in specific assays), and CC chemokines are not recognized by the human receptor. Refine to C-X-C chemokine receptor activity. Proposed replacements: C-X-C chemokine receptor activity Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:9064356 but does not recognize the CXC-chemokines IL-8, GRO alpha, NAP-2, GCP-2. ENA78, PF4, the CC-chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-1 alpha, MIP-1 beta. RANTES, 1309, eotaxin, nor lymphotactin file:human/CXCR3/CXCR3-uniprot.txt Receptor for the C-X-C chemokines CXCL9, CXCL10 |
| GO:0004950 chemokine receptor activity | TAS PMID:9064356 Chemokine receptor specific for IP10 and mig: structure, fun... | MODIFY | Summary: Traceable author statement from the original cloning paper describing the IP10/Mig receptor. Reason: The cloning paper shows Ca2+ mobilization and chemotaxis in response to IP10 (CXCL10) and Mig (CXCL9) and no response to the CC chemokines tested, so the supported activity is the more specific C-X-C chemokine receptor activity. Proposed replacements: C-X-C chemokine receptor activity Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:9064356 but does not recognize the CXC-chemokines IL-8, GRO alpha, NAP-2, GCP-2. ENA78, PF4, the CC-chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-1 alpha, MIP-1 beta. RANTES, 1309, eotaxin, nor lymphotactin |
| GO:0005515 protein binding | IPI PMID:23170857 Identification and profiling of CXCR3-CXCR4 chemokine recept... | MODIFY | Summary: IPI with CXCR4 from co-immunoprecipitation, TR-FRET and BRET showing CXCR3-CXCR4 heteromers. Reason: Bare protein binding is uninformative. The partner is another chemokine GPCR and the paper characterizes receptor heteromers with negative binding cooperativity, which is captured by G protein-coupled receptor binding. Whether heteromerization matters at endogenous expression levels is unresolved, so this is not core. Proposed replacements: G protein-coupled receptor binding Supporting Evidence: PMID:23170857 chemokine receptors CXCR3 and CXCR4 form heteromeric complexes in HEK293T cells |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary yeast two-hybrid interaction (HuRI) with C2CD2L. Reason: Generic protein binding from a proteome-scale screen carries no functional information and no follow-up work establishes a role. Removal does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary yeast two-hybrid interaction (HuRI) with a CLDN19 isoform. Reason: Generic protein binding from a proteome-scale screen carries no functional information. Removal does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary yeast two-hybrid interaction (HuRI) with TMEM14A. Reason: Generic protein binding from a proteome-scale screen carries no functional information. Removal does not assert that the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Multiplexed GPCR-RAMP interactome screen: CXCR3 co-captured with RAMP1. Reason: Bare protein binding is uninformative, and the screen does not show that RAMP1 alters CXCR3 ligand selectivity, trafficking or signaling. Removal does not assert that the complex is false. Supporting Evidence: PMID:39083597 Receptor activity-modifying proteins (RAMPs) form complexes with G protein-coupled receptors (GPCRs) and may regulate their cellular trafficking and pharmacology |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Multiplexed GPCR-RAMP interactome screen: CXCR3 co-captured with RAMP2. Reason: Bare protein binding is uninformative and the screen reports no functional consequence for CXCR3. Removal does not assert that the complex is false. Supporting Evidence: PMID:39083597 Receptor activity-modifying proteins (RAMPs) form complexes with G protein-coupled receptors (GPCRs) and may regulate their cellular trafficking and pharmacology |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Multiplexed GPCR-RAMP interactome screen: CXCR3 co-captured with RAMP3. Reason: Bare protein binding is uninformative and the screen reports no functional consequence for CXCR3. Removal does not assert that the complex is false. Supporting Evidence: PMID:39083597 Receptor activity-modifying proteins (RAMPs) form complexes with G protein-coupled receptors (GPCRs) and may regulate their cellular trafficking and pharmacology |
