CTLA4 (CD152) is an inhibitory immune receptor whose canonical protein is a single-pass type I membrane glycoprotein with an extracellular Ig-like V-type domain and a disulfide-linked homodimeric organization. It binds the B7 ligands CD80 and CD86 more strongly than the stimulatory receptor CD28, restricting their availability for T-cell costimulation. Ligand capture and transendocytosis remove B7 molecules from neighboring antigen-presenting cells, reducing responder T-cell activation and proliferation. CTLA4 is constitutively expressed in regulatory T cells and induced in activated conventional T cells. Much of the protein resides in intracellular vesicles and cycles to the surface. Its cytoplasmic YVKM motif regulates trafficking: phosphorylation of Tyr201 in the canonical precursor prevents AP-2 binding and favors surface retention. Heterozygous pathogenic CTLA4 variants cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). CTLA4 is targeted by the blocking antibody ipilimumab, whereas the soluble CTLA4-Ig fusion abatacept exploits B7 binding to inhibit costimulation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the valid inherited external-plasma-membrane localization. Reason: The actual target is within the on-path IBD clade. Human PMID18641304 uses live 37-degree CTLA4 cycling/surface staining; the extracellular structural constructs support topology but are not by themselves full-length cellular-localization assays. This does not assign surface localization to all short splice products. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002608477 SUPPORTS TRANSFER The actual ancestral IBD has human/mouse CTLA4 and CD28 descendant evidence. Current full-length CTLA4 topology and human live-cell surface assays support the inherited external-side localization. Supporting Evidence: GO_REF:0000033 |
| GO:0045590 negative regulation of regulatory T cell differentiation | IBA GO_REF:0000033 | MODIFY | Summary: The current target path and PTN000160996 IBD are authentic, and human self evidence is legitimate. Reason: However, its same-term human experimental grounding, PMID18641304, demonstrates acquisition of suppressive capacity and decreased division of responder T cells, with CTLA4 transfection and blocking controls. It does not demonstrate reduced differentiation of regulatory T cells. Correct the functional endpoint to negative regulation of T cell proliferation, preserving the original IBA/PTN/source fields and explaining a source-scope correction rather than target divergence, missing ancestry, weak donor count or circularity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000160996 SOURCE BAD The authentic on-path IBD uses legitimate human experimental self evidence. The actual source PMID:18641304 measures acquired suppression/reduced responder proliferation, not negative Treg differentiation; correct the shared source/target term scope. Proposed replacements: negative regulation of T cell proliferation |
| GO:0050852 T cell receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the broad inherited TCR-signaling participation assertion at its regulatory scope. Reason: Both actual GO-CAMs place CTLA4 ligand sequestration in negative regulation of TCR signaling, upstream of CD80/CD86 ligand activity and CD28. Actual functional PMID18641304 and additive PMID21474713 corroborate regulation in TCR-activated human-cell systems. Do not import an unexamined PI3K/SHP2 mechanism, intrinsic kinase/phosphatase activity, or direct CD28 binding from a structural introduction. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002608477 SUPPORTS TRANSFER The actual ancestral IBD uses mouse Cd28/MGI:88327 experimental evidence. Current mouse P31041 IMP PMID:23793062 supports TCR/CD28 co-stimulation; independent human CTLA4 inhibitory regulation supports broad pathway participation without transferring the activating sign. |
| GO:0050853 B cell receptor signaling pathway | IBA GO_REF:0000033 | UNDECIDED | Summary: The 98-node current PAINT tree places the target below PTN000160996, and its literal BCR-signaling IBD legitimately cites the human experimental seed. Reason: Self evidence is not circular and the ancestry is sound. The full original PMID:17875758 remains unavailable. Later primary CLL depletion experiments in PMID:23936412 demonstrate CTLA4-dependent proliferation, survival and changes in downstream molecules, but do not directly test signals initiated by BCR crosslinking. B-cell expression is real; a T-cell-only exclusion is invalid. The precise pathway assertion remains unresolved for both the experimental seed and its inherited annotation. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000160996 UNRESOLVED The authentic on-path IBD and human self seed are valid provenance. Original PMID:17875758 full text is unresolved; later PMID:23936412 functional CLL outcomes do not directly resolve BCR-crosslink-initiated signaling. |
