IL2RA (CD25, p55, TAC antigen) encodes the alpha subunit of the interleukin-2 receptor. IL2RA is a type I transmembrane glycoprotein containing two Sushi/CCP (complement control protein) domains in its extracellular region. It binds IL-2 with low affinity (Kd ~10 nM) on its own, but its primary role is to capture IL-2 and present it to the signaling-competent IL-2Rbeta/gammac heterodimer, thereby forming the high-affinity trimeric receptor complex (Kd ~10 pM). IL2RA itself has a very short cytoplasmic tail (13 residues) and does not directly transduce signals. It is constitutively expressed on FOXP3+ regulatory T cells (Tregs) and is induced on activated conventional T cells. By enabling Tregs to respond to very low concentrations of IL-2, IL2RA is critical for immune tolerance and T cell homeostasis. Loss-of-function mutations cause immunodeficiency with lymphoproliferation and autoimmunity (IMD41), and common variants at the IL2RA locus are associated with type 1 diabetes and multiple sclerosis susceptibility.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006954 inflammatory response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation to inflammatory response based on phylogenetic inference. IL2RA is part of the IL-2 signaling axis that regulates immune responses, and loss of CD25 leads to autoimmune inflammatory disease (PMID:23416241, PMID:9096364). However, IL2RA itself is a receptor subunit rather than a direct inflammatory mediator. The inflammatory phenotype arises indirectly from loss of immune tolerance. The IBA annotation is at an appropriate level of generality given that IL-2 signaling through this receptor modulates inflammatory processes. Reason: IL2RA participates in inflammatory response indirectly by controlling IL-2 signaling and Treg function. Loss of CD25 leads to severe inflammation and autoimmunity (PMID:23416241), confirming involvement. However, this is not the core molecular function of IL2RA; it is a downstream consequence of its receptor role. The IBA annotation is phylogenetically supported and reasonable as a non-core annotation. Supporting Evidence: PMID:23416241 The chronic effect of this mutation led to the development of progressive manifestations of both autoimmunity, such as enteropathy, erythrodermia and severe alopecia, and immunodeficiency with chronic CMV infection. PMID:9096364 Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation. |
| GO:0019976 interleukin-2 binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for interleukin-2 binding based on phylogenetic inference. This is a well-established core function of IL2RA. The crystal structure of the quaternary complex (PMID:16293754, PMID:16477002) shows IL2RA forms the largest interface with IL-2 among the three receptor chains, consistent with its role in initial IL-2 capture. IL2RA alone binds IL-2 with ~10 nM affinity. Reason: IL-2 binding is the primary molecular function of IL2RA. Structural studies demonstrate extensive direct contacts between IL2RA and IL-2 (PMID:16477002, PMID:16293754). The IBA annotation is accurate and well-supported. Supporting Evidence: PMID:16477002 The IL-2R alpha subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2R alpha with IL-2 at the cell surface. PMID:16293754 the binding of IL-2Ralpha to IL-2 stabilizes a secondary binding site for presentation to IL-2Rbeta. |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProtKB keyword mapping (Immunity). IL2RA is clearly an immune system component. This is a very broad term that is subsumed by more specific annotations already present. Reason: Correct but very general. IL2RA is unambiguously involved in immune system processes. This broad IEA annotation is acceptable as a general umbrella even though more specific annotations exist. |
| GO:0002682 regulation of immune system process | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation from ARBA model. IL2RA is central to the regulation of immune responses through its role in the IL-2 receptor complex. It controls Treg function and effector T cell expansion, which are key immune regulatory processes (PMID:23416241). Reason: Appropriate general annotation. IL2RA is a key regulator of immune system processes through its role in IL-2 signaling and Treg homeostasis. More specific annotations exist (e.g., regulation of T cell tolerance induction), so this broader term is also acceptable. Supporting Evidence: PMID:23416241 In conclusion, we show that CD25 expression is required to maintain immune homeostasis, and CD25 deficiency is a distinct immunological disease that leads to both an autoimmune and immunodeficiency syndrome that clinically resembles IPEX syndrome. |
