CTLA4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0009897 external side of plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: CTLA4 is detected on the external side of the plasma membrane of T cells upon activation. IBA annotation is supported by phylogenetic inference from CTLA4 orthologs including mouse Ctla4 and human CD28. Multiple experimental studies confirm CTLA4 surface expression, including flow cytometry studies (PMID:18641304) and structural studies showing the extracellular domain in complex with B7 ligands (PMID:11279501, PMID:11279502). UniProt notes CTLA4 is a cell membrane single-pass type I membrane protein with regulated surface expression. The deep research report (CTLA4-deep-research-falcon.md) confirms CTLA4 resides largely in intracellular vesicles at steady state with regulated surface expression. Reason: Well-supported localization. CTLA4 is a transmembrane receptor whose extracellular Ig-like domain binds B7 ligands on APCs at the cell surface. IBA annotation is consistent with direct experimental evidence from structural studies and flow cytometry. Supporting Evidence: PMID:11279501 the 3.2-A resolution structure of the complex between the disulphide-linked homodimer of human CTLA-4 and the receptor-binding domain of human B7-2 PMID:18641304 Acquisition of suppressive function by activated human CD4+ CD25- T cells is associated with the expression of CTLA-4
GO:0045590 negative regulation of regulatory T cell differentiation	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for negative regulation of Treg differentiation. CTLA4 is constitutively expressed on Tregs and plays complex roles in Treg biology. PMID:18641304 showed that activated CD4+CD25- T cells acquiring CTLA4 expression gain suppressive capacity, suggesting CTLA4 may regulate the threshold for Treg-like function. CTLA4 haploinsufficiency leads to dysregulated Treg function. However, CTLA4 is also required for Treg suppressive function, so its role in negatively regulating Treg differentiation is nuanced. The IBA annotation is phylogenetically supported and consistent with the IDA annotation from PMID:18641304. Reason: Phylogenetically supported by IBA and consistent with the experimental IDA annotation from PMID:18641304 already in the annotation set. CTLA4 engagement can modulate the balance of Treg differentiation. Supporting Evidence: PMID:18641304 Acquisition of suppressive function by activated human CD4+ CD25- T cells is associated with the expression of CTLA-4 not FoxP3
GO:0050852 T cell receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: CTLA4 is a key modulator of T cell receptor signaling. It competes with CD28 for B7 ligand binding to attenuate TCR-dependent T cell activation (PMID:11279501, PMID:11279502). Phosphorylation of its cytoplasmic YVKM motif recruits PI3K and SHP-2 phosphatase, directly modulating TCR downstream signaling. IBA annotation is well-supported. Reason: CTLA4 is a central component of the TCR co-stimulatory signaling axis. Its engagement with B7 ligands directly modulates TCR signaling output. Phylogenetically conserved function supported by extensive literature. Supporting Evidence: PMID:11279501 Regulation of T-cell activity is dependent on antigen-independent co-stimulatory signals provided by the disulphide-linked homodimeric T-cell surface receptors, CD28 and CTLA-4 PMID:11279502 Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it
GO:0050853 B cell receptor signaling pathway	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: IBA annotation for B cell receptor signaling pathway. CTLA4 is primarily a T cell receptor. PMID:17875758 reported CTLA4 expression in B-CLL cells and found CTLA4 overexpression associated with good clinical outcome, but this study examined CTLA4 as a differentially expressed gene in CLL cells rather than demonstrating a direct mechanistic role in BCR signaling. CTLA4 expression on B cells has been reported but is not a core function. Reason: CTLA4 is primarily a T cell co-inhibitory receptor. While expression on B cells has been reported (PMID:17875758), its primary evolved function is in T cell biology. CTLA4 does not have a well-established direct role in BCR signaling. This IBA (node PTN000160996) is seeded by CTLA4's own IMP annotation for the same term, which derives from a correlative B-CLL gene-expression study rather than a mechanistic BCR-signaling assay; the on-target seed is therefore too weak to propagate confidently. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P16410 · CTLA4 SOURCE WEAK OR INFERRED The on-target seed is CTLA4's own IMP for BCR signaling from a correlative B-CLL gene-expression study (PMID:17875758), not a mechanistic assay of a role in BCR signaling. PANTHER:PTN000160996 SOURCE WEAK OR INFERRED IBD node placement rests on that weak on-target seed; CTLA4 acts in the TCR/CD28 co-inhibitory axis, so a B cell receptor signaling role does not transfer confidently. Supporting Evidence: PMID:17875758 the overexpression of CTLA4 and MNDA was associated with good outcome
GO:0002250 adaptive immune response	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping (KW-1064 Adaptive immunity). CTLA4 is a central regulator of adaptive immune responses, specifically T cell activation. This is a broad but accurate annotation. Reason: CTLA4 is unquestionably involved in adaptive immunity as a key checkpoint receptor on T cells. While broad, this term is accurate and appropriately captures the biological context. More specific annotations (negative regulation of T cell activation, etc.) are also present to provide detail.