| GO:0005737 cytoplasm | TAS PMID:10903743 IL-4 enhances keratinocyte expression of CXCR3 agonistic che... | MARK AS OVER ANNOTATED | Summary: Cytoplasm, traceable author statement from an immunohistochemistry study of CXCR3-positive T cells in allergic contact dermatitis. Reason: CXCR3 is a seven-pass plasma membrane receptor. The cited work reports CXCR3 staining on infiltrating T cells, not a cytoplasmic pool. Ligand-induced internalization gives transient endosomal receptor, but cytoplasm is not where this receptor acts and the cited study does not localize it there. Supporting Evidence: PMID:10903743 CXCR3 staining colocalized in CD4+ and CD8+ T cells file:human/CXCR3/CXCR3-uniprot.txt FT TRANSMEM 54..80 |
| GO:0005886 plasma membrane | IDA P49682-2 PMID:12782716 An alternatively spliced variant of CXCR3 mediates the inhib... | ACCEPT | Summary: CXCR3-A and CXCR3-B detected at the surface of transfected HMEC-1 cells and on endothelium in situ. Reason: Direct experimental localization; UniProt curates cell membrane for both isoforms from this paper. The plasma membrane is where this 7TM receptor recognizes extracellular chemokines. Supporting Evidence: PMID:12782716 transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B file:human/CXCR3/CXCR3-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Cell membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane from combined automated methods. Reason: Consistent with the seven-transmembrane topology of the curated record and with direct experimental surface detection. Supporting Evidence: file:human/CXCR3/CXCR3-uniprot.txt FT TRANSMEM 54..80 PMID:12782716 transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B |
| GO:0005886 plasma membrane | TAS PMID:10741397 Human intestinal lamina propria and intraepithelial lymphocy... | ACCEPT | Summary: Surface CXCR3 on human intestinal lamina propria and intraepithelial lymphocytes. Reason: Flow-cytometric surface expression on lymphocytes together with functional migration to CXCL11 supports plasma membrane localization. Supporting Evidence: PMID:10741397 CXCR3 and CCR5 receptors were functional, as LPL and IEL migrated to their respective ligands I-TAC and RANTES |
| GO:0005886 plasma membrane | TAS PMID:9064356 Chemokine receptor specific for IP10 and mig: structure, fun... | ACCEPT | Summary: Plasma membrane, from the original CXCR3 cloning paper. Reason: Seven-transmembrane GPCR that responds to extracellular chemokines at the cell surface. Supporting Evidence: PMID:9064356 The sequence includes seven putative transmembrane segments characteristic of |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-374248 | ACCEPT | Summary: Reactome: receptor CXCR3 binds ligands CXCL9 to 11 at the plasma membrane. Reason: Consistent with the receptor's established site of action. Supporting Evidence: Reactome:R-HSA-374248 CXCR3 binds to three highly related ligands in mammals, CXCL9, CXCL10 and CXCL11 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Reactome: liganded Gi-activating GPCR acts as a GEF for Gi, at the plasma membrane. Reason: CXCR3 signaling is pertussis-toxin sensitive, consistent with Gi coupling at the plasma membrane. Supporting Evidence: PMID:18174362 CXCL4-induced chemotaxis of T lymphocytes was inhibited by a CXCR3 antagonist and pretreatment of cells with pertussis toxin (PTX), suggestive of CXCR3-mediated G-protein signaling via |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Reactome: the Ligand:GPCR:Gi complex dissociates, at the plasma membrane. Reason: Generic Gi-coupled GPCR event in which CXCR3 participates; the stated location is correct. Supporting Evidence: PMID:18174362 CXCL4-induced chemotaxis of T lymphocytes was inhibited by a CXCR3 antagonist and pretreatment of cells with pertussis toxin (PTX), suggestive of CXCR3-mediated G-protein signaling via |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Reactome: liganded Gi-activating GPCRs bind inactive heterotrimeric Gi, at the plasma membrane. Reason: Generic Gi-coupled GPCR event in which CXCR3 participates; the stated location is correct. Supporting Evidence: PMID:18174362 CXCL4-induced chemotaxis of T lymphocytes was inhibited by a CXCR3 antagonist and pretreatment of cells with pertussis toxin (PTX), suggestive of CXCR3-mediated G-protein signaling via |