| GO:0004911 interleukin-2 receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for IL-2 receptor activity from combined automated methods. This is a core function of IL2RA. Note that IL2RA contributes_to this activity as part of the trimeric complex, since the alpha chain alone does not transduce signal. Reason: Correct. IL2RA is an essential component of the IL-2 receptor complex. This IEA annotation is concordant with the IDA and IMP annotations for the same term. |
| GO:0005886 plasma membrane | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation for plasma membrane localization from ARBA. IL2RA is a type I transmembrane protein that functions at the plasma membrane (UniProt: Membrane; Single-pass type I membrane protein). Reason: Correct. IL2RA is a well-established plasma membrane protein. This is concordant with multiple other annotations for the same term from different evidence codes. |
| GO:0006915 apoptotic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IEA annotation for apoptotic process from ARBA. IL-2 signaling through the IL-2 receptor can influence apoptosis (IL-2 withdrawal leads to apoptosis; CD25 deficiency affects bcl-2 expression in thymocytes per PMID:9096364). However, IL2RA is not a direct apoptosis regulator; its connection to apoptosis is indirect through modulation of IL-2 signaling strength. Reason: IL2RA does not directly regulate apoptosis. The connection is indirect: IL-2 signaling promotes survival via STAT5/bcl-2, and its withdrawal can lead to apoptosis. The CD25-deficient patient thymocytes showed altered bcl-2 levels (PMID:9096364), but this is a downstream consequence of impaired IL-2 signaling, not a direct function of IL2RA. This is an over-annotation of a pleiotropic downstream effect. Supporting Evidence: PMID:9096364 CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2. |
| GO:0006955 immune response | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation for immune response from ARBA. IL2RA is clearly involved in immune responses as a component of the IL-2 receptor on T cells and other immune cells. Reason: Correct general annotation. IL2RA is an integral part of the immune response machinery. This is broader than the more specific annotations but acceptable. |
| GO:0016020 membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: IEA annotation for membrane localization from UniProtKB subcellular location mapping. IL2RA is a transmembrane protein. This is a very generic CC annotation; more specific plasma membrane annotations exist. Reason: Correct but very generic, and wholly subsumed by the more specific plasma membrane annotations the gene already carries. [2026-08 SL project re-review] Uninformative parent from the UniProt subcellular-location pipeline. The sole source for this annotation is GO_REF:0000044 (UniProtKB-SubCell), and the gene already carries strictly more specific term(s) from independent evidence, namely GO:0005893 interleukin-2 receptor complex (TAS), GO:0009897 external side of plasma membrane, and GO:0005886 plasma membrane. The term is not false; it is an under-specified location that adds no information over what is already annotated, which is the dominant failure mode of the SL pipeline (see projects/SL.md). Marked over-annotated rather than MODIFY because the more precise term is already present, so there is nothing to replace it with. |
| GO:0019976 interleukin-2 binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for interleukin-2 binding from combined automated methods. Duplicate of the IBA annotation for the same GO term. IL-2 binding is a well-established core function of IL2RA. Reason: Correct. IL2RA directly binds IL-2. This IEA annotation is concordant with the IBA annotation. Duplicate GO IDs from different evidence sources are acceptable. |