GO:0002376 immune system process	IEA GO_REF:0000043	ACCEPT	Summary: IEA from UniProt keyword mapping (KW-0391 Immunity). Very broad term. CTLA4 is clearly involved in immune system processes. More specific terms are already annotated. Reason: Very broad but correct. More informative child terms (adaptive immune response, negative regulation of T cell activation, etc.) are already annotated, making this redundant but not incorrect. Acceptable as an IEA.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA from UniProt subcellular location vocabulary mapping. CTLA4 is a type I transmembrane protein localized to the plasma membrane. This is well-supported by UniProt annotation and multiple experimental studies. Reason: Correct localization. CTLA4 is a single-pass type I membrane protein confirmed at the plasma membrane by multiple structural and cell biological studies (PMID:11279501, PMID:11279502, PMID:28484017).
GO:0006955 immune response	IEA GO_REF:0000002	ACCEPT	Summary: IEA from InterPro domain mapping (IPR008096 CTLA4). Broad but correct. CTLA4 is a key immune regulator. More specific terms are present. Reason: Broad but accurate IEA. More specific terms provide the detail. The InterPro mapping from the CTLA4 domain correctly identifies immune function.
GO:0009897 external side of plasma membrane	IEA GO_REF:0000117	ACCEPT	Summary: IEA from ARBA machine learning model. Consistent with the IBA annotation for the same term and experimental evidence from IDA (PMID:18641304). CTLA4 extracellular domain is exposed on the cell surface. Reason: Correct and consistent with other evidence sources (IBA and IDA annotations for the same term). CTLA4 extracellular domain binds B7 ligands at the cell surface.
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: IEA from InterPro domain mapping (IPR008096 CTLA4). Very broad CC term. CTLA4 is indeed a membrane protein. More specific terms (plasma membrane, external side of plasma membrane) are already annotated. Reason: Very broad but correct. CTLA4 is a transmembrane protein. More specific membrane localizations are captured by other annotations.
GO:0042129 regulation of T cell proliferation	IEA GO_REF:0000002	ACCEPT	Summary: IEA from InterPro domain mapping (IPR040216 CTLA4/CD28). CTLA4 is a well-established negative regulator of T cell proliferation. The neutral "regulation" rather than "negative regulation" is acceptable for an IEA, though the more specific term GO:0042130 (negative regulation of T cell proliferation) is also present via Ensembl IEA transfer. Reason: Correct. CTLA4 is a major regulator (specifically negative regulator) of T cell proliferation. The broader "regulation" term is acceptable for an InterPro-derived IEA since the family includes both CD28 (positive) and CTLA4 (negative).
GO:0005515 protein binding	IPI PMID:11279501 Structural basis for co-stimulation by the human CTLA-4/B7-2...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with CD86 (P42081). PMID:11279501 (Schwartz et al. 2001) determined the 3.2A crystal structure of the CTLA4/B7-2 (CD86) complex, providing direct structural evidence for this interaction. This is a core functional interaction for CTLA4. The term "protein binding" is uninformative; the interaction with CD86 is better captured by the receptor decoy activity annotation (GO:0140319). Reason: While the physical interaction is real and well-documented by crystal structure, the term "protein binding" (GO:0005515) is uninformative per GO curation guidelines. The functional significance of this interaction is better captured by receptor decoy activity (GO:0140319) and signaling receptor inhibitor activity. The IPI annotation is a consequence of IntAct import and adds little beyond what is captured by more specific MF terms. Supporting Evidence: PMID:11279501 the 3.2-A resolution structure of the complex between the disulphide-linked homodimer of 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...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with CD80 (P33681). PMID:11279502 (Stamper et al. 2001) determined the 3.0A crystal structure of the CTLA4/B7-1 (CD80) complex. Core functional interaction, but "protein binding" is uninformative. Reason: Same reasoning as the CTLA4-CD86 interaction. The physical interaction is real but "protein binding" is uninformative. Functional significance captured by receptor decoy activity (GO:0140319). Supporting Evidence: PMID:11279502 the crystal structure of the human CTLA-4/B7-1 co-stimulatory complex at 3.0 A resolution
