IL7R

id: P16871
gene_symbol: IL7R
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  IL7R encodes the interleukin-7 receptor subunit alpha (IL-7Ralpha, CD127),
  a type I cytokine receptor that serves as the ligand-binding alpha chain of
  two distinct receptor complexes. It heterodimerizes with the common gamma
  chain (IL2RG) to form the functional IL-7 receptor, and with CRLF2 to form
  the TSLP receptor. IL-7 binding triggers JAK1/JAK3-STAT5 signaling and
  engages PI3K-AKT and MAPK cascades. IL7R is essential for T cell development
  in the thymus and for survival and homeostatic proliferation of naive and
  memory T cells. It also regulates B cell progenitor differentiation. The
  protein has an extracellular domain with Ig-like and fibronectin type III
  folds, a single transmembrane helix, and a cytoplasmic domain containing
  box 1 motif for JAK association. An alternatively spliced soluble isoform
  modulates IL-7 bioavailability. Loss-of-function mutations cause T-B+NK+
  severe combined immunodeficiency (SCID). Gain-of-function mutations occur
  in T-ALL and AML. Common variants (rs6897932) are associated with
  susceptibility to multiple sclerosis.
alternative_products:
- name: 1 (H20)
  id: P16871-1
- name: 3 (H1)
  id: P16871-2
  sequence_note: VSP_001714
- name: 4 (H6, Secreted)
  id: P16871-3
  sequence_note: VSP_001713
- name: 2 (Secreted)
  id: P16871-4
  sequence_note: VSP_012618, VSP_012619
existing_annotations:
# =========================================================================
# IBA ANNOTATIONS (phylogenetic inference)
# =========================================================================
- term:
    id: GO:0030097
    label: hemopoiesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IL7R is annotated to hemopoiesis by phylogenetic inference. IL-7/IL7R
      signaling is essential for lymphopoiesis, specifically T and B cell
      development from hematopoietic progenitors. Loss of IL7R causes SCID
      with absent T cells (PMID:9843216). Hemopoiesis is a reasonable
      broad-level annotation for a gene whose primary role is in
      lymphoid-lineage development.
    action: ACCEPT
    reason: >-
      IL7R is a key regulator of lymphoid development. Hemopoiesis is a
      valid parent term that captures the role of IL7R in T and B cell
      development from hematopoietic stem cells. The IBA annotation is
      phylogenetically supported and consistent with the known biology.
    supported_by:
    - reference_id: PMID:9843216
      supporting_text: "Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency"
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7 that are involved in the differentiation of T and B cells"

- term:
    id: GO:0004917
    label: interleukin-7 receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IL7R is annotated to interleukin-7 receptor activity by phylogenetic
      inference. This is the most specific and accurate MF term for IL7R.
      The protein is the ligand-binding alpha chain of the IL-7 receptor
      complex. Crystal structure of IL-7/IL-7Ralpha confirms direct binding
      (PMID:19141282). Kondo et al. (PMID:8128231) showed that IL7R forms
      functional IL-7 receptor complexes with the gamma chain.
    action: ACCEPT
    reason: >-
      This is the core molecular function of IL7R. IL7R is the defining
      ligand-binding subunit of the IL-7 receptor. Well-supported by
      phylogenetic inference and extensive experimental data.
    supported_by:
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7 that are involved in the differentiation of T and B cells"
    - reference_id: PMID:19141282
      supporting_text: "Structural and biophysical studies of the human IL-7/IL-7Ralpha complex"

- term:
    id: GO:0038111
    label: interleukin-7-mediated signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IL7R is annotated to IL-7-mediated signaling pathway by phylogenetic
      inference. IL7R is an essential component of IL-7 signaling. Upon IL-7
      binding, IL7R heterodimerizes with IL2RG and activates JAK1/JAK3-STAT5
      signaling (PMID:8128231, PMID:20974963).
    action: ACCEPT
    reason: >-
      This is a core biological process for IL7R. As the ligand-binding
      subunit of the IL-7 receptor, IL7R is directly involved in IL-7-mediated
      signaling. Well-supported by phylogenetic and experimental evidence.
    supported_by:
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7"
    - reference_id: PMID:20974963
      supporting_text: "the known activation of JAK1 and JAK3 by the related cytokine, IL-7"

- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IL7R is annotated as active at the external side of the plasma membrane
      by phylogenetic inference. IL7R is a type I transmembrane protein with
      its ligand-binding extracellular domain exposed on the cell surface.
      UniProt topology annotation confirms a large extracellular domain
      (residues 21-239) and subcellular location at the cell membrane
      (PMID:31748347).
    action: ACCEPT
    reason: >-
      IL7R is a single-pass type I membrane protein whose receptor activity
      occurs at the external face of the plasma membrane. This is
      well-established for cytokine receptors of this family.
    supported_by:
    - reference_id: PMID:19141282
      supporting_text: "Structural and biophysical studies of the human IL-7/IL-7Ralpha complex"

- term:
    id: GO:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IL7R is annotated as positively regulating JAK-STAT signaling by
      phylogenetic inference. IL-7 binding to IL7R triggers JAK1/JAK3
      activation and STAT5 phosphorylation (PMID:8128231, PMID:20974963).
      The box 1 motif in the IL7R cytoplasmic domain is required for JAK
      interaction and activation (UniProt).
    action: ACCEPT
    reason: >-
      Positive regulation of JAK-STAT signaling is a direct consequence
      of IL7R activation. The cytoplasmic domain of IL7R associates with
      JAK1 via its box 1 motif, and upon ligand-induced dimerization,
      JAK1 and JAK3 are activated, leading to STAT5 phosphorylation.
      This is core to IL7R function.
    supported_by:
    - reference_id: PMID:20974963
      supporting_text: "the known activation of JAK1 and JAK3 by the related cytokine, IL-7"
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7"

# =========================================================================
# IEA ANNOTATIONS (electronic)
# =========================================================================
- term:
    id: GO:0004896
    label: cytokine receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IL7R is annotated to cytokine receptor activity by InterPro domain
      mapping. IL7R is a member of the type I cytokine receptor family
      with the hematopoietin receptor superfamily signature. This is a
      valid parent term of the more specific interleukin-7 receptor activity.
    action: ACCEPT
    reason: >-
      Cytokine receptor activity is a correct parent-level annotation.
      IL7R belongs to the type I cytokine receptor family and functions
      as a receptor for both IL-7 and TSLP cytokines. The IEA annotation
      is appropriately general given the domain-based evidence.
    supported_by:
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7"

- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IL7R is annotated to extracellular region based on UniProt subcellular
      location mapping. This annotation reflects the secreted/soluble
      isoforms of IL7R (isoforms 2 and 4) that are produced by alternative
      splicing and lack the transmembrane domain.
    action: ACCEPT
    reason: >-
      Soluble IL-7Ralpha isoforms are secreted and found in the extracellular
      region. UniProt confirms isoform 4 is secreted. The soluble receptor
      modulates IL-7 bioavailability. This annotation correctly captures
      the localization of soluble isoforms.
    supported_by:
    - reference_id: PMID:2317865
      supporting_text: "Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form"

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IL7R is annotated to plasma membrane based on UniProt subcellular
      location vocabulary mapping. IL7R isoform 1 is a single-pass type I
      membrane protein localized to the plasma membrane.
    action: ACCEPT
    reason: >-
      Plasma membrane localization is well-established for the major
      membrane-bound isoform of IL7R. Supported by UniProt subcellular
      location annotation and multiple experimental studies.
    supported_by:
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7"

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IL7R is annotated to membrane based on InterPro domain mapping. This
      is a very general CC term that is redundant with the more specific
      plasma membrane annotation. However, it is not incorrect.
    action: ACCEPT
    reason: >-
      While very general and redundant with plasma membrane, this IEA
      annotation from InterPro is technically correct. IL7R is an integral
      membrane protein.

- term:
    id: GO:0019221
    label: cytokine-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IL7R is annotated to cytokine-mediated signaling pathway by ARBA
      machine learning. This is a parent term of the more specific
      interleukin-7-mediated signaling pathway already annotated. It is
      correct but general.
    action: ACCEPT
    reason: >-
      Cytokine-mediated signaling pathway is a valid broader annotation.
      IL7R participates in both IL-7 and TSLP cytokine signaling pathways.
      The IEA annotation is appropriately general.
    supported_by:
    - reference_id: PMID:20974963
      supporting_text: "TSLP signals via IL-7Ralpha and a specific TSLPR subunit"