| GO:0005515 protein binding | IPI PMID:16477002 Crystal structure of the IL-2 signaling complex: paradigm fo... | MODIFY | Summary: IPI annotation for protein binding based on the crystal structure of the IL-2 signaling complex (PMID:16477002). The interacting partner is IL-2 (UniProtKB:P60568). While the physical interaction is real and demonstrated by crystallography, the term 'protein binding' is uninformative. The more specific term 'interleukin-2 binding' (GO:0019976) already captures this interaction more precisely. Reason: The term 'protein binding' is uninformative per curation guidelines. The crystal structure demonstrates direct IL2RA:IL-2 binding (PMID:16477002), which is better captured by GO:0019976 (interleukin-2 binding). The with/from column shows UniProtKB:P60568 (IL-2), confirming the specific interaction. Proposed replacements: interleukin-2 binding Supporting Evidence: PMID:16477002 IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2R alpha, IL-2R beta, and gamma(c). Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 A resolution. |
| GO:0005515 protein binding | IPI PMID:17032757 Hot-spot mimicry of a cytokine receptor by a small molecule. | MODIFY | Summary: IPI annotation for protein binding based on PMID:17032757 (Thanos et al. 2006), which describes a small molecule (SP4206) that mimics IL2RA in binding IL-2. The with/from column indicates UniProtKB:P60568 (IL-2). This study indirectly demonstrates IL2RA-IL-2 interaction by showing a small molecule mimics IL2RA hot-spot contacts on IL-2. Again, 'protein binding' is uninformative. Reason: Same issue as above: 'protein binding' is too generic. The underlying interaction is IL2RA binding to IL-2, better captured by GO:0019976. PMID:17032757 validates the IL2RA:IL-2 binding interface through small molecule mimicry studies. Proposed replacements: interleukin-2 binding Supporting Evidence: PMID:17032757 a high-affinity small molecule, SP4206 (Kd approximately 70 nM), was found to block binding of the IL-2alpha receptor (IL-2Ralpha) to IL-2 (Kd approximately 10 nM). |
| GO:0002437 inflammatory response to antigenic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA annotation from Ensembl Compara ortholog transfer (rat IL2RA). IL2RA is involved in immune responses including inflammation following antigenic stimulation. However, this is an overly specific downstream biological process; IL2RA does not directly mediate inflammatory responses to antigens. Its role is in modulating IL-2 signaling sensitivity, which indirectly affects inflammatory outcomes. Reason: IL2RA does not directly drive inflammatory responses to antigenic stimuli. Its role is to capture IL-2 and form the high-affinity receptor. Inflammatory consequences are downstream and indirect. This term is too specific for the actual role of IL2RA. |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara ortholog transfer (mouse IL2RA). IL2RA is a type I transmembrane protein with its Sushi/CCP domains exposed on the external side of the plasma membrane, where it captures IL-2. This is accurate and more specific than the generic plasma membrane annotation. Reason: Correct and more informative than generic plasma membrane. The IL-2 binding domain of IL2RA (extracellular region, residues 22-240) is on the external side of the plasma membrane (UniProt topology annotation). |
| GO:0009986 cell surface | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara ortholog transfer (rat IL2RA). IL2RA is well-established as a cell surface receptor, detectable by flow cytometry with anti-CD25 antibodies on T cells and other immune cells (PMID:23416241). Reason: Correct. IL2RA/CD25 is a canonical cell surface marker widely used in immunology. Supporting Evidence: PMID:23416241 Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. |