GO:0005515 protein binding	IPI PMID:20587542 PD-L1 and PD-L2 differ in their molecular mechanisms of inte...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with CD80 (P33681). PMID:20587542 (Ghiotto et al. 2010) is primarily a study of PD-L1 and PD-L2 interaction mechanisms with PD-1 but also detected CTLA4-CD80 interaction. The CTLA4-CD80 interaction is well-established by structural studies. Reason: "Protein binding" is uninformative. The CTLA4-CD80 interaction is well-established and functionally captured by receptor decoy activity (GO:0140319). Supporting Evidence: PMID:20587542 PD-L1 behaved in a similar manner with its second ligand, CD80 [study also detected CTLA4 interactions with CD80]
GO:0005515 protein binding	IPI PMID:21982860 A secreted protein microarray platform for extracellular pro...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with CD80 (P33681) and CD86 (P42081). PMID:21982860 is a secreted protein microarray platform study. High-throughput detection of known interactions. Reason: "Protein binding" is uninformative. CTLA4 interactions with CD80 and CD86 are well-documented by structural studies and are functionally captured by more specific MF terms. Supporting Evidence: PMID:21982860 we screened a set of 89 immunoglobulin (Ig)-type receptors against a highly diverse extracellular protein microarray with 686 genes represented
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with CD86 (P42081). PMID:25241761 used in situ proximity ligation assay (PLA) to systematically profile protein-protein interactions. Confirms the known CTLA4-CD86 interaction. Reason: "Protein binding" is uninformative. The CTLA4-CD86 interaction is functionally captured by receptor decoy activity and other specific terms. Supporting Evidence: PMID:25241761 Herein, we collected ∼ 700 primary antibodies and employed a highly sensitive and specific technique, an in situ proximity ligation assay, to investigate 1204 endogenous PPIs in HeLa cells, and 557 PPIs of them tested positive
GO:0005515 protein binding	IPI PMID:26206937 AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with LRBA (P50851). LRBA is critical for CTLA4 trafficking; it protects CTLA4 from lysosomal degradation, enabling recycling to the cell surface. LRBA deficiency phenocopies CTLA4 haploinsufficiency (PMID:26206937). The deep research report (CTLA4-deep-research-falcon.md) confirms LRBA deficiency increases lysosomal degradation of CTLA4. This is a functionally important interaction but "protein binding" is still uninformative. Reason: The CTLA4-LRBA interaction is biologically significant for CTLA4 trafficking and stability. However, "protein binding" does not capture this functional relationship. A more informative annotation would describe the trafficking role. Supporting Evidence: PMID:26206937 LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3(+) regulatory and activated conventional T cells file:human/CTLA4/CTLA4-deep-research-falcon.md recycling to the surface (e.g., after TCR stimulation) is regulated by LRBA and Rab11 pathways
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with TMEM218 (A2RU14), MALL (Q13021), and CTXN3 (Q4LDR2). PMID:32296183 is a reference map of the human binary protein interactome (HuRI). High-throughput yeast two-hybrid. These are not well-characterized interactions for CTLA4 and may represent false positives or non-core interactions. Reason: High-throughput IPI data. Interactions with TMEM218, MALL, and CTXN3 are not well-characterized for CTLA4 function. "Protein binding" is uninformative and these interactions lack follow-up validation in the context of CTLA4 biology. Supporting Evidence: PMID:32296183 HI-III-20 (Human Interactome obtained from screening Space III, published in 2020), contains 52,569 verified PPIs involving 8,275 proteins
GO:0005515 protein binding	IPI PMID:32822567 A Human IgSF Cell-Surface Interactome Reveals a Complex Netw...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with CD80 (P33681) and CD86 (P42081). PMID:32822567 is a human IgSF cell-surface interactome study. Confirms known CTLA4-B7 interactions. Reason: "Protein binding" is uninformative. These are well-established interactions captured by more specific MF annotations. Supporting Evidence: PMID:32822567 We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with LRBA (P50851). Dual proteome-scale network study confirming CTLA4-LRBA interaction. Biologically significant but "protein binding" is uninformative. Reason: The CTLA4-LRBA interaction is important for CTLA4 stability and trafficking but "protein binding" does not capture this. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks
GO:0005515 protein binding	IPI PMID:35922511 A physical wiring diagram for the human immune system.	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with CD80 (P33681) and CD86 (P42081). PMID:35922511 is a physical wiring diagram for the human immune system. Confirms known CTLA4-B7 interactions. Reason: "Protein binding" is uninformative. These well-established interactions are captured by more specific MF terms. Supporting Evidence: PMID:35922511 using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with LRBA (P50851). Multimodal cell maps study. Confirms CTLA4-LRBA interaction. Reason: "Protein binding" is uninformative. CTLA4-LRBA interaction is functionally significant for trafficking but not captured by this generic term. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics
GO:0005515 protein binding	IPI PMID:7807015 CTLA-4 binding to the lipid kinase phosphatidylinositol 3-ki...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with PIK3R1 (P27986, the p85 subunit of PI3K). CTLA4 cytoplasmic tail YVKM motif, when phosphorylated, recruits PI3K p85 subunit. This is a known signaling interaction downstream of CTLA4. However, "protein binding" does not capture this signaling relationship. Reason: The CTLA4-PI3K interaction via the phosphorylated YVKM motif is functionally important for downstream signaling, but "protein binding" is uninformative. The interaction is better described in the context of signaling pathway annotations. Supporting Evidence: PMID:7807015 CTLA-4 can also associate with PI 3-kinase as detected by lipid kinase analysis and immunoblotting with anti-p85 antiserum
GO:0005515 protein binding	IPI PMID:9398332 Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with PIK3R1 (P27986). Further evidence for the CTLA4-PI3K p85 interaction. Same reasoning as above. Reason: "Protein binding" is uninformative. The CTLA4-PI3K p85 interaction is real but better described functionally. Supporting Evidence: PMID:9398332 we demonstrate association of the mu2 subunit of AP-2, the clathrin-associated complex found in plasma membrane-associated coated pits, with the cytoplasmic tail of CTLA-4, but not CD28
GO:0005515 protein binding	IPI PMID:9813138 Resting lymphocyte kinase (Rlk/Txk) phosphorylates the YVKM ...	MARK AS OVER ANNOTATED	Summary: IPI for protein binding with PIK3R1 (P27986). PMID:9813138 (Schneider et al. 1998) showed that Rlk/Txk phosphorylates the YVKM motif and regulates PI3K binding to CTLA4. Provides mechanistic detail about the CTLA4-PI3K interaction. Reason: While mechanistically informative, "protein binding" does not capture the functional significance. The interaction is real and well-characterized but the GO term is uninformative. Supporting Evidence: PMID:9813138 Resting lymphocyte kinase (Rlk/Txk) phosphorylates the YVKM motif and regulates PI 3-kinase binding to T-cell antigen CTLA-4
GO:0042130 negative regulation of T cell proliferation	IEA GO_REF:0000107	ACCEPT	Summary: IEA from Ensembl Compara ortholog transfer. CTLA4 is a well-established negative regulator of T cell proliferation. This is a core function of the protein. Reason: Core function of CTLA4. It attenuates T cell activation and proliferation by competing with CD28 for B7 ligand binding and delivering inhibitory signals. Supported by extensive literature and more specific experimental annotations already present (negative regulation of T cell activation, negative regulation of TCR signaling).
GO:0140319 receptor decoy activity	IDA PMID:11279501 Structural basis for co-stimulation by the human CTLA-4/B7-2...	ACCEPT	Summary: IDA for receptor decoy activity based on the CTLA4/B7-2 crystal structure (Schwartz et al. 2001). CTLA4 binds CD80 and CD86 with higher avidity than CD28, effectively sequestering these ligands and preventing CD28-mediated co-stimulation. UniProt explicitly describes CTLA4 as acting as a decoy receptor. The GO term definition -- "Binding and sequestering a specific receptor ligand to prevent it from binding to its regular receptor" -- accurately describes CTLA4 function. Reason: Core molecular function of CTLA4. It competitively binds B7 ligands (CD80/CD86) with higher affinity than CD28, sequestering them from the stimulatory receptor. Structural evidence from crystal structures directly supports this. Supporting Evidence: PMID:11279501 Regulation of T-cell activity is dependent on antigen-independent co-stimulatory signals provided by the disulphide-linked homodimeric T-cell surface receptors, CD28 and CTLA-4 ... subsequent engagement of CTLA-4 with these same ligands results in attenuation of the response