| GO:0006935 chemotaxis | IEA GO_REF:0000002 | MODIFY | Summary: Chemotaxis from the InterPro chemokine receptor signature. Reason: Correct but general. CXCR3 directly mediates chemotaxis of activated T lymphocytes, its principal role, and of eosinophils and stimulated CD34+ progenitors in specific contexts. Refine to T cell chemotaxis, which this gene already carries. Proposed replacements: T cell chemotaxis Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:9064356 the IP10/Mig receptor is involved in the selective recruitment of effector T cells |
| GO:0006935 chemotaxis | TAS PMID:10903763 CXCR3 expression and activation of eosinophils: role of IFN-... | MODIFY | Summary: Traceable author statement from a study of CXCR3 on human eosinophils. Reason: The cited work shows CXCL10- and CXCL9-induced eosinophil chemotaxis blocked by an anti-CXCR3 antibody, so the precise supported term is eosinophil chemotaxis. Proposed replacements: eosinophil chemotaxis Supporting Evidence: PMID:10903763 gamma IP-10 and Mig induce eosinophil chemotaxis via CXCR3 |
| GO:0006954 inflammatory response | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Inflammatory response from the InterPro chemokine receptor signature. Reason: CXCR3 recruits Th1 and cytotoxic effector T cells to interferon-driven inflammatory sites such as contact dermatitis skin and gut mucosa. Its contribution is through chemotaxis rather than an inflammatory effector activity, so the term is kept as non-core context. Supporting Evidence: PMID:10903743 CXCR3 agonistic chemokines released by stimulated keratinocytes triggered calcium mobilization in skin-derived nickel-specific CD4+ T cells and promoted their migration PMID:9064356 the IP10/Mig receptor is involved in the selective recruitment of effector T cells |
| GO:0006955 immune response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Immune response by phylogenetic inference from PAINT node PTN001628461 in the chemokine receptor family. Reason: Immune response is inherited at a deep chemokine-receptor node, and CXCR3 does contribute to adaptive immune responses by recruiting effector T cells, so the node placement holds for this gene. The term is very broad and the specific participation is T cell chemotaxis, so it is retained as non-core. Supporting Evidence: PMID:9064356 the IP10/Mig receptor is involved in the selective recruitment of effector T cells |
| GO:0007155 cell adhesion | TAS PMID:10942362 CXC chemokine receptor 3 expression on CD34(+) hematopoietic... | MODIFY | Summary: Cell adhesion, traceable author statement from a study of CXCR3 on GM-CSF-stimulated CD34+ progenitors. Reason: CXCR3 is not an adhesion molecule. Its ligands induce integrin up-regulation and progenitor adhesion through CXCR3 signaling, which is regulation of cell adhesion, a term this gene already carries, rather than participation in adhesion itself. Proposed replacements: regulation of cell adhesion Supporting Evidence: PMID:10942362 gamma IP-10 and Mig also induced GM-CSF-stimulated CD34(+) progenitor adhesion and aggregation by means of CXCR3 PMID:10942362 up-regulation of integrins (CD49a and CD49b) was found to play a crucial role in adhesion |
| GO:0007166 cell surface receptor signaling pathway | IDA PMID:11554781 Human B cell-attracting chemokine 1 (BCA-1; CXCL13) is an ag... | MODIFY | Summary: Cell surface receptor signaling pathway: CXCL13 stimulates GTP-gamma-S binding and chemotaxis through human CXCR3. Reason: Correct but general; the pathway is G protein-coupled chemokine signaling initiated by CXCR3. Refine to chemokine-mediated signaling pathway, which this gene already carries. Proposed replacements: chemokine-mediated signaling pathway Supporting Evidence: PMID:11554781 human BCA-1 competes with radiolabeled interferon gamma (IFN-gamma) inducible protein 10 (IP-10) for binding to the human CXCR3 receptor PMID:11554781 human BCA-1 is an agonist in stimulating GTP gamma S binding |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: G protein-coupled receptor signaling pathway from InterPro. Reason: Correct but general for a chemokine receptor; refine to the descendant chemokine-mediated signaling pathway, which this gene already carries. Proposed replacements: chemokine-mediated signaling pathway Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:18174362 CXCL4-induced chemotaxis of T lymphocytes was inhibited by a CXCR3 antagonist and pretreatment of cells with pertussis toxin (PTX), suggestive of CXCR3-mediated G-protein signaling via |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA P49682-2 PMID:12782716 An alternatively spliced variant of CXCR3 mediates the inhib... | KEEP AS NON CORE | Summary: CXCR3-B ligation raises cAMP in a pertussis-toxin-insensitive manner. Reason: Isoform-specific signaling output measured directly in CXCR3-B transfectants. CXCR3-A signals through Gi, so cAMP elevation is not the general signaling mode of this gene product; kept as non-core isoform biology. Direct Gs coupling was not established by the cited work. Supporting Evidence: PMID:12782716 The increase of cAMP levels induced by CXCL10, CXCL9, CXCL11, or CXCL4 in CXCR3-B transfectants was PTX insensitive |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of cytosolic calcium ion concentration, by phylogenetic inference from PAINT node PTN001628461. Reason: Ligand-induced Ca2+ mobilization is a conserved output of this chemokine receptor clade and is directly demonstrated for human CXCR3, including loss of the response when the second extracellular loop residue R216 is mutated. The inherited claim matches the target's own experimental data. Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:16847335 residue R216 in the second extracellular loop is required for CXCR3-mediated chemotaxis and calcium mobilization |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of calcium mobilization from rat Cxcr3. Reason: The donor is the rat ortholog in the same PANTHER subfamily (PTHR10489:SF671), and the claim is independently shown for the human protein. Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | TAS PMID:10903743 IL-4 enhances keratinocyte expression of CXCR3 agonistic che... | ACCEPT | Summary: Keratinocyte-derived CXCR3 agonists trigger calcium mobilization in skin-derived T cells. Reason: Consistent with the direct cloning-paper evidence that CXCR3 mediates Ca2+ mobilization in response to its ligands. Supporting Evidence: PMID:10903743 CXCR3 agonistic chemokines released by stimulated keratinocytes triggered calcium mobilization in skin-derived nickel-specific CD4+ T cells and promoted their migration PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: External side of plasma membrane, by phylogenetic inference. Reason: The N terminus, residues 1-53 including the sulfated ligand-binding tyrosines 27 and 29, faces the extracellular side, and surface CXCR3 is detected by antibodies on intact lymphocytes. Supporting Evidence: PMID:16847335 We found that CXCR3 is sulfated on its N terminus and that sulfation is required for binding and activation by all three ligands file:human/CXCR3/CXCR3-uniprot.txt FT TRANSMEM 54..80 |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: External side of plasma membrane from combined automated methods. Reason: Same claim as the phylogenetic row, supported by the curated topology and by antibody detection on intact cells. Supporting Evidence: PMID:16847335 We found that CXCR3 is sulfated on its N terminus and that sulfation is required for binding and activation by all three ligands file:human/CXCR3/CXCR3-uniprot.txt FT TRANSMEM 54..80 |
| GO:0009986 cell surface | IDA PMID:20608915 Robust expression of CCR3 as a single basophil selection mar... | ACCEPT | Summary: Cell surface, direct assay recorded in GO-CAM model SPModule-PGRP1-S100A4. Reason: The cached record is abstract-only and its abstract concerns CCR3 as a basophil marker, so the CXCR3 measurement cannot be checked here. The curator read the full text, and cell-surface CXCR3 is independently well established on lymphocytes and transfectants, so the row is accepted. Supporting Evidence: PMID:10741397 CXCR3 and CCR5 receptors were functional, as LPL and IEL migrated to their respective ligands I-TAC and RANTES PMID:12782716 transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B |
| GO:0009986 cell surface | IEA GO_REF:0000120 | ACCEPT | Summary: Cell surface from combined automated methods. Reason: Consistent with antibody detection of CXCR3 on intact lymphocytes and transfected cells. Supporting Evidence: PMID:10741397 CXCR3 and CCR5 receptors were functional, as LPL and IEL migrated to their respective ligands I-TAC and RANTES |
