IL2RA

id: P01589
gene_symbol: IL2RA
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
- term:
    id: GO:0006954
    label: inflammatory response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:23416241
      supporting_text: 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.
    - reference_id: PMID:9096364
      supporting_text: Extensive lymphocytic infiltration of tissues, including lung,
        liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation.
- term:
    id: GO:0019976
    label: interleukin-2 binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:16477002
      supporting_text: 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.
    - reference_id: PMID:16293754
      supporting_text: the binding of IL-2Ralpha to IL-2 stabilizes a secondary binding
        site for presentation to IL-2Rbeta.
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0002682
    label: regulation of immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:23416241
      supporting_text: 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.
- term:
    id: GO:0004911
    label: interleukin-2 receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).'
    action: ACCEPT
    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.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.'
    supported_by:
    - reference_id: PMID:9096364
      supporting_text: CD25-deficient cortical thymocytes do not express CD1, and
        furthermore they fail to normally down-regulate levels of the anti-apoptotic
        protein bcl-2.
- term:
    id: GO:0006955
    label: immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    reason: Correct general annotation. IL2RA is an integral part of the immune response
      machinery. This is broader than the more specific annotations but acceptable.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    reason: Correct but very generic. Subsumed by the more specific plasma membrane
      annotations. Acceptable as an IEA.
- term:
    id: GO:0019976
    label: interleukin-2 binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16477002
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0019976
      label: interleukin-2 binding
    supported_by:
    - reference_id: PMID:16477002
      supporting_text: 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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17032757
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0019976
      label: interleukin-2 binding
    supported_by:
    - reference_id: PMID:17032757
      supporting_text: 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).
- term:
    id: GO:0002437
    label: inflammatory response to antigenic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: ACCEPT
    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).
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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).
    action: ACCEPT
    reason: Correct. IL2RA/CD25 is a canonical cell surface marker widely used in
      immunology.
    supported_by:
    - reference_id: PMID:23416241
      supporting_text: Cell-surface CD25 expression is critical for maintaining immune
        function and homeostasis.
- term:
    id: GO:0042102
    label: positive regulation of T cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:23416241
      supporting_text: The patient's PBMCs had poor in vitro proliferation response
        to TCR-mediated activation compared to healthy controls (Fig
    - reference_id: PMID:22446627
      supporting_text: The principle functional effect of IL-2 is to promote T cell
        proliferation, particularly for naïve T cells.
- term:
    id: GO:0045582
    label: positive regulation of T cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: NAS
  original_reference_id: PMID:22446627
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:22446627
      supporting_text: 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.
- term:
    id: GO:0038110
    label: interleukin-2-mediated signaling pathway
  evidence_type: NAS
  original_reference_id: PMID:22446627
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22446627
      supporting_text: 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.
- term:
    id: GO:0070665
    label: positive regulation of leukocyte proliferation
  evidence_type: NAS
  original_reference_id: PMID:22446627
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:22446627
      supporting_text: The principle functional effect of IL-2 is to promote T cell
        proliferation, particularly for naïve T cells.
- term:
    id: GO:1902107
    label: positive regulation of leukocyte differentiation
  evidence_type: NAS
  original_reference_id: PMID:16477002
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.'
    supported_by:
    - reference_id: PMID:16477002
      supporting_text: 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).
- term:
    id: GO:0004911
    label: interleukin-2 receptor activity
  evidence_type: IDA
  original_reference_id: PMID:16293754
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:16293754
      supporting_text: 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.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IC
  original_reference_id: PMID:16293754
  review:
    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.
    action: ACCEPT
    reason: Correct. IL2RA is a single-pass type I transmembrane protein localized
      to the plasma membrane (UniProt subcellular location annotation).
    supported_by:
    - reference_id: PMID:16293754
      supporting_text: 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.
- term:
    id: GO:0038110
    label: interleukin-2-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:16293754
  review:
    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.
    action: ACCEPT
    reason: Core function. IL2RA is essential for high-affinity IL-2 signaling. The
      crystal structure demonstrates the molecular mechanism of receptor assembly.
    supported_by:
    - reference_id: PMID:16293754
      supporting_text: 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.
- term:
    id: GO:0004911
    label: interleukin-2 receptor activity
  evidence_type: IMP
  original_reference_id: PMID:2467293
  qualifier: contributes_to
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:2467293
      supporting_text: '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.'