GO:0140319 receptor decoy activity	IDA PMID:11279502 Crystal structure of the B7-1/CTLA-4 complex that inhibits h...	ACCEPT	Summary: IDA for receptor decoy activity based on the CTLA4/B7-1 crystal structure (Stamper et al. 2001). Demonstrates that CTLA4 forms a zipper-like array with B7-1, creating stable signaling complexes at the T cell surface that sequester B7 ligands. Reason: Core molecular function. The crystal structure of CTLA4/B7-1 complex demonstrates the structural basis for ligand sequestration. The zipper-like oligomerization provides a mechanism for potent inhibitory signaling. Supporting Evidence: PMID:11279502 CTLA-4 and B7-1 pack in a strikingly periodic arrangement in which bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers. This zipper-like oligomerization provides the structural basis for forming unusually stable signalling complexes at the T-cell surface
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: IDA for negative regulation of T cell activation. PMID:11279501 demonstrates through structural analysis that CTLA4 competitively binds B7 ligands to attenuate T cell responses. This is a core biological process function of CTLA4. Reason: Core function. CTLA4 is the canonical negative regulator of T cell activation. The structural evidence demonstrates how CTLA4-B7 interactions provide the basis for inhibiting CD28-dependent T cell activation. Supporting Evidence: PMID:11279501 subsequent engagement of CTLA-4 with these same ligands results in attenuation of the response
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: IDA for negative regulation of T cell activation from the CTLA4/B7-1 crystal structure study. The zipper-like oligomerization of CTLA4 and B7-1 provides potent inhibitory signaling. Reason: Core function. Same core function as above, supported by complementary structural evidence from the B7-1 complex. Supporting Evidence: PMID:11279502 underscoring the importance of potent inhibitory signalling in human immune responses
GO:0050868 negative regulation of T cell activation	IDA PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin...	ACCEPT	Summary: IDA for negative regulation of T cell activation based on PMID:17875758, which studied CTLA4 expression in B-CLL. This paper primarily examined gene expression profiles in CLL, not direct T cell activation experiments. The paper found CTLA4 overexpression associated with good clinical outcome in B-CLL, but this is indirect evidence for T cell regulation. However, CTLA4 as a negative regulator of T cell activation is overwhelmingly supported by other evidence (PMID:11279501, PMID:11279502, CTLA4-deep-research-falcon.md). Reason: The annotation of CTLA4 to negative regulation of T cell activation is correct and represents a core function of CTLA4, even though this particular reference (PMID:17875758) provides only indirect evidence from CLL gene expression profiling. The function is strongly validated by structural studies (PMID:11279501, PMID:11279502) and extensive literature on CTLA4 as an immune checkpoint. Supporting Evidence: PMID:17875758 the overexpression of CTLA4 and MNDA was associated with good outcome
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: IDA for negative regulation of TCR signaling pathway. CTLA4 attenuates TCR signaling by competitively binding B7 ligands (PMID:11279501). The structural data shows how CTLA4/B7-2 network formation at the immunological synapse provides a mechanism for inhibiting TCR co-stimulation. Reason: Core function. CTLA4 directly modulates TCR signaling output by competing with CD28 for B7 ligand binding, as demonstrated by the crystal structure. Supporting Evidence: PMID:11279501 provides a model for the periodic organization of these molecules within the immunological synapse and suggests a distinct mechanism for signalling by dimeric cell-surface receptors
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: IDA for negative regulation of TCR signaling based on the CTLA4/B7-1 crystal structure. The formation of stable CTLA4-B7-1 complexes directly inhibits CD28-mediated co-stimulation of TCR signaling. Reason: Core function. Same reasoning as above; structural evidence demonstrates the mechanism for inhibiting TCR signaling. Supporting Evidence: PMID:11279502 CTLA-4 signalling attenuates it ... underscoring the importance of potent inhibitory signalling in human immune responses
GO:0005886 plasma membrane	TAS Reactome:R-HSA-388829	ACCEPT	Summary: TAS from Reactome pathway "SHP2 phosphatase binds CTLA-4" (R-HSA-388829). CTLA4 is at the plasma membrane where SHP-2 binds to its cytoplasmic tail. Well-supported. Reason: Correct localization. CTLA4 is a plasma membrane protein. Reactome annotation is consistent with extensive experimental evidence.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-388833	ACCEPT	Summary: TAS from Reactome pathway "Phosphorylation of CTLA-4" (R-HSA-388833). CTLA4 is phosphorylated at the plasma membrane. Reason: Correct localization. Consistent with other evidence.