| GO:0002250 adaptive immune response | IEA GO_REF:0000043 | ACCEPT | Summary: The historical UniProt adaptive-immunity keyword mapping is biologically appropriate for a regulator of antigen-responsive T-cell costimulation. Reason: This source assertion is retained even though the exact keyword-derived GOA record is absent from the captured current response; the current official protein still carries the adaptive-immunity keyword. Direct ligand depletion and responder-cell assays support immune regulation without assigning a distinct adaptive-effector mechanism to each splice product. |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: Retain the historical broad immune-system-process mapping. Reason: The current official Immunity keyword and direct human T-cell regulatory experiments support this ancestor-level biology. The exact old keyword-derived GOA tuple is absent in the current snapshot; this is recorded as provenance retirement, not functional loss or a reason to delete the historical assertion. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt subcellular-location mapping to plasma membrane is consistent with the displayed product topology and live human-cell CTLA4 surface/cycling assays. Reason: Substantial intracellular storage and rapid internalization do not contradict transient surface localization. This does not assign membrane residence to all five official products. |
| GO:0006955 immune response | IEA GO_REF:0000002 | ACCEPT | Summary: Current InterPro IPR008096 is the CTLA4-specific family and actually maps to immune response. Reason: Direct CTLA4 ligand capture and inhibition of responder T-cell activation support the biological assertion. This is regulatory participation, not an assertion that CTLA4 supplies intrinsic catalytic signaling activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR008096 SUPPORTS TRANSFER The current IPR008096 InterPro2GO output includes GO:0006955; CTLA4 is a member of this target-specific family. |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA00043397 currently outputs external side of plasma membrane. Reason: Of its 19 condition sets, zero-based branch 14 matches the actual CTLA4 FunFam 2.60.40.10:FF:000686 and the human Euteleostomi lineage; all predicates were evaluated. The predicted localization is independently supported by extracellular topology and live human-cell CTLA4 surface staining. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00043397 SUPPORTS TRANSFER Of 19 ARBA00043397 condition sets, zero-based branch 14 matches CTLA4 FunFam 2.60.40.10:FF:000686 and the human Euteleostomi lineage; it outputs GO:0009897. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: The actual IPR008096 family-to-GO mapping includes membrane. Reason: This broad location remains correct for the canonical single-pass product, whose extracellular domain and regulated plasma-membrane exposure are independently supported. The broad mapping does not identify a membrane compartment or imply equivalent topology for truncated products. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR008096 SUPPORTS TRANSFER The current IPR008096 InterPro2GO output includes GO:0016020. This broad family mapping does not specify a membrane subcompartment. |
| GO:0042129 regulation of T cell proliferation | IEA GO_REF:0000002 | ACCEPT | Summary: The actual IPR040216 CTLA4/CD28 family maps to regulation of T-cell proliferation. Reason: Its deliberately broad regulatory direction accommodates both co-stimulatory CD28 and inhibitory CTLA4; human CTLA4 gain/blocking experiments directly demonstrate reduced responder proliferation. Retain this valid broad assertion alongside the existing target-specific negative-regulation annotations. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR040216 SUPPORTS TRANSFER IPR040216 includes both CTLA4 and CD28 and outputs the unsigned GO:0042129 regulation term; it does not transfer CD28-specific activating direction. |
| GO:0005515 protein binding | IPI PMID:11279501 Structural basis for co-stimulation by the human CTLA-4/B7-2... | MODIFY | Summary: The human CTLA4–CD86 interaction is directly established by the soluble-domain structure in PMID11279501. Reason: In combination with the actual GO-CAM ligand-input role and functional ligand-depletion evidence in PMID21474713, receptor decoy activity is an evidence-backed refinement. Do not label supported generic binding as over-annotation merely for being broad. Preserve this IPI source separately from the existing IDA decoy assertion; the crystal structure alone does not measure cellular inhibitory signaling. The preserved GOA WITH/FROM partner field identifies CD86 (UniProtKB:P42081); it anchors the ligand identity, while the decoy mechanism is assessed from the combined binding and functional evidence. Proposed replacements: receptor decoy activity Supporting Evidence: PMID:11279501 human CTLA-4 and the receptor-binding domain of human B7-2 |