- term:
    id: GO:0005893
    label: interleukin-2 receptor complex
  evidence_type: TAS
  original_reference_id: PMID:2467293
  review:
    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.
    action: ACCEPT
    reason: Core annotation. IL2RA is unambiguously a component of the IL-2 receptor
      complex. This is directly demonstrated by coprecipitation, crosslinking, and
      structural studies.
    supported_by:
    - reference_id: PMID:2467293
      supporting_text: 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.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-450027
  review:
    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.
    action: ACCEPT
    reason: Correct. IL2RA functions at the plasma membrane. Reactome correctly places
      it there for IL-2 signaling.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-450054
  review:
    summary: TAS annotation from Reactome reaction R-HSA-450054 (IL2RA binds IL-2).
      IL2RA captures IL-2 at the plasma membrane.
    action: ACCEPT
    reason: Correct. This is the primary event in IL-2 receptor assembly at the plasma
      membrane.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-450063
  review:
    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.
    action: ACCEPT
    reason: Correct. IL2RA functions at the plasma membrane.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-451942
  review:
    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.
    action: ACCEPT
    reason: Correct. IL2RA is part of the signaling complex at the plasma membrane.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-452091
  review:
    summary: TAS annotation from Reactome (IL2RB Y338 phosphorylation enables SHC
      recruitment). IL2RA is part of the receptor complex at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein participating in these signaling
      events.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-452097
  review:
    summary: TAS annotation from Reactome (STAT5 phosphorylation at the IL-2 receptor
      complex). IL2RA is part of the complex at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is at the plasma membrane.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-452100
  review:
    summary: TAS annotation from Reactome (SHC1 phosphorylation at the IL2 receptor).
      IL2RA is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA functions at the plasma membrane as part of the signaling
      complex.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-452108
  review:
    summary: TAS annotation from Reactome (IL2RB phosphorylation enables STAT recruitment).
      IL2RA is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane component of the IL-2 receptor.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-452122
  review:
    summary: TAS annotation from Reactome (JAK1 phosphorylates IL2RB). IL2RA is at
      the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA functions at the plasma membrane.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-453104
  review:
    summary: TAS annotation from Reactome (phosphorylated SHC1 recruits GRB2:GAB2).
      IL2RA is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-453111
  review:
    summary: TAS annotation from Reactome (phosphorylated SHC recruits GRB2:SOS1).
      IL2RA is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-508247
  review:
    summary: TAS annotation from Reactome (Gab2 binds p85 of PI3K). IL2RA is at the
      plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-508282
  review:
    summary: TAS annotation from Reactome (SYK is a substrate for JAK1). IL2RA is
      at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-508292
  review:
    summary: TAS annotation from Reactome (SYK binds IL2RB). IL2RA is at the plasma
      membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672965
  review:
    summary: TAS annotation from Reactome (RAS GEFs promote RAS nucleotide exchange).
      IL2RA is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8877396
  review:
    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.
    action: ACCEPT
    reason: Correct. IL2RA protein is at the plasma membrane regardless of the specific
      Reactome reaction annotated.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-912527
  review:
    summary: TAS annotation from Reactome (SHC1 mediates cytokine-induced GAB2 phosphorylation).
      IL2RA is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-913374
  review:
    summary: TAS annotation from Reactome (phosphorylated SHC1 recruits SHIP). IL2RA
      is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-913424
  review:
    summary: TAS annotation from Reactome (SHC1:SHIP1 complex stabilized by GRB2).
      IL2RA is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-919404
  review:
    summary: TAS annotation from Reactome (phosphorylated STAT5 is released). IL2RA
      is at the plasma membrane.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein.
- term:
    id: GO:0002664
    label: regulation of T cell tolerance induction
  evidence_type: IMP
  original_reference_id: PMID:23416241
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:23416241
      supporting_text: 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.
    - reference_id: PMID:23416241
      supporting_text: 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.
- term:
    id: GO:0004911
    label: interleukin-2 receptor activity
  evidence_type: TAS
  original_reference_id: PMID:9096364
  review:
    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.
    action: ACCEPT
    reason: Core function. IL2RA is the alpha subunit of the IL-2 receptor. PMID:9096364
      provides human genetic evidence demonstrating its essential role.
    supported_by:
    - reference_id: PMID:9096364
      supporting_text: 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.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:2467293
  review:
    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.
    action: ACCEPT
    reason: Correct. IL2RA is a plasma membrane protein. This paper identifies IL2RA
      (p55) as recognized by the anti-Tac mAb on the cell surface.
    supported_by:
    - reference_id: PMID:2467293
      supporting_text: p55 (alpha chain), recognized by the anti-Tac monoclonal antibody
        (mAb)
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:2983318
  review:
    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.
    action: ACCEPT
    reason: Correct. IL2RA (Tac antigen) is at the plasma membrane.
    supported_by:
    - reference_id: PMID:2983318
      supporting_text: 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.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: TAS
  original_reference_id: PMID:9096364
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:9096364
      supporting_text: CD25-deficient cortical thymocytes do not express CD1, and
        furthermore they fail to normally down-regulate levels of the anti-apoptotic
        protein bcl-2.