GO:0005886 plasma membrane	IMP PMID:28484017 Structural basis for cancer immunotherapy by the first-in-cl...	ACCEPT	Summary: IMP for plasma membrane localization based on PMID:28484017 (Ramagopal et al. 2017). This study determined the crystal structure of ipilimumab bound to CTLA4 and performed cell-based binding assays with CTLA4 mutants, demonstrating CTLA4 expression at the cell surface (plasma membrane). Mutagenesis of surface residues affected B7 ligand binding. Reason: The cell-based binding assays using CTLA4 mutants confirm plasma membrane localization and surface expression. Supporting Evidence: PMID:28484017 The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants
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: IDA for protein complex involved in cell adhesion. PMID:7544393 (Fargeas et al. 1995) identified residues in the V domain of CD80 implicated in functional interactions with CD28 and CTLA4. CTLA4 does form complexes with B7 ligands at the cell surface in the immunological synapse, which could be considered cell adhesion-like. However, CTLA4 is fundamentally a signaling receptor rather than an adhesion molecule; its primary function is signal modulation rather than physical cell-cell adhesion. Reason: While CTLA4/B7 interactions occur at the T cell-APC interface, calling this "cell adhesion" is a stretch. CTLA4 functions primarily in signaling modulation rather than adhesion. The annotation may reflect CTLA4's participation in the immunological synapse, but the GO term is misleading for this protein's core function. Supporting Evidence: PMID:7544393 Two hydrophobic residues in the V-like domain of CD80 were identified as critical for binding to CD28 and are also important for the interaction with CTLA4
GO:0005886 plasma membrane	TAS Reactome:R-HSA-388809	ACCEPT	Summary: TAS from Reactome pathway "CTLA-4 binds B7-1/B7-2" (R-HSA-388809). CTLA4 binds B7 ligands at the plasma membrane. Reason: Correct localization consistent with all other evidence.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-389532	ACCEPT	Summary: TAS from Reactome pathway "PP2A binds CTLA4 dimer" (R-HSA-389532). PP2A interacts with CTLA4 at the plasma membrane. Reason: Correct localization consistent with all other evidence.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8877421	ACCEPT	Summary: TAS from Reactome pathway "CTLA4 gene expression is stimulated by FOXP3 and inhibited by RUNX1" (R-HSA-8877421). This Reactome entry describes transcriptional regulation of CTLA4 by FOXP3 in Tregs. Reason: Correct. CTLA4 protein is ultimately targeted to the plasma membrane. The Reactome annotation reflects CTLA4 as a membrane protein in the context of Treg biology.
GO:0006974 DNA damage response	IMP PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin...	UNDECIDED	Summary: IMP for DNA damage response based on PMID:17875758. This paper studied gene expression in CD38-high vs CD38-low B-CLL. The study found CTLA4 was differentially expressed and also examined ATM (a DNA damage response gene). However, the paper's focus was on gene expression profiling in CLL, and CTLA4 itself is not known to have a direct role in DNA damage response. The association appears to be correlative rather than functional. CTLA4 is not a DNA damage response gene -- it is an immune checkpoint receptor. Reason: CTLA4 has no known molecular role in DNA damage sensing, signaling, or repair, and the deep research report (CTLA4-deep-research-falcon.md) describes it exclusively as an immune checkpoint receptor. The annotation looks like a theme-transfer over-annotation from a CLL expression-profiling paper whose title foregrounds ATM (a DNA-damage gene). However, this is an experimental IMP and the cached publication is abstract-only (full text unavailable), so the full-text evidence the curator relied on cannot be verified. Per curation policy, an inaccessible experimental annotation is marked UNDECIDED rather than REMOVE. Supporting Evidence: PMID:17875758 Gene expression analysis identified 76 differentially expressed genes in CD38 high versus low groups. Out of these genes, HEM1, CTLA4, and MNDA were selected for further studies
GO:0030889 negative regulation of B cell proliferation	IMP PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin...	MARK AS OVER ANNOTATED	Summary: IMP for negative regulation of B cell proliferation. PMID:17875758 found CTLA4 overexpression was associated with good outcome in B-CLL (characterized by lower proliferative burden), and low CD38 CLL. However, this is a correlative observation from expression profiling rather than a direct functional assay showing CTLA4 negatively regulates B cell proliferation. CTLA4 is primarily a T cell receptor. Reason: The evidence from PMID:17875758 is correlative gene expression data from CLL, not a direct demonstration that CTLA4 negatively regulates B cell proliferation. While CTLA4 expression has been reported on some B cells, and its overexpression correlates with better outcomes in B-CLL, this does not establish a direct mechanistic role in B cell proliferation regulation. CTLA4's primary function is T cell co-inhibition. Supporting Evidence: PMID:17875758 the overexpression of CTLA4 and MNDA was associated with good outcome