| GO:0010818 T cell chemotaxis | IEA GO_REF:0000107 | ACCEPT | Summary: T cell chemotaxis transferred from rat Cxcr3 by Ensembl Compara. Reason: Core process. Human CXCR3 mediates chemotaxis of activated T lymphocytes toward CXCL9, CXCL10 and CXCL11, and toward CXCL4 in a pertussis-toxin- and antagonist-sensitive manner. The donor is the rat ortholog in the same PANTHER subfamily, and the claim is directly supported in human cells. Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:9064356 the IP10/Mig receptor is involved in the selective recruitment of effector T cells PMID:18174362 CXCL4-induced chemotaxis of T lymphocytes was inhibited by a CXCR3 antagonist and pretreatment of cells with pertussis toxin (PTX), suggestive of CXCR3-mediated G-protein signaling via |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Membrane, from InterPro. Reason: Correct but general; the receptor resides in the plasma membrane, which this gene already carries with direct experimental evidence. Proposed replacements: plasma membrane Supporting Evidence: file:human/CXCR3/CXCR3-uniprot.txt FT TRANSMEM 54..80 PMID:12782716 transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B |
| GO:0016493 C-C chemokine receptor activity | IBA GO_REF:0000033 | REMOVE | Summary: C-C chemokine receptor activity by phylogenetic inference from PAINT node PTN001628461. Reason: C-C chemokine receptor activity is not supported for human CXCR3. The inherited claim comes from PAINT node PTN001628461, a deep node in PTHR10489 whose descendants include the CC receptors (donors P32246/CCR2, P51681/CCR5, P51684/CCR6 and the MGI Ccr genes) as well as the CXCR lineages. Human CXCR3 (subfamily PTHR10489:SF671) does sit inside that clade, but ligand class is a lineage-specific property in this family and there is direct target-specific evidence of divergence: the cloned human receptor did not respond to any of ten CC chemokines tested, the Lasagni panel found no CC chemokine competing for CXCL10 binding, and human CCL21, the CC ligand that does act on mouse Cxcr3, is not a ligand for human CXCR3. No human study reports a CC chemokine acting on CXCR3. The inherited C-C claim is therefore contradicted for this gene product, while the correct ligand-class terms are accepted on other rows. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001628461 · PAINT ancestral node in PTHR10489 SUPPORTS SOURCE BUT NOT TARGET Deep chemokine-receptor node whose descendants include both the CC-receptor branches and the CXCR branches. Human CXCR3 descends from it, so the IBA follows mechanically, but ligand class diverged within the clade. UniProtKB:P32246 · CCR1, human SUPPORTS SOURCE BUT NOT TARGET Genuine CC chemokine receptor; its experimental ligand class does not transfer to the CXCR3 branch. UniProtKB:P51681 · CCR5, human SUPPORTS SOURCE BUT NOT TARGET Genuine CC chemokine receptor; its ligand class does not transfer to the CXCR3 branch. UniProtKB:P49682 · CXCR3, human (the target itself) SUPPORTS SOURCE BUT NOT TARGET The target's own GOA carries a C-C receptor row citing Lasagni et al. 2003, but the full text of that paper reports no CC chemokine binding, so this source does not sustain the C-C claim either. Supporting Evidence: PMID:9064356 but does not recognize the CXC-chemokines IL-8, GRO alpha, NAP-2, GCP-2. ENA78, PF4, the CC-chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-1 alpha, MIP-1 beta. RANTES, 1309, eotaxin, nor lymphotactin PMID:12782716 CXCR3-B did not react with any of the other 17 chemokines tested, including CCL21 PMID:10201891 human CC chemokine 6Ckine is not a ligand for the human or mouse CXC chemokine receptor CXCR3 file:human/CXCR3/CXCR3-uniprot.txt In contrast to its murine ortholog, human chemokine CCL21 does |
| GO:0016493 C-C chemokine receptor activity | IDA PMID:12782716 An alternatively spliced variant of CXCR3 mediates the inhib... | MODIFY | Summary: C-C chemokine receptor activity, direct assay citing Lasagni et al. 2003, recorded in GO-CAM model SPModule-PGRP1-S100A4 where CXCR3 appears alongside CCR5. Reason: The cited paper, read in full, shows that CXCR3-A and CXCR3-B bind the C-X-C chemokines CXCL9, CXCL10 and CXCL11 and that CXCR3-B binds CXCL4, and it explicitly reports that CXCR3-B reacted with none of the seventeen other chemokines tested, including the CC chemokines CCL1 through CCL25. The receptor activity is real but the ligand class in this row is wrong, so it should read C-X-C chemokine receptor activity; the GO-CAM activity node should be retyped to match. Proposed replacements: C-X-C chemokine receptor activity Supporting Evidence: PMID:12782716 transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B PMID:12782716 CXCR3-B did not react with any of the other 17 chemokines tested, including CCL21 |