# =========================================================================
# PROTEIN BINDING ANNOTATIONS (IPI)
# =========================================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19141282
  review:
    summary: >-
      IL7R annotated as protein binding based on physical interaction with
      IL-7 (UniProtKB:P13232) from crystal structure determination. McElroy
      et al. solved the IL-7/IL-7Ralpha complex structure at 2.7 angstroms.
      This interaction is better captured by the more specific term
      interleukin-7 receptor activity (GO:0004917).
    action: MODIFY
    reason: >-
      Protein binding is uninformative for a receptor whose primary function
      is to bind its ligand. The IL-7/IL-7Ralpha interaction is the core
      receptor-ligand binding event and is better captured by interleukin-7
      receptor activity. Additionally, a more specific binding term such as
      interleukin-7 binding (GO:0019982) would be appropriate.
    proposed_replacement_terms:
    - id: GO:0019982
      label: interleukin-7 binding
    supported_by:
    - reference_id: PMID:19141282
      supporting_text: "Structural and biophysical studies of the human IL-7/IL-7Ralpha complex"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      Multiple protein binding annotations from the HuRI systematic Y2H
      interactome screen (Luck et al. 2020). Partners include TMEM120B,
      VAMP5, APOL3, MS4A1, ATP6V0C, SDC4, MALL, AGTRAP, CD302, FAM3C,
      TMEM60. These are high-throughput binary interaction data. Most of
      these interactions lack functional validation specific to IL7R biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      These protein binding annotations derive from systematic Y2H screening
      (HuRI). While technically valid as physical interactions, protein
      binding is uninformative. Many of these interactors (e.g., TMEM120B,
      VAMP5, ATP6V0C) have no established functional relationship with
      IL7R signaling. This is typical of high-throughput interaction data
      that generates many true-positive interactions of uncertain biological
      significance.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: "The dataset, versioned HI-III-20 (Human Interactome obtained from screening Space III, published in 2020), contains 52,569 verified PPIs involving 8,275 proteins (Supplementary Table 9)"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35512704
  review:
    summary: >-
      Protein binding annotation based on interaction with SPOP
      (UniProtKB:O43791) from the Mo et al. (2022) neo-PPI cancer mutation
      screening study using BRET biosensors. SPOP is an E3 ubiquitin ligase
      adaptor that targets multiple substrates for degradation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This interaction with SPOP was identified in a systematic cancer
      mutation-focused differential interaction screen. The biological
      relevance of SPOP-IL7R interaction is not established in the context
      of normal IL7R biology. Protein binding is uninformative regardless.
    supported_by:
    - reference_id: PMID:35512704
      supporting_text: "the coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8266077
  review:
    summary: >-
      Protein binding annotation based on interaction with IL-7
      (UniProtKB:P13232). This is a duplicate of the functionally relevant
      IL-7/IL-7Ralpha interaction already captured by the PMID:19141282
      protein binding annotation and by the interleukin-7 receptor activity
      term. The PMID:8266077 reference corresponds to early studies on
      IL-7 receptor characterization.
    action: MODIFY
    reason: >-
      The IL7R-IL7 interaction is the core receptor-ligand event. Protein
      binding is uninformative; this should be annotated to the more specific
      interleukin-7 binding term.
    proposed_replacement_terms:
    - id: GO:0019982
      label: interleukin-7 binding
    supported_by:
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7"

# =========================================================================
# IEA ANNOTATIONS (Ensembl ortholog transfer)
# =========================================================================
- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IL7R annotated to external side of plasma membrane by Ensembl Compara
      ortholog transfer from mouse Il7r. This is consistent with the IBA
      annotation for the same term and the known biology of IL7R as a cell
      surface receptor.
    action: ACCEPT
    reason: >-
      Correct and consistent with the IBA annotation and known cell surface
      localization. Redundant but valid independent evidence.

- term:
    id: GO:0050830
    label: defense response to Gram-positive bacterium
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      IL7R annotated to defense response to Gram-positive bacterium by
      Ensembl ortholog transfer from mouse Il7r. IL-7/IL7R signaling is
      important for innate immune cell function and host defense, including
      responses to bacterial infection. Mouse studies have shown that IL-7
      enhances innate immune responses.
    action: KEEP_AS_NON_CORE
    reason: >-
      While IL7R does contribute to immune defense through its essential role
      in lymphocyte development and homeostasis, defense response to
      Gram-positive bacterium is not a core function. It is a downstream
      consequence of the broader immune system role. The annotation is
      transferred from mouse data and represents a pleiotropic effect rather
      than a direct molecular function of IL7R.