| GO:0042102 positive regulation of T cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer (rat IL2RA). IL2RA enables high-affinity IL-2 signaling, which drives T cell proliferation. PMID:22446627 demonstrates that CD25 expression enhances IL-2-driven T cell proliferation, and PMID:23416241 shows CD25-null T cells have impaired proliferative responses. Reason: IL2RA contributes to T cell proliferation by enabling high-affinity IL-2 signaling. However, this is a downstream biological consequence rather than the core molecular function. The CD25-null patient study shows impaired polyclonal proliferative responses (PMID:23416241), confirming IL2RA's role, but the proliferative effect is mediated by IL2RB/IL2RG signaling. Supporting Evidence: PMID:23416241 The patient's PBMCs had poor in vitro proliferation response to TCR-mediated activation compared to healthy controls (Fig PMID:22446627 The principle functional effect of IL-2 is to promote T cell proliferation, particularly for naïve T cells. |
| GO:0045582 positive regulation of T cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer (rat IL2RA). IL2RA/CD25 promotes Treg differentiation and maintenance by enabling high-affinity IL-2 signaling, which drives STAT5-dependent FOXP3 transcription. The deep research review confirms that CD25 expression determines which cells respond to low IL-2 levels and differentiate appropriately. Reason: IL2RA contributes to T cell differentiation (especially Treg differentiation) by enabling high-affinity IL-2 signaling. However, differentiation is a downstream process mediated by intracellular signaling through IL2RB/IL2RG, not directly by IL2RA. This is a biologically important but non-core function. |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | NAS PMID:22446627 Exploiting a natural conformational switch to engineer an in... | KEEP AS NON CORE | Summary: NAS annotation for JAK-STAT signaling from ComplexPortal, citing the IL-2 superkine paper (PMID:22446627). IL-2 signaling through the trimeric receptor activates JAK1/JAK3 and STAT5. While IL2RA contributes to this pathway by forming the high-affinity receptor, it does not itself signal via JAK-STAT; the signaling is mediated by IL2RB and IL2RG (which bind JAK1 and JAK3 respectively). Reason: IL2RA participates in the IL-2 receptor complex that signals via JAK-STAT, but JAK-STAT signaling is transduced by IL2RB (JAK1) and IL2RG (JAK3), not by IL2RA. IL2RA's 13-residue cytoplasmic tail has no signaling capacity. This annotation is acceptable as a non-core annotation since IL2RA is part of the complex, but the signaling itself is not a direct function of IL2RA. Supporting Evidence: PMID:22446627 On activated T cells, IL-2 signals through a quaternary 'high affinity' receptor complex consisting of IL-2, IL-2Ralpha (termed CD25), IL-2Rbeta and IL-2Rgamma. |
| GO:0038110 interleukin-2-mediated signaling pathway | NAS PMID:22446627 Exploiting a natural conformational switch to engineer an in... | ACCEPT | Summary: NAS annotation for IL-2-mediated signaling pathway from ComplexPortal, citing PMID:22446627. IL2RA is essential for high-affinity IL-2 signaling by forming the trimeric receptor complex. The superkine study demonstrates that CD25 expression determines cell sensitivity to IL-2 signaling. Reason: IL2RA is a critical component of the IL-2 signaling pathway. Without CD25, cells respond only to high IL-2 concentrations via the intermediate-affinity IL2RB/IL2RG receptor. This annotation is a core function of IL2RA. Supporting Evidence: PMID:22446627 Naive T cells express only a low density of IL-2Rbeta and IL-2Rgamma, and are therefore relatively insensitive to IL-2, but acquire sensitivity after CD25 expression, which captures the cytokine and presents it to IL-2Rbeta and IL-2Rgamma. |
| GO:0070665 positive regulation of leukocyte proliferation | NAS PMID:22446627 Exploiting a natural conformational switch to engineer an in... | KEEP AS NON CORE | Summary: NAS annotation for positive regulation of leukocyte proliferation from ComplexPortal. IL2RA enables high-affinity IL-2 signaling that drives T cell and other leukocyte proliferation. This is a broader parent term of T cell proliferation. Reason: This is a biologically relevant but broad downstream consequence of IL2RA function. By forming the high-affinity IL-2 receptor, IL2RA enables IL-2-driven proliferation of leukocytes. However, proliferation is mediated by intracellular signaling through IL2RB/IL2RG, not directly by IL2RA. Acceptable as non-core. Supporting Evidence: PMID:22446627 The principle functional effect of IL-2 is to promote T cell proliferation, particularly for naïve T cells. |