- term:
    id: GO:0006955
    label: immune response
  evidence_type: TAS
  original_reference_id: PMID:9096364
  review:
    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.
    action: ACCEPT
    reason: Correct. IL2RA is essential for normal immune responses. CD25 deficiency
      causes immunodeficiency (PMID:9096364).
    supported_by:
    - reference_id: PMID:9096364
      supporting_text: Profound cellular immunodeficiency occurs as the result of
        mutations in proteins involved in both the differentiation and function of
        mature lymphoid cells.
- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:2983318
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:2983318
      supporting_text: 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.
- term:
    id: GO:0030159
    label: signaling receptor complex adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:16477002
  review:
    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.'
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:16477002
      supporting_text: 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.
    - reference_id: PMID:16293754
      supporting_text: the binding of IL-2Ralpha to IL-2 stabilizes a secondary binding
        site for presentation to IL-2Rbeta.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16293754
  title: Structure of the quaternary complex of interleukin-2 with its alpha, beta,
    and gammac receptors.
  findings:
  - statement: Crystal structure at 2.3 angstroms of IL-2 bound to IL2RA, IL2RB, and
      IL2RG ectodomains
    supporting_text: In the structure of the quaternary ectodomain complex as visualized
      at a resolution of 2.3 angstroms, the binding of IL-2Ralpha to IL-2 stabilizes
      a secondary binding site for presentation to IL-2Rbeta.
  - statement: IL2RA binding to IL-2 stabilizes a secondary binding site for presentation
      to IL2RB
    supporting_text: 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.
  - statement: IL2RA makes no contacts with IL2RB or IL2RG
    supporting_text: gammac is then recruited to the composite surface formed by the
      IL-2/IL-2Rbeta complex. Consistent with its role as a shared receptor for IL-4,
      IL-7, IL-9, IL-15, and IL-21, gammac forms degenerate contacts with IL-2.
- id: PMID:16477002
  title: 'Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric
    cytokine receptor.'
  findings:
  - statement: Crystal structure at 3.0 angstroms of trimeric IL-2 receptor ectodomains
      in complex with IL-2
    supporting_text: 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.
  - statement: IL2RA forms the largest of the three IL-2/IL-2R interfaces
    supporting_text: 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.
  - statement: IL2RA makes no contacts with IL2RB or gammac; its principal role is
      to deliver IL-2 to the signaling complex
    supporting_text: Surprisingly, 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.
  - statement: Quaternary structure consistent with stepwise assembly from IL-2/IL2RA
      to IL-2/IL2RA/IL2RB to full complex
    supporting_text: The quaternary structure is consistent with a stepwise assembly
      from IL-2/IL-2R alpha to IL-2/IL-2R alpha/IL-2R beta to IL-2/IL-2R alpha/IL-2R
      beta/gamma(c).
- id: PMID:17032757
  title: Hot-spot mimicry of a cytokine receptor by a small molecule.
  findings:
  - statement: Small molecule SP4206 (Kd ~70 nM) blocks IL2RA binding to IL-2
    supporting_text: 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).
  - statement: SP4206 targets same hot-spot residues on IL-2 that drive IL2RA binding
    supporting_text: Mutational studies show that SP4206 targets virtually the same
      critical "hot-spot" residues on IL-2 that drive binding of IL-2Ralpha.
  - statement: Confirms the IL2RA-IL-2 binding interface through independent drug
      discovery approach
    supporting_text: our studies suggest that precise structural mimics of receptors
      are not required for high-affinity binding of small molecules, and they show
      that there are multiple solutions to tight binding at shared and adaptive hot
      spots.
- id: PMID:22446627
  title: Exploiting a natural conformational switch to engineer an interleukin-2 superkine.
  findings:
  - statement: Engineered IL-2 superkine with increased IL2RB affinity eliminates
      functional requirement for CD25
    supporting_text: we eliminated the functional requirement of IL-2 for CD25 expression
      by engineering an IL-2 'superkine' (also called super-2) with increased binding
      affinity for IL-2Rbeta.
  - statement: CD25 expression determines cell sensitivity to IL-2; superkine bypasses
      this requirement
    supporting_text: 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.