| GO:0016494 C-X-C chemokine receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: C-X-C chemokine receptor activity from combined automated methods, drawing on InterPro IPR004070 and ortholog transfer. Reason: Core molecular function. CXCR3 binds CXCL9, CXCL10 and CXCL11 through a sulfotyrosine-dependent N-terminal site and transduces Gi-dependent Ca2+ mobilization and chemotaxis. This is the most specific receptor-activity term available for the protein. Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:12782716 transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B PMID:16847335 We found that CXCR3 is sulfated on its N terminus and that sulfation is required for binding and activation by all three ligands file:human/CXCR3/CXCR3-uniprot.txt Receptor for the C-X-C chemokines CXCL9, CXCL10 |
| GO:0016525 negative regulation of angiogenesis | IDA P49682-2 PMID:12782716 An alternatively spliced variant of CXCR3 mediates the inhib... | KEEP AS NON CORE | Summary: CXCR3-B mediates the angiostatic activity of CXCL9, CXCL10, CXCL11 and CXCL4. Reason: Direct isoform-specific evidence from endothelial growth and in vitro vessel-formation assays. Real, but restricted to the CXCR3-B isoform in endothelium and peripheral to the leukocyte chemotaxis function of the canonical product. Supporting Evidence: PMID:12782716 mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4 PMID:12782716 overexpression of CXCR3-B dramatically reduced DNA synthesis and up-regulated apoptotic HMEC-1 death through activation of distinct signal transduction pathways |
| GO:0019722 calcium-mediated signaling | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Calcium-mediated signaling by phylogenetic inference from PAINT node PTN001628461. Reason: Ca2+ mobilization downstream of CXCR3 is well documented, but whether calcium is the second messenger that executes the chemotactic response is less clear, since CXCL13 drives CXCR3-dependent chemotaxis without a calcium flux. Kept as non-core signaling context. Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:11554781 BCA-1 does not induce a calcium flux |
| GO:0019722 calcium-mediated signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Calcium-mediated signaling transferred from rat Cxcr3 by Ensembl Compara. Reason: Same claim as the phylogenetic row, from the rat ortholog in the same PANTHER subfamily; kept as non-core for the same reason. Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in |
| GO:0019956 chemokine binding | IPI PMID:11554781 Human B cell-attracting chemokine 1 (BCA-1; CXCL13) is an ag... | MODIFY | Summary: Chemokine binding: CXCL13 competes with radiolabeled CXCL10 for binding to human CXCR3. Reason: The competing ligand is a C-X-C chemokine, so the precise term is C-X-C chemokine binding, which this gene already carries from direct binding assays. Proposed replacements: C-X-C chemokine binding Supporting Evidence: PMID:11554781 human BCA-1 competes with radiolabeled interferon gamma (IFN-gamma) inducible protein 10 (IP-10) for binding to the human CXCR3 receptor |
| GO:0019957 C-C chemokine binding | IBA GO_REF:0000033 | REMOVE | Summary: C-C chemokine binding by phylogenetic inference from PAINT node PTN001628461. Reason: C-C chemokine binding is not supported for human CXCR3. The inherited claim comes from PAINT node PTN001628461, a deep node in PTHR10489 whose descendants include the CC receptors (donors P32246/CCR2, P51681/CCR5, P51684/CCR6 and the MGI Ccr genes) as well as the CXCR lineages. Human CXCR3 (subfamily PTHR10489:SF671) does sit inside that clade, but ligand class is a lineage-specific property in this family and there is direct target-specific evidence of divergence: the cloned human receptor did not respond to any of ten CC chemokines tested, the Lasagni panel found no CC chemokine competing for CXCL10 binding, and human CCL21, the CC ligand that does act on mouse Cxcr3, is not a ligand for human CXCR3. No human study reports a CC chemokine acting on CXCR3. The inherited C-C claim is therefore contradicted for this gene product, while the correct ligand-class terms are accepted on other rows. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001628461 · PAINT ancestral node in PTHR10489 SUPPORTS SOURCE BUT NOT TARGET Deep chemokine-receptor node whose descendants include both the CC-receptor branches and the CXCR branches. Human CXCR3 descends from it, so the IBA follows mechanically, but ligand class diverged within the clade. UniProtKB:P32246 · CCR1, human SUPPORTS SOURCE BUT NOT TARGET Genuine CC chemokine receptor; its experimental ligand class does not transfer to the CXCR3 branch. UniProtKB:P51681 · CCR5, human SUPPORTS SOURCE BUT NOT TARGET Genuine CC chemokine receptor; its ligand class does not transfer to the CXCR3 branch. UniProtKB:P49682 · CXCR3, human (the target itself) SUPPORTS SOURCE BUT NOT TARGET The target's own GOA carries a C-C receptor row citing Lasagni et al. 2003, but the full text of that paper reports no CC chemokine binding, so this source does not sustain the C-C claim either. Supporting Evidence: PMID:9064356 but does not recognize the CXC-chemokines IL-8, GRO alpha, NAP-2, GCP-2. ENA78, PF4, the CC-chemokines MCP-1, MCP-2, MCP-3, MCP-4, MIP-1 alpha, MIP-1 beta. RANTES, 1309, eotaxin, nor lymphotactin PMID:12782716 CXCR3-B did not react with any of the other 17 chemokines tested, including CCL21 PMID:10201891 human CC chemokine 6Ckine is not a ligand for the human or mouse CXC chemokine receptor CXCR3 |
| GO:0019958 C-X-C chemokine binding | IDA P49682-2 PMID:12782716 An alternatively spliced variant of CXCR3 mediates the inhib... | ACCEPT | Summary: Both CXCR3 isoforms bind CXCL9, CXCL10 and CXCL11, and CXCR3-B binds CXCL4 with high affinity. Reason: Direct radioligand binding to transfected cells, with the N-terminal sulfotyrosines independently shown to be required for ligand binding. This is the defining molecular interaction of the protein. Supporting Evidence: PMID:12782716 transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B PMID:16847335 We found that CXCR3 is sulfated on its N terminus and that sulfation is required for binding and activation by all three ligands |
| GO:0030155 regulation of cell adhesion | IDA PMID:19703720 Adhesion of human haematopoietic (CD34+) stem cells to human... | KEEP AS NON CORE | Summary: Adhesion of CD34+ cells to liver endothelium and epithelium is integrin dependent and modulated by CXCR3 and CXCR4 ligands. Reason: Chemokine receptor signaling activates integrins by inside-out signaling, so regulation of adhesion is a plausible direct output, and an independent study shows CXCR3-dependent integrin up-regulation and progenitor adhesion. The cached abstract supports a pertussis-toxin-sensitive chemokine contribution; the CXCR3-specific detail is in the full text the curator read. Non-core relative to chemotaxis. Supporting Evidence: PMID:19703720 Pertussis toxin was shown to decrease binding of CD34(+) cells and the cells migrated to CXCR3 and CXCR4 ligands PMID:10942362 gamma IP-10 and Mig also induced GM-CSF-stimulated CD34(+) progenitor adhesion and aggregation by means of CXCR3 |
| GO:0038023 signaling receptor activity | IDA P49682-2 PMID:12782716 An alternatively spliced variant of CXCR3 mediates the inhib... | MODIFY | Summary: Signaling receptor activity for CXCR3-B as a functional receptor for CXCL4 and for CXCL9 to CXCL11. Reason: Correct but general; the ligands demonstrated in this experiment are C-X-C chemokines, so refine to the descendant C-X-C chemokine receptor activity. Proposed replacements: C-X-C chemokine receptor activity Supporting Evidence: PMID:12782716 mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4 PMID:12782716 transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA P49682-2 PMID:12782716 An alternatively spliced variant of CXCR3 mediates the inhib... | MARK AS OVER ANNOTATED | Summary: CXCL4 raises p21 mRNA levels in CXCR3-B transfectants. Reason: An mRNA increase measured several steps downstream of receptor activation is an indirect consequence of signaling. CXCR3 is a plasma membrane receptor that performs none of the work of RNA polymerase II transcription, so it should not be annotated as participating in its positive regulation. Supporting Evidence: PMID:12782716 CXCL4 significantly up-regulated p21 mRNA transcription in CXCR3-B transfectants |