| GO:0005515 protein binding | IPI PMID:11279502 Crystal structure of the B7-1/CTLA-4 complex that inhibits h... | MODIFY | Summary: The human CTLA4–CD80 interaction is directly established by the soluble-domain structure in PMID11279502. Reason: Refine the broad binding assertion to receptor decoy activity using the known ligand-sequestering role, the corresponding GO-CAM CD80 input, and independent functional evidence. Keep the IPI source distinct from the existing IDA assertion. The actual crystallized CTLA4 construct is C122S and not a covalently linked wild-type full-length dimer; publisher correction DOI 10.1038/35079149 changes the PDB accession to 1I8L. The preserved GOA WITH/FROM partner field identifies CD80 (UniProtKB:P33681); it anchors the ligand identity, while the decoy mechanism is assessed from the combined binding and functional evidence. Proposed replacements: receptor decoy activity |
| GO:0005515 protein binding | IPI PMID:20587542 PD-L1 and PD-L2 differ in their molecular mechanisms of inte... | MODIFY | Summary: Five exact CD80–CTLA4 records in the PMID:20587542 IntAct set document SPR and cell-binding assays with extracellular Fc constructs. Reason: The selected abstract foregrounds PD-1 ligands, but the literal target records establish that CTLA4 was also assayed; a wrong-gene inference from the title is unwarranted. The full original remains unrecovered. Refine the positive CD80 interaction to receptor decoy activity using independently established CTLA4 ligand sequestration, without pretending that this paper measured transendocytosis. The preserved GOA WITH/FROM partner field identifies CD80 (UniProtKB:P33681); it anchors the ligand identity, while the decoy mechanism is assessed from the combined binding and functional evidence. Proposed replacements: receptor decoy activity |
| GO:0005515 protein binding | IPI PMID:21982860 A secreted protein microarray platform for extracellular pro... | MODIFY | Summary: Three exact PMID:21982860 protein-microarray records identify CTLA4 binding CD80/CD86 with multivalent extracellular Fc constructs. Reason: The abstract describes the platform and its multivalent-bait design; complete original target-table text was not recovered. These measured ligand interactions, combined with independent human ligand-depletion experiments, justify receptor decoy activity rather than an informational exclusion of positive binding. The preserved GOA WITH/FROM partner field identifies CD80 (UniProtKB:P33681) and CD86 (UniProtKB:P42081); it anchors the ligand identity, while the decoy mechanism is assessed from the combined binding and functional evidence. Proposed replacements: receptor decoy activity |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | MODIFY | Summary: The exact PMID:25241761 record is an in situ proximity-ligation association between CTLA4 and CD86 in HeLa cells. Reason: Proximity alone does not establish direct molecular contact or a physiological T-cell mechanism. Independent CTLA4–CD86 structural and ligand-depletion evidence establishes the same positive ligand interaction and its decoy role, supporting the refinement while preserving the original proximity-assay scope. The preserved GOA WITH/FROM partner field identifies CD86 (UniProtKB:P42081); it anchors the ligand identity, while the decoy mechanism is assessed from the combined binding and functional evidence. Proposed replacements: receptor decoy activity |
| GO:0005515 protein binding | IPI PMID:26206937 AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4... | UNDECIDED | Summary: The PMID:26206937 abstract directly supports LRBA–CTLA4 endosomal colocalization, increased CTLA4 turnover after LRBA loss and rescue of CTLA4 levels by lysosomal inhibition. Reason: The abstract establishes colocalization, turnover and rescue, but the original binding experiment and exact target interaction record remain unavailable. Independent PMID:33961781 supports the CTLA4–LRBA association without adjudicating this source-specific IPI assertion. Leave this annotation undecided; this is an access limitation, not evidence against binding. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Nine exact HuRI records link CTLA4 to TMEM218, MALL and CTXN3 in yeast two-hybrid configurations. Reason: The complete participant backbone checks match the official human sequences, while experimental fragment/tag features remain explicit. This supports positive binary assay interactions; no measured partner-specific physiological mechanism warrants a more informative molecular-function term. Retain the generic assertion as non-core, without inferring native colocalization or rejecting an interaction merely because its in vivo role is unknown. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32822567 A Human IgSF Cell-Surface Interactome Reveals a Complex Netw... | MODIFY | Summary: The PMID:32822567 main text describes recombinant extracellular-domain apECIA screening, deconvolution and triplicate retesting. Reason: Its CTLA4 target table was not recovered, so this source-specific experimental detail remains unresolved. The preserved GOA assertion names CD80/CD86 and the same direct interactions and ligand-sequestering role are independently established by the two structural originals and PMID:21474713. The holistic refinement is receptor decoy activity; it is not a claim to have inspected the missing table. The preserved GOA WITH/FROM partner field identifies CD80 (UniProtKB:P33681) and CD86 (UniProtKB:P42081); it anchors the ligand identity, while the decoy mechanism is assessed from the combined binding and functional evidence. Proposed replacements: receptor decoy activity |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: The literal PMID:33961781 IntAct record associates CTLA4 with LRBA by affinity purification in HEK293T cells using C-terminally tagged CTLA4. Reason: The source discusses the context dependence and limits of AP-MS, and the selected cache omits its detailed Methods. Preserve this positive association as non-core without equating co-purification with purified binary contact or assigning CTLA4 an unmeasured trafficking-adaptor function. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:35922511 A physical wiring diagram for the human immune system. | MODIFY | Summary: The genuine PMID:35922511 workbook contains the CTLA4 extracellular construct and both CD80/CD86 interaction entries. Reason: Table 3 explicitly identifies these as literature-grounded interactions; Table 2 supplies the primary screening matrix. Do not conflate previously curated affinities with new kinetic measurements. These data and independent functional ligand-depletion experiments support refinement of the positive B7-ligand binding assertion to receptor decoy activity. The preserved GOA WITH/FROM partner field identifies CD80 (UniProtKB:P33681) and CD86 (UniProtKB:P42081); it anchors the ligand identity, while the decoy mechanism is assessed from the combined binding and functional evidence. Proposed replacements: receptor decoy activity |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | UNDECIDED | Summary: The PMID:40205054 main Methods describe C-terminal HA-Flag AP-MS in U2OS cells and comparison with the separate HEK293 BioPlex network. Reason: The precise CTLA4–LRBA target record and its network origin were not recovered. Independent PMID:33961781 supports the association, but cannot establish whether this source supplies a new U2OS experiment or a comparison-network interaction. Leave this source-specific assertion undecided without treating the missing record as negative evidence. |
| GO:0005515 protein binding | IPI PMID:7807015 CTLA-4 binding to the lipid kinase phosphatidylinositol 3-ki... | MODIFY | Summary: The complete abstract reports co-association with PI3K and binding of a CTLA4 phosphopeptide to the amino- and carboxy-terminal SH2 domains of p85. Reason: The exact MINT record identifies human P27986/PIK3R1 and the CTLA4 cytoplasmic phosphotyrosine region. Refine generic binding to phosphatidylinositol 3-kinase regulatory subunit binding, which names the bound p85 subunit and does not assign PI3K catalytic activity to CTLA4. Full original text remains unrecovered; literal assay records and the explicit abstract support the binding specificity. Historical paper Tyr165 and current precursor Tyr201 numbering must be distinguished; the original insert sequence and numbering convention were not recovered. Proposed replacements: phosphatidylinositol 3-kinase regulatory subunit binding Supporting Evidence: PMID:7807015 the NH2- and COOH-terminal SH2 domains of p85 |