  - statement: On CD25-negative cells, superkine shows >10-fold improved signaling
      potency over WT IL-2
    supporting_text: On CD25- YT-1 cells, the EC50 of H9 and D10 were decreased over
      10-fold (EC50 = 2.5 and 1.8 ng/mL, respectively) compared to IL-2 (EC50 = 39
      ng/mL)
  - statement: On CD25-positive cells, the difference between WT IL-2 and superkine
      is minimal
    supporting_text: On CD25+ YT-1 cells, the EC50 of IL-2 decreased over 50-fold
      relative to CD25- YT-1 cells, from 39 to 0.66 ng/mL
- id: PMID:23416241
  title: Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation
    and autoimmunity.
  findings:
  - statement: IL2RA null mutation (S166N) abrogates CD25 surface expression
    supporting_text: The patient was homozygous for a c.497G>A transition in exon
      4, leading to an amino acid substitution at codon 166 (S166N) of the protein.
  - statement: Loss of CD25 causes immunodeficiency with lymphoproliferation and autoimmunity
      (IMD41)
    supporting_text: 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.
  - statement: CD25 expression is required to maintain immune homeostasis
    supporting_text: 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.
  - statement: FOXP3+ Tregs remain present but quantitatively insufficient; still
      first to respond to IL-2
    supporting_text: CD25 null FOXP3+ Tregs from the patient were still the first
      to respond to IL-2 (in vitro) albeit at higher concentrations than required
      by healthy subject Tregs.
  - statement: IL-2 signaling hierarchy is altered; CD8+ T cells become more reactive
      than CD4+ T cells
    supporting_text: CD25 deficiency altered the hierarchical signaling in response
      to IL-2 in favor of CD8+ T cells over the CD4+ T cells, contrary to what is
      observed in healthy subjects.
  - statement: CD25 deficiency impairs Treg-mediated IL-2 consumption, a critical
      tolerance mechanism
    supporting_text: 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.
- id: PMID:2467293
  title: Characterization of the interleukin 2 receptor beta chain using three distinct
    monoclonal antibodies.
  findings:
  - statement: High-affinity IL-2 receptor is a complex of p55 (alpha, CD25) and p75
      (beta) chains
    supporting_text: '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.'
  - statement: Alpha chain alone is nonfunctional for signal transduction
    supporting_text: Whereas the alpha chain itself has been shown to be nonfunctional,
      the beta chain appears to be pivotal in the IL-2 signal transduction
  - statement: Beta chain is indispensable for high-affinity binding and signal transduction
    supporting_text: 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.
  - statement: Blocking beta chain with Mik-beta 1 completely abolishes high-affinity
      IL-2 binding
    supporting_text: High-affinity IL-2 binding was completely abolished by Mik-beta
      1.
- id: PMID:2983318
  title: Interleukin 2 regulates its own receptors.
  findings:
  - statement: Cell surface density of high-affinity IL-2 receptors determines rate
      of T-cell-cycle progression
    supporting_text: 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.
  - statement: IL-2 binding promotes increase in Tac epitope expression but decreases
      high-affinity binding sites
    supporting_text: Addition of homogeneous immunoaffinity-purified IL-2 to cell
      populations that expressed equivalent IL-2 and anti-Tac binding sites resulted
      in a time- and temperature-dependent 8- to 10-fold enhancement of Tac epitope
      expression and, simultaneously, a 20-30% diminishment of detectable high-affinity
      IL-2 binding sites.
  - statement: IL-2-receptor interactions promote loss of IL-2 responsiveness via
      receptor downregulation
    supporting_text: 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.
- id: PMID:9096364
  title: Human immune disorder arising from mutation of the alpha chain of the interleukin-2
    receptor.
  findings:
  - statement: First report of human CD25 deficiency
    supporting_text: 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.
  - statement: Truncation mutation of IL2RA causes profound cellular immunodeficiency
    supporting_text: Profound cellular immunodeficiency occurs as the result of mutations
      in proteins involved in both the differentiation and function of mature lymphoid
      cells.
  - statement: Decreased peripheral T cells with abnormal proliferation but normal
      B cell development
    supporting_text: This immunodeficiency is characterized by decreased numbers of
      peripheral T cells displaying abnormal proliferation but normal B cell development.
  - statement: Extensive lymphocytic infiltration of tissues with inflammation
    supporting_text: Extensive lymphocytic infiltration of tissues, including lung,
      liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation.
  - statement: CD25-deficient thymocytes fail to down-regulate bcl-2
    supporting_text: CD25-deficient cortical thymocytes do not express CD1, and furthermore
      they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2.