GO:0043065 positive regulation of apoptotic process	IMP PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin...	MARK AS OVER ANNOTATED	Summary: IMP for positive regulation of apoptotic process. PMID:17875758 studied gene expression in B-CLL. The paper found CTLA4 overexpression associated with good clinical outcomes, which could imply pro-apoptotic effects in CLL cells, but this is a correlative association from expression profiling, not a direct apoptosis assay. Reason: The evidence from PMID:17875758 is correlative. CTLA4 is not a direct positive regulator of apoptosis. While CTLA4 signaling in T cells can lead to T cell anergy (which is distinct from apoptosis), and CTLA4 expression in CLL correlates with better outcomes, this does not establish a direct pro-apoptotic molecular function for CTLA4. Supporting Evidence: PMID:17875758 the overexpression of CTLA4 and MNDA was associated with good outcome ... genes that may be involved in cell proliferation and survival
GO:0050853 B cell receptor signaling pathway	IMP PMID:17875758 ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressin...	MARK AS OVER ANNOTATED	Summary: IMP for B cell receptor signaling pathway. PMID:17875758 studied CTLA4 expression in B-CLL cells, which have constitutive BCR signaling. However, the paper demonstrates differential CTLA4 expression in CLL, not a direct role of CTLA4 in BCR signaling. CTLA4 is a co-inhibitory receptor for TCR signaling, not BCR signaling. Reason: PMID:17875758 is a gene expression study in B-CLL that does not demonstrate a mechanistic role for CTLA4 in BCR signaling. CTLA4 is expressed on some B cells but its primary signaling role is in T cells (TCR/CD28 pathway). Supporting Evidence: PMID:17875758 Gene expression analysis identified 76 differentially expressed genes in CD38 high versus low groups
GO:0005794 Golgi apparatus	IDA PMID:15814706 Exocytosis of CTLA-4 is dependent on phospholipase D and ADP...	ACCEPT	Summary: IDA for Golgi apparatus localization. PMID:15814706 (Mead et al. 2005) showed that exocytosis of CTLA-4 is dependent on phospholipase D and ADP ribosylation factor-1, and is stimulated during activation of regulatory T cells. CTLA4 is known to traffic through the Golgi during biosynthesis and recycling. UniProt notes that CTLA4 exists primarily as an intracellular antigen with regulated trafficking. The deep research report (CTLA4-deep-research-falcon.md) confirms CTLA4 resides largely in intracellular vesicles at steady state. Reason: CTLA4 is a transmembrane glycoprotein that undergoes N-glycosylation (Asn-113, Asn-145) and traffics through the Golgi as part of its biosynthetic and recycling pathways. The annotation is consistent with known CTLA4 trafficking biology. Supporting Evidence: PMID:15814706 CTLA-4 was identified in a perinuclear compartment overlapping with the cis-Golgi marker GM-130 but did not colocalize strongly with lysosomal markers such as CD63 and lysosome-associated membrane protein
GO:0009897 external side of plasma membrane	IDA PMID:18641304 Acquisition of suppressive function by activated human CD4+ ...	ACCEPT	Summary: IDA for external side of plasma membrane. PMID:18641304 (Zheng et al. 2008) showed that activated CD4+CD25- T cells express CTLA4 on their surface and acquire suppressive function. Flow cytometry detection of surface CTLA4 demonstrates external plasma membrane localization. Reason: Direct experimental evidence for surface expression of CTLA4, detected by flow cytometry on activated T cells. Supporting Evidence: PMID:18641304 Acquisition of suppressive function by activated human CD4+ CD25- T cells is associated with the expression of CTLA-4 not FoxP3
GO:0045334 clathrin-coated endocytic vesicle	IDA PMID:15814706 Exocytosis of CTLA-4 is dependent on phospholipase D and ADP...	ACCEPT	Summary: IDA for clathrin-coated endocytic vesicle localization. CTLA4 is known to undergo constitutive clathrin-mediated endocytosis. Its cytoplasmic YVKM motif interacts with the AP-2 adaptor complex, and phosphorylation at Tyr-201 regulates this interaction (PMID:9175836). PMID:15814706 (Mead et al. 2005) studied CTLA4 exocytosis and trafficking in regulatory T cells. Reason: CTLA4 is constitutively endocytosed via clathrin-mediated endocytosis. The YVKM motif in the cytoplasmic tail binds AP-2, and its localization in clathrin-coated vesicles is well-established. This annotation is consistent with known CTLA4 trafficking biology. Supporting Evidence: PMID:15814706 expression of CTLA-4 at the plasma membrane (PM) is controlled by exocytosis of CTLA-4-containing vesicles and followed by rapid endocytosis