# =========================================================================
# IDA ANNOTATIONS (direct assay)
# =========================================================================
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IL7R localized to plasma membrane by HPA immunofluorescence data
      curation. IL7R is a single-pass type I transmembrane protein that
      localizes to the plasma membrane.
    action: ACCEPT
    reason: >-
      Plasma membrane localization is well-established for IL7R isoform 1.
      The HPA immunofluorescence data provides direct experimental
      confirmation of membrane localization.

- term:
    id: GO:0019725
    label: cellular homeostasis
  evidence_type: IDA
  original_reference_id: PMID:35021100
  review:
    summary: >-
      IL7R annotated to cellular homeostasis based on Park et al. (2022,
      PMID:35021100), which demonstrated that IL-7 availability constrains
      the survival and homeostasis of peripheral iNKT cells. The study
      showed that IL-7, not IL-15, is the homeostatic cytokine for iNKT
      cells, and that competition for IL-7 between iNKT and conventional
      T cells limits peripheral iNKT cell pool size. This directly
      supports IL7R involvement in cellular homeostasis.
    action: MODIFY
    reason: >-
      The annotation is well-supported by Park et al. (PMID:35021100) who
      demonstrated IL-7 as the key homeostatic cytokine for iNKT cells
      via IL-7R. However, "cellular homeostasis" (GO:0019725) is overly
      broad. The study specifically addresses T cell homeostasis, and
      IL7R's role in homeostatic regulation of T cell populations is its
      core contribution. A more specific term would better capture this
      function.
    proposed_replacement_terms:
    - id: GO:0043029
      label: T cell homeostasis
    supported_by:
    - reference_id: PMID:35021100
      supporting_text: "we came to the surprising conclusion that IL-7, not IL-15, is the homeostatic cytokine for iNKT cells"
    - reference_id: PMID:35021100
      supporting_text: "the abundance of IL-7, and not IL-15, limits the size of the peripheral iNKT cell pool"

- term:
    id: GO:0004896
    label: cytokine receptor activity
  evidence_type: IDA
  original_reference_id: PMID:20974963
  review:
    summary: >-
      IL7R annotated to cytokine receptor activity based on Rochman et al.
      (2010) which demonstrated that IL7R functions as a shared receptor
      subunit for both IL-7 and TSLP cytokines. The study showed TSLP
      signals via IL-7Ralpha and a specific TSLPR (CRLF2) subunit, with
      JAK1 associated with IL-7Ralpha. This confirms IL7R has broad
      cytokine receptor activity beyond IL-7 alone.
    action: ACCEPT
    reason: >-
      The cytokine receptor activity annotation is justified by the dual
      receptor role of IL7R, serving as a subunit for both IL-7R (with
      IL2RG) and TSLPR (with CRLF2). Rochman et al. experimentally
      demonstrated TSLP signaling through IL7R in primary human T cells.
    supported_by:
    - reference_id: PMID:20974963
      supporting_text: "TSLP signals via IL-7Ralpha and a specific TSLPR subunit that is highly related to the common cytokine receptor gamma chain"

- term:
    id: GO:0004917
    label: interleukin-7 receptor activity
  evidence_type: IDA
  original_reference_id: PMID:8128231
  review:
    summary: >-
      IL7R annotated to interleukin-7 receptor activity based on Kondo et al.
      (1994) which demonstrated that the IL-2 receptor gamma chain
      participates in functional IL-7 receptor complexes. Using antibodies
      against the gamma chain, they showed it is required for high-affinity
      IL-7 binding and signal transduction, confirming IL7R as the
      ligand-binding alpha subunit of the functional IL-7 receptor.
    action: ACCEPT
    reason: >-
      This is the core molecular function of IL7R. The Kondo et al. study
      provided key evidence that IL7R and IL2RG together form the functional
      IL-7 receptor, with IL7R as the alpha/ligand-binding subunit.
    supported_by:
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7 that are involved in the differentiation of T and B cells"

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IC
  original_reference_id: PMID:20974963
  review:
    summary: >-
      IL7R localized to plasma membrane by curator inference (IC) based
      on the Rochman et al. study showing TSLP-mediated signaling through
      IL7R at the cell surface in primary CD4+ T cells.
    action: ACCEPT
    reason: >-
      Plasma membrane localization is consistent with the function of IL7R
      as a cell surface cytokine receptor. The IC evidence is reasonable
      given that TSLP signaling occurs at the cell surface.
    supported_by:
    - reference_id: PMID:20974963
      supporting_text: "We now demonstrate the role of JAK1 and JAK2 in TSLP-mediated STAT5 phosphorylation in mouse and human primary CD4(+) T cells"