| GO:0060326 cell chemotaxis | IBA GO_REF:0000033 | MODIFY | Summary: Cell chemotaxis by phylogenetic inference from PAINT node PTN001628461. Reason: The inherited claim is sound, since directed migration is a conserved output of this chemokine receptor clade, but for CXCR3 the specific supported term is T cell chemotaxis, which this gene already carries; eosinophil chemotaxis is a secondary context captured on another row. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001628461 · PAINT ancestral node in PTHR10489 SUPPORTS TRANSFER Directed migration is a conserved output across the chemokine receptor clade, so the node placement is sound; only the term's granularity is at issue for this gene. Proposed replacements: T cell chemotaxis Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:9064356 the IP10/Mig receptor is involved in the selective recruitment of effector T cells |
| GO:0070098 chemokine-mediated signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Chemokine-mediated signaling pathway from combined automated methods. Reason: Core process. CXCR3 initiates G protein-coupled signaling in response to CXCL9, CXCL10 and CXCL11; the response is pertussis-toxin sensitive and depends on receptor sulfation and on R216 in the second extracellular loop. Supporting Evidence: PMID:9064356 It mediates Ca2+ mobilization and chemotaxis in PMID:18174362 CXCL4-induced chemotaxis of T lymphocytes was inhibited by a CXCR3 antagonist and pretreatment of cells with pertussis toxin (PTX), suggestive of CXCR3-mediated G-protein signaling via PMID:16847335 residue R216 in the second extracellular loop is required for CXCR3-mediated chemotaxis and calcium mobilization |
| GO:1900119 positive regulation of execution phase of apoptosis | IDA P49682-2 PMID:12782716 An alternatively spliced variant of CXCR3 mediates the inhib... | KEEP AS NON CORE | Summary: CXCR3-B overexpression and ligation increase apoptosis of microvascular endothelial cells. Reason: Direct isoform-specific evidence from sub-G1 and TUNEL assays. Real but peripheral to the receptor's chemotactic role, and partly a consequence of high CXCR3-B expression itself rather than of ligand alone. Supporting Evidence: PMID:12782716 overexpression of CXCR3-B dramatically reduced DNA synthesis and up-regulated apoptotic HMEC-1 death through activation of distinct signal transduction pathways |
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Download this section (compressed HTML)Q: Does the CXCR3-B isoform couple directly to Gs, or is the cAMP rise it produces an indirect consequence of another transducer?
Q: What are the endogenous expression levels and cell types of CXCR3-A, CXCR3-B and CXCR3-alt, and how much of each isoform's reported biology survives at physiological receptor density rather than in overexpressing transfectants?
Q: Is CXCL4 a direct orthosteric CXCR3 agonist, or does it act largely through glycosaminoglycan presentation, as the low-affinity binding in GAG-deficient cells suggests?
Q: Do CXCR3-CXCR4 and CXCR3-ACKR4 heteromers form at endogenous receptor levels in primary lymphocytes, and do they change ligand selectivity there?
Q: Which interaction surface do the RAMP proteins use on CXCR3, and does any of them alter its trafficking or ligand pharmacology, so that an informative molecular function could replace the generic protein-binding annotations?
Experiment: Measure G protein coupling of each CXCR3 isoform directly (for example by BRET-based G protein activation sensors across the Gi, Gs and Gq families) in cells expressing matched, physiological receptor levels.
Experiment: Knock in epitope tags or isoform-selective reporters at the endogenous CXCR3 locus in primary human T cells and endothelial cells to quantify CXCR3-A and CXCR3-B abundance and to test whether the angiostatic responses require CXCR3-B.
Experiment: Test CXCL4 and CXCL13 binding and signaling at CXCR3 in glycosaminoglycan-deficient cells and with GAG-binding-deficient chemokine mutants, to separate direct receptor agonism from GAG-mediated presentation.
Experiment: Use proximity labeling or single-molecule imaging in primary lymphocytes to test whether CXCR3 forms heteromers with CXCR4 or ACKR4 at endogenous expression, and measure the effect on CXCL10-driven chemotaxis.
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