| GO:1902107 positive regulation of leukocyte differentiation | NAS PMID:16477002 Crystal structure of the IL-2 signaling complex: paradigm fo... | KEEP AS NON CORE | Summary: NAS annotation for positive regulation of leukocyte differentiation from ComplexPortal, citing the crystal structure paper. IL2RA contributes to leukocyte differentiation through enabling high-affinity IL-2 signaling, which drives differentiation programs including Treg differentiation. Reason: Similar to the proliferation annotation: IL2RA contributes indirectly to differentiation by enabling high-affinity signaling. The differentiation programs are driven by downstream STAT5/PI3K/MAPK signaling, not by IL2RA directly. Acceptable as non-core. Supporting Evidence: PMID:16477002 IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2R alpha, IL-2R beta, and gamma(c). |
| GO:0004911 interleukin-2 receptor activity | IDA PMID:16293754 Structure of the quaternary complex of interleukin-2 with it... | ACCEPT | Summary: IDA annotation for IL-2 receptor activity based on the crystal structure of the quaternary IL-2 receptor complex (Wang et al. 2005, Science). This 2.3 angstrom structure shows IL2RA in complex with IL-2, IL2RB, and IL2RG, demonstrating that IL2RA binding to IL-2 stabilizes a secondary binding site for IL2RB presentation, and that IL2RA makes no direct contacts with IL2RB or IL2RG. Reason: This is a core function of IL2RA, directly demonstrated by structural analysis at 2.3 angstrom resolution. IL2RA is an integral component of the IL-2 receptor. Supporting Evidence: PMID:16293754 Interleukin-2 (IL-2) is an immunoregulatory cytokine that acts through a quaternary receptor signaling complex containing alpha (IL-2Ralpha), beta (IL-2Rbeta), and common gamma chain (gc) receptors. |
| GO:0005886 plasma membrane | IC PMID:16293754 Structure of the quaternary complex of interleukin-2 with it... | ACCEPT | Summary: IC annotation for plasma membrane localization inferred from the crystal structure of the IL-2 receptor ectodomain complex (PMID:16293754). IL2RA is a type I transmembrane protein that functions at the plasma membrane. Reason: Correct. IL2RA is a single-pass type I transmembrane protein localized to the plasma membrane (UniProt subcellular location annotation). Supporting Evidence: PMID:16293754 Interleukin-2 (IL-2) is an immunoregulatory cytokine that acts through a quaternary receptor signaling complex containing alpha (IL-2Ralpha), beta (IL-2Rbeta), and common gamma chain (gc) receptors. |
| GO:0038110 interleukin-2-mediated signaling pathway | IDA PMID:16293754 Structure of the quaternary complex of interleukin-2 with it... | ACCEPT | Summary: IDA annotation for involvement in the IL-2-mediated signaling pathway based on the quaternary receptor structure (PMID:16293754). The structure demonstrates how IL2RA captures IL-2 and facilitates assembly of the signaling complex. Reason: Core function. IL2RA is essential for high-affinity IL-2 signaling. The crystal structure demonstrates the molecular mechanism of receptor assembly. Supporting Evidence: PMID:16293754 the binding of IL-2Ralpha to IL-2 stabilizes a secondary binding site for presentation to IL-2Rbeta. gammac is then recruited to the composite surface formed by the IL-2/IL-2Rbeta complex. |
| GO:0004911 interleukin-2 receptor activity | IMP PMID:2467293 Characterization of the interleukin 2 receptor beta chain us... | ACCEPT | Summary: IMP annotation with contributes_to qualifier for IL-2 receptor activity, based on Tsudo et al. 1989 (PMID:2467293). This paper characterizes the IL-2 receptor beta chain and demonstrates that the alpha chain (p55/IL2RA) contributes to high-affinity IL-2 binding. Blocking the beta chain with Mik-beta 1 antibody completely abolished high-affinity IL-2 binding, showing both chains are required. Reason: The contributes_to qualifier is appropriate because IL2RA alone does not constitute the full receptor activity -- it requires IL2RB and IL2RG for signal transduction. The IMP evidence from this foundational paper is valid. Supporting Evidence: PMID:2467293 The human high-affinity receptor for interleukin 2 (IL-2) has been proposed as being a membrane complex composed of at least two distinct polypeptide chains: p55 (alpha chain), recognized by the anti-Tac monoclonal antibody (mAb), and p75 (beta chain), both of which are capable of binding IL-2. Whereas the alpha chain itself has been shown to be nonfunctional, the beta chain appears to be pivotal in the IL-2 signal transduction, although the beta chain is otherwise poorly characterized. |