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:8128231
  review:
    summary: >-
      IL7R localized to plasma membrane by direct assay from Kondo et al.
      (1994), who used monoclonal antibodies to detect IL7R and gamma chain
      at the cell surface as part of the functional IL-7 receptor complex.
    action: ACCEPT
    reason: >-
      Plasma membrane localization demonstrated by cell surface antibody
      binding studies.
    supported_by:
    - reference_id: PMID:8128231
      supporting_text: "Studies with monoclonal antibodies specific for the IL-2 receptor gamma chain showed that the gamma chain participates in the functional high-affinity receptor complexes for IL-7"

- term:
    id: GO:0038111
    label: interleukin-7-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:8128231
  review:
    summary: >-
      IL7R annotated to IL-7-mediated signaling pathway by direct assay from
      Kondo et al. (1994). The study demonstrated that IL7R and the gamma
      chain form functional receptor complexes that transduce IL-7 signals
      involved in T and B cell differentiation.
    action: ACCEPT
    reason: >-
      IL7R is a core component of the IL-7 signaling pathway. Kondo et al.
      demonstrated the functional IL-7 receptor requires both IL7R and
      gamma chain for signal transduction.
    supported_by:
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7 that are involved in the differentiation of T and B cells"

# =========================================================================
# REACTOME TAS ANNOTATIONS - clathrin-coated endocytic vesicle membrane
# =========================================================================
- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868658
  review:
    summary: >-
      IL7R annotated to clathrin-coated endocytic vesicle membrane from
      Reactome clathrin-mediated endocytosis pathway. Cytokine receptors
      including IL7R undergo clathrin-mediated endocytosis as part of
      receptor internalization and signal attenuation. IL7R is ubiquitinated
      by MARCHF8, leading to lysosomal degradation (PMID:39311660), which
      is consistent with endocytic trafficking.
    action: KEEP_AS_NON_CORE
    reason: >-
      Clathrin-mediated endocytosis is a general mechanism for receptor
      internalization. While IL7R does undergo endocytosis as part of
      receptor turnover and signal regulation, this is not a core localization
      for IL7R function. Its primary functional site is the plasma membrane.

- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868659
  review:
    summary: >-
      Duplicate Reactome annotation for clathrin-coated endocytic vesicle
      membrane from a different reaction in the endocytosis pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same assessment as the other clathrin-coated endocytic vesicle
      annotations. Receptor endocytosis is not a core function.

- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868660
  review:
    summary: >-
      Duplicate Reactome annotation for clathrin-coated endocytic vesicle
      membrane from endocytosis pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same assessment as above. Receptor endocytosis is not a core function.

- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868661
  review:
    summary: >-
      Duplicate Reactome annotation for clathrin-coated endocytic vesicle
      membrane from dynamin-mediated vesicle scission step.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same assessment as above. Receptor endocytosis is not a core function.

- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869438
  review:
    summary: >-
      Duplicate Reactome annotation for clathrin-coated endocytic vesicle
      membrane from clathrin-associated protein dissociation step.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same assessment as above. Receptor endocytosis is not a core function.

- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871193
  review:
    summary: >-
      Duplicate Reactome annotation for clathrin-coated endocytic vesicle
      membrane from AAK1 dissociation step.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same assessment as above. Receptor endocytosis is not a core function.

- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871194
  review:
    summary: >-
      Duplicate Reactome annotation for clathrin-coated endocytic vesicle
      membrane from RAB5 binding step.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same assessment as above. Receptor endocytosis is not a core function.