| GO:0005515 protein binding | IPI PMID:9398332 Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a... | MODIFY | Summary: The complete abstract distinguishes unphosphorylated-tail binding to AP-2 mu2 from phosphorylated-tail binding to PI3K SH2 domains; the preserved IPI partner is p85, not AP-2. Reason: The exact MINT record identifies human P27986/PIK3R1 and the CTLA4 cytoplasmic phosphotyrosine region. Refine generic binding to phosphatidylinositol 3-kinase regulatory subunit binding, which names the bound p85 subunit and does not assign PI3K catalytic activity to CTLA4. Full original text remains unrecovered; literal assay records and the explicit abstract support the binding specificity. Historical paper Tyr165 and current precursor Tyr201 numbering must be distinguished; the original insert sequence and numbering convention were not recovered. Proposed replacements: phosphatidylinositol 3-kinase regulatory subunit binding Supporting Evidence: PMID:9398332 a PI3 kinase SH2 domain interacted preferentially when 165Y was phosphorylated |
| GO:0005515 protein binding | IPI PMID:9813138 Resting lymphocyte kinase (Rlk/Txk) phosphorylates the YVKM ... | MODIFY | Summary: The complete abstract identifies Rlk-dependent phosphorylation of the CTLA4 YVKM motif as controlling binding to PI3K SH2 domains. Reason: The exact MINT record identifies human P27986/PIK3R1 and the CTLA4 cytoplasmic phosphotyrosine region. Refine generic binding to phosphatidylinositol 3-kinase regulatory subunit binding, which names the bound p85 subunit and does not assign PI3K catalytic activity to CTLA4. Full original text remains unrecovered; literal assay records and the explicit abstract support the binding specificity. Historical paper Tyr165 and current precursor Tyr201 numbering must be distinguished; the original insert sequence and numbering convention were not recovered. Proposed replacements: phosphatidylinositol 3-kinase regulatory subunit binding Supporting Evidence: PMID:9813138 binding of the SH2 domains of PI 3-kinase to the receptor |
| GO:0042130 negative regulation of T cell proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: Retain negative regulation of T-cell proliferation. Reason: The literal transfer source is rat Ctla4 A0A096MJE4, with experimental IMP evidence from PMID:15849541: anti-rat CTLA4 antagonism increases T-cell proliferation in mixed lymphocyte reactions. Its antibody-specific lack of B7 blocking is not generalized to every CTLA4 mechanism. Independent human PMID:18641304 measures reduced CFSE division and thymidine incorporation after CTLA4 transfection, with antibody reversal; PMID:21474713 links ligand depletion to impaired responder stimulation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:A0A096MJE4 · rat Ctla4 SUPPORTS TRANSFER Current rat Ctla4 IMP0042130 cites PMID:15849541; its complete abstract reports anti-rat CTLA4 antagonism increasing T-cell proliferation in mixed lymphocyte reactions. The human homologous function is independently demonstrated; no antibody-specific signaling mechanism is generalized. |
| GO:0140319 receptor decoy activity | IDA PMID:11279501 Structural basis for co-stimulation by the human CTLA-4/B7-2... | ACCEPT | Summary: Retain receptor decoy activity. Reason: PMID11279501 establishes direct binding of a human CTLA4 extracellular construct to CD86; the exact GO-CAM models CD86 as the ligand input rather than a CD28 contact. Actual human functional evidence in PMID21474713 strengthens sequestration/depletion and inhibitory consequences. Separate what the structural original measured from the holistic functional assignment. |
| GO:0140319 receptor decoy activity | IDA PMID:11279502 Crystal structure of the B7-1/CTLA-4 complex that inhibits h... | ACCEPT | Summary: Retain receptor decoy activity with direct CTLA4–CD80 structural support and the same ligand-sequestering mechanism. Reason: PMID11279502 uses engineered human soluble C122S CTLA4 and cleaved CD80 ectodomains, initially expressed as CHO fusion proteins. Crystal packing does not establish obligatory full-length native stoichiometry. The operative PDB-accession correction is acknowledged, not misrepresented as a functional retraction. |
| GO:0050868 negative regulation of T cell activation | IDA PMID:11279501 Structural basis for co-stimulation by the human CTLA-4/B7-2... | ACCEPT | Summary: Retain negative regulation of T-cell activation by holistic functional synthesis and the curator-established source, without claiming that PMID11279501 itself performed a cellular activation assay. Reason: Its direct contribution is the CD86-binding interface. Human CTLA4 gain/blocking and ligand-depletion/responder experiments in PMID18641304 and PMID21474713 independently corroborate the inhibitory outcome. |