| GO:0005893 interleukin-2 receptor complex | TAS PMID:2467293 Characterization of the interleukin 2 receptor beta chain us... | ACCEPT | Summary: TAS annotation for IL-2 receptor complex membership, based on Tsudo et al. 1989 (PMID:2467293). IL2RA (p55) is a well-established component of the IL-2 receptor complex, forming the high-affinity trimeric receptor with IL2RB and IL2RG. Reason: Core annotation. IL2RA is unambiguously a component of the IL-2 receptor complex. This is directly demonstrated by coprecipitation, crosslinking, and structural studies. Supporting Evidence: PMID:2467293 These results clearly indicate that the beta chain is an indispensable component to the high-affinity IL-2 receptor and is responsible for the IL-2 signal transduction. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-450027 | ACCEPT | Summary: TAS annotation from Reactome reaction R-HSA-450027 (IL2RA:IL2 binds IL2RB). IL2RA is at the plasma membrane during IL-2 receptor complex assembly. Reason: Correct. IL2RA functions at the plasma membrane. Reactome correctly places it there for IL-2 signaling. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-450054 | ACCEPT | Summary: TAS annotation from Reactome reaction R-HSA-450054 (IL2RA binds IL-2). IL2RA captures IL-2 at the plasma membrane. Reason: Correct. This is the primary event in IL-2 receptor assembly at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-450063 | ACCEPT | Summary: TAS annotation from Reactome reaction R-HSA-450063 (IL2:IL2RA:IL2RB binds IL2RG). IL2RA is at the plasma membrane as the trimeric complex assembles. Reason: Correct. IL2RA functions at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-451942 | ACCEPT | Summary: TAS annotation from Reactome reaction R-HSA-451942 (JAK3 phosphorylates JAK1 within the IL-2R complex). IL2RA is a component of this complex at the plasma membrane. Reason: Correct. IL2RA is part of the signaling complex at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-452091 | ACCEPT | Summary: TAS annotation from Reactome (IL2RB Y338 phosphorylation enables SHC recruitment). IL2RA is part of the receptor complex at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein participating in these signaling events. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-452097 | ACCEPT | Summary: TAS annotation from Reactome (STAT5 phosphorylation at the IL-2 receptor complex). IL2RA is part of the complex at the plasma membrane. Reason: Correct. IL2RA is at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-452100 | ACCEPT | Summary: TAS annotation from Reactome (SHC1 phosphorylation at the IL2 receptor). IL2RA is at the plasma membrane. Reason: Correct. IL2RA functions at the plasma membrane as part of the signaling complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-452108 | ACCEPT | Summary: TAS annotation from Reactome (IL2RB phosphorylation enables STAT recruitment). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane component of the IL-2 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-452122 | ACCEPT | Summary: TAS annotation from Reactome (JAK1 phosphorylates IL2RB). IL2RA is at the plasma membrane. Reason: Correct. IL2RA functions at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-453104 | ACCEPT | Summary: TAS annotation from Reactome (phosphorylated SHC1 recruits GRB2:GAB2). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-453111 | ACCEPT | Summary: TAS annotation from Reactome (phosphorylated SHC recruits GRB2:SOS1). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-508247 | ACCEPT | Summary: TAS annotation from Reactome (Gab2 binds p85 of PI3K). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-508282 | ACCEPT | Summary: TAS annotation from Reactome (SYK is a substrate for JAK1). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-508292 | ACCEPT | Summary: TAS annotation from Reactome (SYK binds IL2RB). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5672965 | ACCEPT | Summary: TAS annotation from Reactome (RAS GEFs promote RAS nucleotide exchange). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8877396 | ACCEPT | Summary: TAS annotation from Reactome (IL2RA gene expression regulation by FOXP3/RUNX1). This Reactome entry concerns transcriptional regulation of IL2RA itself, not its localization. The plasma membrane annotation is still correct for the IL2RA protein. Reason: Correct. IL2RA protein is at the plasma membrane regardless of the specific Reactome reaction annotated. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-912527 | ACCEPT | Summary: TAS annotation from Reactome (SHC1 mediates cytokine-induced GAB2 phosphorylation). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-913374 | ACCEPT | Summary: TAS annotation from Reactome (phosphorylated SHC1 recruits SHIP). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-913424 | ACCEPT | Summary: TAS annotation from Reactome (SHC1:SHIP1 complex stabilized by GRB2). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-919404 | ACCEPT | Summary: TAS annotation from Reactome (phosphorylated STAT5 is released). IL2RA is at the plasma membrane. Reason: Correct. IL2RA is a plasma membrane protein. |
| GO:0002664 regulation of T cell tolerance induction | IMP PMID:23416241 Human IL2RA null mutation mediates immunodeficiency with lym... | ACCEPT | Summary: IMP annotation for regulation of T cell tolerance induction based on the study of a human IL2RA null mutation (PMID:23416241, Goudy et al. 2013). The CD25-deficient patient developed severe autoimmunity (enteropathy, erythrodermia) with impaired immune tolerance, demonstrating that IL2RA is required for proper T cell tolerance induction. The study shows that loss of CD25 surface expression results in impaired Treg function and failure to maintain immune homeostasis. Reason: This is a well-supported annotation from a detailed human genetic study. The IMP evidence from a CD25-null patient directly demonstrates that IL2RA is required for immune tolerance. Loss of CD25 leads to immunodeficiency with autoimmunity, consistent with IL2RA's role in Treg homeostasis and tolerance induction. Supporting Evidence: PMID:23416241 we show that CD25 expression is required to maintain immune homeostasis, and CD25 deficiency is a distinct immunological disease that leads to both an autoimmune and immunodeficiency syndrome that clinically resembles IPEX syndrome. PMID:23416241 IL-2 consumption by FOXP3+ Tregs is a critical event to maintain the homeostasis of the immune system, and the loss of CD25 surface expression by FOXP3+ Tregs in CD25 deficient patients is likely a contributing factor in the preferential CD8+ T cell proliferation, which are the mediators of autoimmunity. |
| GO:0004911 interleukin-2 receptor activity | TAS PMID:9096364 Human immune disorder arising from mutation of the alpha cha... | ACCEPT | Summary: TAS annotation for IL-2 receptor activity citing the first report of human CD25 deficiency (Sharfe et al. 1997, PMID:9096364). This paper describes a truncation mutation of IL2RA causing immunodeficiency, confirming IL2RA is a functional component of the IL-2 receptor in humans. Reason: Core function. IL2RA is the alpha subunit of the IL-2 receptor. PMID:9096364 provides human genetic evidence demonstrating its essential role. Supporting Evidence: PMID:9096364 We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2. |
| GO:0005886 plasma membrane | TAS PMID:2467293 Characterization of the interleukin 2 receptor beta chain us... | ACCEPT | Summary: TAS annotation for plasma membrane localization citing Tsudo et al. 1989 (PMID:2467293). The paper studies IL-2 binding at the cell surface and describes the alpha chain (p55) as a membrane receptor component. Reason: Correct. IL2RA is a plasma membrane protein. This paper identifies IL2RA (p55) as recognized by the anti-Tac mAb on the cell surface. Supporting Evidence: PMID:2467293 p55 (alpha chain), recognized by the anti-Tac monoclonal antibody (mAb) |