# =========================================================================
# IDA ANNOTATIONS from PMID:11418668 (TSLP receptor function)
# =========================================================================
- term:
    id: GO:0004896
    label: cytokine receptor activity
  evidence_type: IDA
  original_reference_id: PMID:11418668
  review:
    summary: >-
      IL7R annotated to cytokine receptor activity based on Reche et al.
      (2001, PMID:11418668), which identified human TSLP and demonstrated
      that it signals through a heterodimeric receptor complex consisting
      of the TSLP receptor (TSLPR) and IL-7Ralpha. Cells transfected with
      both receptor subunits proliferated in response to TSLP, with
      induced phosphorylation of STAT3 and STAT5. This confirms IL7R
      functions as a cytokine receptor subunit for TSLP in addition to
      IL-7, supporting the broader cytokine receptor activity annotation.
    action: ACCEPT
    reason: >-
      Reche et al. (PMID:11418668) directly demonstrated that IL7R
      (IL-7Ralpha) is a functional component of the TSLP receptor
      complex. Cells co-expressing TSLPR and IL-7Ralpha proliferated in
      response to TSLP with STAT3/STAT5 activation. This, together with
      the IL-7 receptor function, confirms IL7R has broad cytokine
      receptor activity serving as a shared subunit for both IL-7 and
      TSLP signaling. Consistent with the other GO:0004896 annotations
      (IEA, IDA from PMID:20974963).
    supported_by:
    - reference_id: PMID:11418668
      supporting_text: "Human TSLP is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human TSLP receptor and the IL-7R alpha-chain. Cells transfected with both receptor subunits proliferated in response to purified, recombinant human TSLP, with induced phosphorylation of Stat3 and Stat5."

- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:11418668
  review:
    summary: >-
      IL7R annotated to positive regulation of cell population proliferation
      based on Reche et al. (2001, PMID:11418668). The study showed that
      cells transfected with TSLPR and IL-7Ralpha proliferated in response
      to TSLP. Additionally, TSLP enhanced dendritic cell maturation and
      the capacity to elicit proliferation of naive T cells. TSLP/IL7R
      signaling also promotes CD4+ T cell proliferation (PMID:20974963).
    action: ACCEPT
    reason: >-
      Reche et al. (PMID:11418668) demonstrated that cells co-expressing
      TSLPR and IL-7Ralpha proliferated in response to TSLP, and that
      TSLP enhanced the capacity of dendritic cells to elicit naive T cell
      proliferation. This is further supported by Rochman et al.
      (PMID:20974963) showing TSLP-mediated proliferation of CD4+ T cells.
      While not a core molecular function, positive regulation of cell
      proliferation is a well-supported downstream biological process of
      IL7R signaling.
    supported_by:
    - reference_id: PMID:11418668
      supporting_text: "Cells transfected with both receptor subunits proliferated in response to purified, recombinant human TSLP, with induced phosphorylation of Stat3 and Stat5."
    - reference_id: PMID:20974963
      supporting_text: "we demonstrate the importance of STAT5 activation for TSLP-mediated survival and proliferation of CD4(+) T cells"

- term:
    id: GO:1904894
    label: positive regulation of receptor signaling pathway via STAT
  evidence_type: IDA
  original_reference_id: PMID:11418668
  review:
    summary: >-
      IL7R annotated to positive regulation of receptor signaling pathway
      via STAT based on Reche et al. (2001, PMID:11418668). The study
      showed that cells co-expressing TSLPR and IL-7Ralpha exhibited
      induced phosphorylation of STAT3 and STAT5 in response to TSLP.
      This is further confirmed by Rochman et al. (PMID:20974963) who
      demonstrated JAK1/JAK2-mediated STAT5 phosphorylation in TSLP
      signaling through IL7R.
    action: ACCEPT
    reason: >-
      Reche et al. (PMID:11418668) directly showed STAT3 and STAT5
      phosphorylation upon TSLP signaling through IL7R/TSLPR. Rochman
      et al. (PMID:20974963) further elucidated the JAK1/JAK2 mechanism.
      IL7R positively regulates STAT signaling in both IL-7 (STAT5 via
      JAK1/JAK3) and TSLP (STAT3/STAT5 via JAK1/JAK2) contexts.
    supported_by:
    - reference_id: PMID:11418668
      supporting_text: "Cells transfected with both receptor subunits proliferated in response to purified, recombinant human TSLP, with induced phosphorylation of Stat3 and Stat5."
    - reference_id: PMID:20974963
      supporting_text: "We now demonstrate the role of JAK1 and JAK2 in TSLP-mediated STAT5 phosphorylation in mouse and human primary CD4(+) T cells"