GO:0045590 negative regulation of regulatory T cell differentiation	IDA PMID:18641304 Acquisition of suppressive function by activated human CD4+ ...	ACCEPT	Summary: IDA for negative regulation of Treg differentiation. PMID:18641304 showed that CTLA4 expression (rather than FoxP3) is associated with acquisition of suppressive function by activated CD4+CD25- T cells, suggesting CTLA4 modulates the threshold for Treg-like function. Reason: Consistent with the IBA annotation for the same term. PMID:18641304 provides direct evidence that CTLA4 expression modulates T cell suppressive function and Treg differentiation. Supporting Evidence: PMID:18641304 Acquisition of suppressive function by activated human CD4+ CD25- T cells is associated with the expression of CTLA-4 not FoxP3
GO:0048471 perinuclear region of cytoplasm	IDA PMID:15814706 Exocytosis of CTLA-4 is dependent on phospholipase D and ADP...	ACCEPT	Summary: IDA for perinuclear region of cytoplasm localization. CTLA4 is known to accumulate in intracellular compartments, including the perinuclear region, at steady state due to constitutive endocytosis. UniProt notes CTLA4 "exists primarily as an intracellular antigen." PMID:15814706 (Mead et al. 2005) demonstrated CTLA4 trafficking and subcellular distribution in T cells. Reason: Consistent with known CTLA4 cell biology. At steady state, the majority of CTLA4 resides intracellularly in perinuclear vesicular compartments, with rapid endocytosis maintaining low surface expression. Supporting Evidence: PMID:15814706 CTLA-4 was identified in a perinuclear compartment overlapping with the cis-Golgi marker GM-130
GO:0005886 plasma membrane	TAS PMID:3220103 Human Ig superfamily CTLA-4 gene chromosomal localization an...	ACCEPT	Summary: TAS for plasma membrane localization from PMID:3220103 (Dariavach et al. 1988). This is the original paper that identified CTLA4 as a human Ig superfamily member and determined its chromosomal location. The sequence predicts a transmembrane protein localized to the plasma membrane. Reason: The original characterization paper identifying CTLA4 as a membrane protein. Consistent with all subsequent experimental evidence. Supporting Evidence: PMID:3220103 The first exon encodes a V-like domain of 116 amino acids, the second one a hydrophobic putative transmembrane region of 37 amino acids and the third one a 34 amino acid putative cytoplasmic domain
GO:0006955 immune response	TAS PMID:3220103 Human Ig superfamily CTLA-4 gene chromosomal localization an...	ACCEPT	Summary: TAS for immune response from PMID:3220103. The original characterization paper identifies CTLA4 as an Ig superfamily member expressed in lymphocytes, implying immune function. Reason: Broad but correct. CTLA4 is clearly involved in immune response. More specific terms provide detail. Supporting Evidence: PMID:3220103 The mouse CTLA-4 gene has been shown to code for an activated lymphocyte-associated sequence belonging to the Ig gene superfamily
GO:0030547 signaling receptor inhibitor activity	IDA PMID:11279501 Structural basis for co-stimulation by the human CTLA-4/B7-2...	NEW	Summary: CTLA4 functions as an inhibitor of CD28 signaling receptor activity by competitively binding B7 ligands (CD80/CD86) with higher avidity, preventing CD28 from receiving co-stimulatory signals. This is a core molecular function. GO:0030547 is defined as "Binds to and modulates the activity of a signaling receptor" -- CTLA4 modulates CD28 activity by sequestering its ligands. Reason: This molecular function term more accurately describes how CTLA4 functionally inhibits CD28 signaling. While receptor decoy activity (GO:0140319) captures the ligand sequestration, signaling receptor inhibitor activity captures the functional consequence on CD28. Together these provide a more complete picture of CTLA4 molecular function than the generic "protein binding" annotations currently in place. Supporting Evidence: PMID:11279501 Engagement of CD28 with B7-1 and B7-2 ligands on antigen-presenting cells (APCs) provides a stimulatory signal for T-cell activation, whereas subsequent engagement of CTLA-4 with these same ligands results in attenuation of the response PMID:11279502 Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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