| GO:0005886 plasma membrane | TAS PMID:2983318 Interleukin 2 regulates its own receptors. | ACCEPT | Summary: TAS annotation for plasma membrane localization citing Smith and Cantrell 1985 (PMID:2983318). This early paper on IL-2 receptor biology describes IL-2 binding sites and Tac antigen at the cell surface, confirming plasma membrane localization. Reason: Correct. IL2RA (Tac antigen) is at the plasma membrane. Supporting Evidence: PMID:2983318 The cell surface density of high-affinity membrane receptors for the T-lymphocytotrophic hormone interleukin 2 (IL-2) determines the rate of T-cell-cycle progression. |
| GO:0006915 apoptotic process | TAS PMID:9096364 Human immune disorder arising from mutation of the alpha cha... | MARK AS OVER ANNOTATED | Summary: TAS annotation for apoptotic process citing PMID:9096364. This paper reports that CD25-deficient thymocytes fail to normally down-regulate bcl-2, suggesting altered apoptotic regulation. However, the direct role of IL2RA in apoptosis is indirect -- it is a consequence of impaired IL-2 signaling affecting survival signals. Reason: IL2RA does not directly regulate apoptosis. The altered bcl-2 expression in CD25-null thymocytes (PMID:9096364) reflects impaired IL-2 signaling rather than a direct apoptotic function of IL2RA. The apoptosis connection is a downstream pleiotropic effect. Supporting Evidence: PMID:9096364 CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2. |
| GO:0006955 immune response | TAS PMID:9096364 Human immune disorder arising from mutation of the alpha cha... | ACCEPT | Summary: TAS annotation for immune response citing PMID:9096364. IL2RA is clearly involved in immune responses as a component of the IL-2 receptor. The CD25-deficient patient showed profound cellular immunodeficiency. Reason: Correct. IL2RA is essential for normal immune responses. CD25 deficiency causes immunodeficiency (PMID:9096364). Supporting Evidence: PMID:9096364 Profound cellular immunodeficiency occurs as the result of mutations in proteins involved in both the differentiation and function of mature lymphoid cells. |
| GO:0007166 cell surface receptor signaling pathway | TAS PMID:2983318 Interleukin 2 regulates its own receptors. | ACCEPT | Summary: TAS annotation for cell surface receptor signaling pathway citing Smith and Cantrell 1985 (PMID:2983318). IL2RA participates in cell surface receptor signaling as part of the IL-2 receptor complex. This is a very broad annotation; more specific terms exist (IL-2-mediated signaling pathway, JAK-STAT signaling). Reason: Correct but very general. IL2RA is part of the IL-2 receptor signaling pathway at the cell surface. More specific annotations already capture this (GO:0038110, GO:0007259). This broad IEA-level annotation is acceptable. Supporting Evidence: PMID:2983318 IL-2-receptor interactions actually promote the loss of IL-2 responsiveness by diminishing the density of high-affinity binding sites at the time that Tac antigen levels are increased. |
| GO:0030159 signaling receptor complex adaptor activity | IDA PMID:16477002 Crystal structure of the IL-2 signaling complex: paradigm fo... | NEW | Summary: IL2RA functions as a signaling receptor complex adaptor: it binds IL-2 and presents it to IL2RB/IL2RG to form the signaling-competent complex. The crystal structure (PMID:16477002) shows IL2RA makes no contacts with IL2RB or IL2RG; its role is to capture IL-2 and deliver it to the signaling subunits. This adaptor/presentation role is a key aspect of IL2RA function not captured by other annotations. Reason: The current annotations do not capture IL2RA's specific role as a non-signaling adaptor that assembles the signaling complex. GO:0030159 (signaling receptor complex adaptor activity) describes the physical support role that IL2RA plays in assembling the IL-2 signaling complex. The crystal structure demonstrates that IL2RA makes no contacts with IL2RB or IL2RG, confirming its role as a ligand-capture and presentation module rather than a signaling subunit. Supporting Evidence: PMID:16477002 IL-2R alpha makes no contacts with IL-2R beta or gamma(c), and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2R alpha to deliver IL-2 to the signaling complex and act as regulator of signal transduction. PMID:16293754 the binding of IL-2Ralpha to IL-2 stabilizes a secondary binding site for presentation to IL-2Rbeta. |
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