| GO:0050868 negative regulation of T cell activation | IDA PMID:11279502 Crystal structure of the B7-1/CTLA-4 complex that inhibits h... | ACCEPT | Summary: Retain negative regulation of T-cell activation with the same evidence distinction: PMID11279502 directly measures/structures CD80–CTLA4 binding, while its signaling interpretation is background/model context. Reason: The independently read human functional studies corroborate the target process. Do not rewrite the original IDA tuple or pretend a crystal measured T-cell activation. |
| GO:0050868 negative regulation of T cell activation | IDA PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin... | ACCEPT | Summary: Retain the biologically well-supported negative regulation of T-cell activation. Reason: The full original PMID:17875758 remains unrecovered, so its precise experimental support cannot be excluded or reconstructed from a CLL-focused abstract. Independent human CTLA4 gain/blocking and ligand-depletion experiments in PMID:18641304 and PMID:21474713 directly corroborate the target process. CLL survival/proliferation results are not used as a substitute for a T-cell activation assay. |
| GO:0050860 negative regulation of T cell receptor signaling pathway | IDA PMID:11279501 Structural basis for co-stimulation by the human CTLA-4/B7-2... | ACCEPT | Summary: Retain negative regulation of TCR signaling at the co-stimulatory regulatory level, matching the actual GO-CAM placement and human TCR-stimulated functional context. Reason: PMID11279501 directly supplies structural ligand-binding evidence, not a TCR-proximal phosphorylation experiment. Ligand competition/depletion can regulate TCR-dependent responses without asserting intrinsic catalytic activity or a direct CTLA4–CD28 contact. |
| GO:0050860 negative regulation of T cell receptor signaling pathway | IDA PMID:11279502 Crystal structure of the B7-1/CTLA-4 complex that inhibits h... | ACCEPT | Summary: Retain negative regulation of TCR signaling, separating the direct CD80–CTLA4 structure in PMID11279502 from the modeled pathway placement and functional corroboration. Reason: The original crystal is not an independent cellular signaling assay. Neither the model nor these bounded reads establish that every inhibitory effect requires a particular cell-intrinsic phosphatase mechanism. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-388829 | ACCEPT | Summary: CTLA4-containing phosphorylated surface complexes are inputs/outputs of SHP2 association; the current event itself cautions that SHP2 association may be indirect. Reason: The complete current event/entity traversal reaches the exact P16410 reference and preserves this modeled location. Independent cell-surface experiments corroborate plasma-membrane localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-388833 | ACCEPT | Summary: CTLA4 is the membrane-associated substrate of Src-family phosphorylation, not the kinase. Reason: The complete current event/entity traversal reaches the exact P16410 reference and preserves this modeled location. Independent cell-surface experiments corroborate plasma-membrane localization. |
| GO:0005886 plasma membrane | IMP PMID:28484017 Structural basis for cancer immunotherapy by the first-in-cl... | ACCEPT | Summary: PMID:28484017 explicitly reports cell-based binding assays against a CTLA4 mutant library alongside the soluble ipilimumab–CTLA4 structure. Reason: Together with independently established canonical topology and live-cell surface staining, this supports plasma-membrane localization. The complete original Methods were not recovered, so no unverified host, clone length or native signaling assembly is inferred from the abstract. |
| GO:0098636 protein complex involved in cell adhesion | IDA PMID:7544393 Identification of residues in the V domain of CD80 (B7-1) im... | MARK AS OVER ANNOTATED | Summary: At the exact PMID7544393 source scope, adhesion is measured using explicitly CD28-positive, CTLA4-negative Jurkat cells and CD80-expressing mouse L cells. Reason: CTLA4 is tested separately as soluble CTLA4-Ig binding to those transfectants. The positive CTLA4–CD80 complex/interaction is real, but assigning that measured complex an adhesion-performing function exceeds the experiment. MARK_AS_OVER_ANNOTATED is preferred; this is not a claim that CTLA4 complexes can never contribute to adhesion, and REMOVE would overstate the result. UNDECIDED is a defensible alternative only for an explicitly unresolved broader capability, not an unavailable-original premise. Supporting Evidence: |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-388809 | ACCEPT | Summary: The surface CTLA4 complex binds the B7 ligand set. Reason: The complete current event/entity traversal reaches the exact P16410 reference and preserves this modeled location. Independent cell-surface experiments