- id: Reactome:R-HSA-450027
  title: Interleukin-2 receptor alpha:IL2 binds Interleukin-2 receptor beta
  findings: []
- id: Reactome:R-HSA-450054
  title: Interleukin-2 receptor alpha binds interleukin-2
  findings: []
- id: Reactome:R-HSA-450063
  title: 'Interleukin-2: IL2 receptor alpha:beta binds IL2 receptor gamma subunit'
  findings: []
- id: Reactome:R-HSA-451942
  title: Within the IL-2R complex JAK3 phosphorylates JAK1
  findings: []
- id: Reactome:R-HSA-452091
  title: Phosphorylation of IL2RB Y338 enables SHC recruitment
  findings: []
- id: Reactome:R-HSA-452097
  title: Recruited STAT5 is phosphorylated
  findings: []
- id: Reactome:R-HSA-452100
  title: SHC1 bound to IL2 receptor is phosphorylated
  findings: []
- id: Reactome:R-HSA-452108
  title: Phosphorylation of IL2RB Y338, Y392 or Y510 enables STAT recruitment
  findings: []
- id: Reactome:R-HSA-452122
  title: JAK1 phosphorylates Y338, Y392 and Y510 of IL2RB
  findings: []
- id: Reactome:R-HSA-453104
  title: Phosphorylated SHC1 recruits GRB2:GAB2
  findings: []
- id: Reactome:R-HSA-453111
  title: Phosphorylated SHC recruits GRB2:SOS1
  findings: []
- id: Reactome:R-HSA-508247
  title: Gab2 binds the p85 subunit of Class 1A PI3 kinases
  findings: []
- id: Reactome:R-HSA-508282
  title: SYK is a substrate for JAK1
  findings: []
- id: Reactome:R-HSA-508292
  title: SYK binds IL2RB
  findings: []
- id: Reactome:R-HSA-5672965
  title: RAS GEFs promote RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-8877396
  title: IL2RA (CD25) gene expression is stimulated by FOXP3 and inhibited by RUNX1
  findings: []
- id: Reactome:R-HSA-912527
  title: SHC1 mediates cytokine-induced phosphorylation of GAB2
  findings: []
- id: Reactome:R-HSA-913374
  title: Phosphorylated SHC1 recruits SHIP
  findings: []
- id: Reactome:R-HSA-913424
  title: The SHC1:SHIP1 complex is stabilized by GRB2
  findings: []
- id: Reactome:R-HSA-919404
  title: Phosphorylated STAT5 is released
  findings: []
core_functions:
- molecular_function:
    id: GO:0019976
    label: interleukin-2 binding
  directly_involved_in:
  - id: GO:0038110
    label: interleukin-2-mediated signaling pathway
  locations:
  - id: GO:0009897
    label: external side of plasma membrane
  in_complex:
    id: GO:0005893
    label: interleukin-2 receptor complex
  description: IL2RA directly binds IL-2 with low affinity (~10 nM Kd) through its
    extracellular Sushi/CCP domains. This is the primary molecular function that enables
    all downstream effects. The crystal structure (PMID:16477002) shows IL2RA forms
    the largest interface with IL-2 among the three receptor chains. IL2RA captures
    IL-2 and presents it to IL2RB, converting the intermediate-affinity beta/gamma
    receptor (Kd ~1 nM) into the high-affinity trimeric receptor (Kd ~10 pM).
  supported_by:
  - reference_id: PMID:16477002
    supporting_text: 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.
  - reference_id: PMID:16293754
    supporting_text: the binding of IL-2Ralpha to IL-2 stabilizes a secondary binding
      site for presentation to IL-2Rbeta.
- molecular_function:
    id: GO:0019976
    label: interleukin-2 binding
  contributes_to_molecular_function:
    id: GO:0004911
    label: interleukin-2 receptor activity
  directly_involved_in:
  - id: GO:0002664
    label: regulation of T cell tolerance induction
  locations:
  - id: GO:0005886
    label: plasma membrane
  description: IL2RA on Tregs enables preferential IL-2 consumption and STAT5 signaling
    at low IL-2 concentrations, maintaining Treg homeostasis and immune tolerance.
    Its expression determines which cells respond to low IL-2 concentrations (constitutively
    expressed on Tregs, induced on activated T cells), thereby gating access to the
    IL-2 signaling pathway. Loss of IL2RA leads to autoimmunity (PMID:23416241).
  supported_by:
  - reference_id: PMID:23416241
    supporting_text: 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.
  - reference_id: PMID:22446627
    supporting_text: 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.