corroborate plasma-membrane localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-389532 | ACCEPT | Summary: The input/output CTLA4 complex binds PP2A at the plasma membrane; membership does not give CTLA4 phosphatase activity. Reason: The complete current event/entity traversal reaches the exact P16410 reference and preserves this modeled location. Independent cell-surface experiments corroborate plasma-membrane localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8877421 | ACCEPT | Summary: CTLA4 is the plasma-membrane protein output of a FOXP3/RUNX1 transcriptional regulation event, not its transcriptional catalyst. Reason: The complete current event/entity traversal reaches the exact P16410 reference and preserves this modeled location. Independent cell-surface experiments corroborate plasma-membrane localization. |
| GO:0006974 DNA damage response | IMP PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin... | UNDECIDED | Summary: The original experimental DNA-damage-response assertion is preserved. Reason: PMID:17875758 full text remains unavailable; its title foregrounding ATM is not evidence of misattribution, and DNA-damage response is broader than DNA repair. Later PMID:23936412 measures CTLA4-dependent CLL proliferation/survival and expression changes but does not supply a defined DNA-damage stimulus or response assay. Neither a rejection nor a precise mechanistic assignment can be made from this accessible evidence. |
| GO:0030889 negative regulation of B cell proliferation | IMP PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin... | KEEP AS NON CORE | Summary: Preserve the original PMID:17875758 assertion while recognizing its unresolved full-text scope. Reason: Independent PMID:23936412 directly tests primary human CLL cells: CTLA4 antisense depletion increases thymidine uptake/MTT readouts, and separate siRNA experiments increase Ki-67. This supports negative regulation of B-cell proliferation in the tested malignant-cell context. The result is contextual rather than the compact T-cell ligand-decoy core; it is not invalidated by CTLA4 being best characterized in T cells. Supporting Evidence: PMID:23936412 Cell proliferation was significantly increased in CTLA4-downregulated CLL cells |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin... | KEEP AS NON CORE | Summary: Independent PMID:23936412 shows reduced Annexin-V/CD19 apoptosis after CTLA4 antisense depletion for 72 hours in three low-CD38/high-CTLA4 primary CLL samples. Reason: This supports a positive contribution to apoptosis in that measured disease context, while the original PMID:17875758 full text remains unresolved. Retain as non-core without claiming a universal pro-apoptotic role, a direct CTLA4–BCL2 interaction or proven equivalent effects of all products. |
| GO:0050853 B cell receptor signaling pathway | IMP PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin... | UNDECIDED | Summary: The original human IMP source PMID:17875758 remains full-text unresolved. Reason: The later CLL depletion study demonstrates functional proliferation/survival effects and changes in molecules associated with BCR signaling, but it does not directly test the GO-defined cascade initiated by BCR crosslinking. This preserves genuine B-cell biology while leaving the exact pathway assignment unresolved; no wrong-gene, T-cell-only or direct-mechanism prerequisite is imposed. |
| GO:0005794 Golgi apparatus | IDA PMID:15814706 Exocytosis of CTLA-4 is dependent on phospholipase D and ADP... | ACCEPT | Summary: The PMID:15814706 abstract explicitly identifies a predominantly perinuclear CTLA4 compartment with GM130 overlap, consistent with the Golgi assignment. Reason: It describes a CHO transfection model compared with activated/regulatory T-cell trafficking. Preserve the established localization while keeping the unrecovered full Methods and product-specific scope explicit. Supporting Evidence: |
| GO:0009897 external side of plasma membrane | IDA PMID:18641304 Acquisition of suppressive function by activated human CD4+ ... | ACCEPT | Summary: Retain external-plasma-membrane localization at the actual human-cell scope. Reason: PMID18641304 detects live cycling CTLA4 using 37-degree antibody labeling and tests function of the CTLA4-positive sorted/transfected cells. Regulated surface exposure is compatible with a large intracellular pool; it does not make every official truncated product a surface receptor. Supporting Evidence: |
| GO:0045334 clathrin-coated endocytic vesicle | IDA PMID:15814706 Exocytosis of CTLA-4 is dependent on phospholipase D and ADP... | ACCEPT | Summary: Retain the curator-supported clathrin-coated endocytic-vesicle annotation, consistent with constitutive CTLA4 internalization and the independently documented phosphotyrosine-sensitive interaction with AP-2. Reason: PMID:15814706 full text remains unrecovered and its abstract does not independently resolve every vesicle subclass; PMID:9175836 provides mechanistic endocytosis corroboration without replacing the original IDA source. |
| GO:0045590 negative regulation of regulatory T cell differentiation | IDA PMID:18641304 Acquisition of suppressive function by activated human CD4+ ... | MODIFY | Summary: PMID18641304 does not show inhibition of regulatory-T-cell differentiation. Reason: It shows CTLA4-dependent acquisition of suppressive function by human CD4-positive/CD25-negative cells, antibody reversal, and directly decreased CFSE division of responder T cells in Figure6. Refine to negative regulation of T-cell proliferation (GO0042130), a typed child of negative regulation of T-cell activation and a more precise match to the measured endpoint. Preserve the positive result and original IDA/reference tuple. CTLA4 transfection exceeded natural Treg expression, and the exact numbered official product was not independently established. Proposed replacements: negative regulation of T cell proliferation Supporting Evidence: PMID:18641304 resting human T cells with CTLA-4 and found that this method conferred suppression |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:15814706 Exocytosis of CTLA-4 is dependent on phospholipase D and ADP... | ACCEPT | Summary: PMID:15814706 explicitly describes a predominantly perinuclear CTLA4 compartment and stimulus-regulated exocytosis in its CHO model and T-cell comparisons. Reason: Retain this spatial observation without assuming that every perinuclear punctum is Golgi, assigning all short products the same location or claiming full Methods access. Supporting Evidence: |
| GO:0005886 plasma membrane | TAS PMID:3220103 Human Ig superfamily CTLA-4 gene chromosomal localization an... | ACCEPT | Summary: The original cloning source PMID:3220103 describes the human extracellular Ig-like, hydrophobic transmembrane and cytoplasmic coding regions. Reason: This sequence/topology evidence is consistent with the independently demonstrated regulated plasma-membrane localization. Retain the historical TAS without treating cloning alone as a live-cell localization experiment. |
| GO:0006955 immune response | TAS PMID:3220103 Human Ig superfamily CTLA-4 gene chromosomal localization an... | ACCEPT | Summary: The historical immune-response TAS is biologically sound for CTLA4-mediated control of T-cell costimulation. Reason: PMID:3220103 is the human cloning/sequence paper, not itself a comprehensive inhibitory-function experiment; later primary CTLA4 functional studies directly corroborate the broader immune-response assertion. |
| GO:0030547 signaling receptor inhibitor activity | IDA PMID:11279501 Structural basis for co-stimulation by the human CTLA-4/B7-2... | REMOVE | Summary: Retire the previous authored NEW signaling-receptor-inhibitor assertion. Reason: Current GO0030547 requires receptor binding that inhibits receptor activity; the demonstrated CTLA4 targets here are CD80/CD86 co-stimulatory ligands, not CD28. GO0140319 explicitly captures ligand sequestration preventing access to the regular receptor, and the actual GO-CAM and PMID21474713 support that role. This is a mechanism-specific correction, not an ancestor/descendant redundancy claim: the current typed closures do not place decoy beneath GO0030547. Preserve the historical authored assertion/provenance through the existing review record; no replacement NEW is needed. |
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Download this section (compressed HTML)Q: Which official truncated CTLA4 products are translated and localized in primary human cells, and do any retain ligand binding or inhibitory activity?
Q: Do the original PMID:17875758 experiments establish a BCR-crosslink-initiated response or a defined DNA-damage response independently of CLL proliferation and survival?
Q: What physiological roles do the supported CTLA4 interactions with LRBA, TMEM218, MALL and CTXN3 perform, and which are direct in native human-cell contexts?
Experiment: Compare sequence-verified official CTLA4 products in matched ligand-binding, surface-trafficking and responder-cell assays, with expression-normalized canonical and empty-vector controls.
Experiment: In primary CLL cells, combine CTLA4 perturbation with controlled BCR crosslinking or a defined DNA-damage stimulus and measure pathway-proximal responses separately from cell viability and proliferation.
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