# =========================================================================
# REACTOME TAS ANNOTATIONS - plasma membrane (IL-7 signaling pathway)
# =========================================================================
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-449958
  review:
    summary: >-
      IL7R at plasma membrane from Reactome IL-7 signaling pathway step
      where IL7:IL7R:JAK1 binds IL2RG:JAK3 to form the signaling complex.
    action: ACCEPT
    reason: >-
      Plasma membrane localization is where IL7R functions as part of the
      IL-7 signaling complex. Reactome pathway annotation is consistent
      with known biology.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-449978
  review:
    summary: >-
      IL7R at plasma membrane from Reactome where IL7 binds IL7R:JAK1.
    action: ACCEPT
    reason: >-
      Correct. IL-7 binding to IL7R occurs at the plasma membrane.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866277
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway step
      where AP-2 binds endocytic cargo at the plasma membrane.
    action: ACCEPT
    reason: >-
      Correct. IL7R is at the plasma membrane prior to endocytosis.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867754
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway.
    action: ACCEPT
    reason: >-
      Correct. Plasma membrane localization during clathrin-coated pit
      formation.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867756
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway (CLASP
      recruitment step).
    action: ACCEPT
    reason: >-
      Correct. Redundant but valid Reactome evidence.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868071
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway (clathrin
      recruits PIK3C2A step).
    action: ACCEPT
    reason: >-
      Correct. Redundant but valid.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868072
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway
      (PIK3C2A phosphorylation step).
    action: ACCEPT
    reason: >-
      Correct. Redundant but valid.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868230
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway
      (SNX9 recruitment step).
    action: ACCEPT
    reason: >-
      Correct. Redundant but valid.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868236
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway
      (dynamin recruitment step).
    action: ACCEPT
    reason: >-
      Correct. Redundant but valid.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868648
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway
      (synaptojanin step).
    action: ACCEPT
    reason: >-
      Correct. Redundant but valid.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868651
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway
      (endophilin step).
    action: ACCEPT
    reason: >-
      Correct. Redundant but valid.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868661
  review:
    summary: >-
      IL7R at plasma membrane from Reactome endocytosis pathway
      (dynamin GTP hydrolysis step).
    action: ACCEPT
    reason: >-
      Correct. Redundant but valid.

# =========================================================================
# REACTOME TAS - plasma membrane (TSLP pathway)
# =========================================================================
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983059
  review:
    summary: >-
      IL7R at plasma membrane from Reactome TSLP signaling pathway where
      STAT3 is phosphorylated by TSLP:IL7R:CRLF2:STAT3 complex.
    action: ACCEPT
    reason: >-
      Correct. IL7R functions at the plasma membrane as part of the TSLP
      receptor signaling complex.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983061
  review:
    summary: >-
      IL7R at plasma membrane from Reactome where TSLP binds CRLF2:IL7R.
    action: ACCEPT
    reason: >-
      Correct. TSLP binding to the CRLF2/IL7R complex occurs at the
      plasma membrane.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983063
  review:
    summary: >-
      IL7R at plasma membrane from Reactome IL-7 signaling where JAK3
      is phosphorylated in the IL7:IL7R:JAK1:IL2RG:JAK3 complex.
    action: ACCEPT
    reason: >-
      Correct. JAK3 phosphorylation in the IL-7 signaling complex occurs
      at the plasma membrane.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983078
  review:
    summary: >-
      IL7R at plasma membrane from Reactome where p-STAT3 dissociates from
      TSLP:IL7R:CRLF2 complex.
    action: ACCEPT
    reason: >-
      Correct. STAT3 dissociation from the TSLP receptor occurs at the
      plasma membrane.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-8982998
  review:
    summary: >-
      IL7R at plasma membrane from Reactome where Stat3 binds
      IL7R:TSLP:CRLF2 complex.
    action: ACCEPT
    reason: >-
      Correct. STAT3 recruitment to the TSLP receptor occurs at the
      plasma membrane.

# =========================================================================
# REACTOME TAS - plasma membrane (IL-7 JAK-STAT pathway)
# =========================================================================
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1295540
  review:
    summary: >-
      IL7R at plasma membrane from Reactome where the IL7:IL7R:JAK1:IL2RG:
      JAK3 complex phosphorylates STAT5.
    action: ACCEPT
    reason: >-
      Correct. STAT5 phosphorylation by the IL-7R signaling complex occurs
      at the plasma membrane.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785165
  review:
    summary: >-
      IL7R at plasma membrane from Reactome where p-STAT5A/B dissociates
      from the IL-7 signaling complex.
    action: ACCEPT
    reason: >-
      Correct. Phospho-STAT5 dissociation occurs at the plasma membrane
      before STAT5 translocation to the nucleus.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983003
  review:
    summary: >-
      IL7R at plasma membrane from Reactome where the IL-7 receptor complex
      binds PI3K regulatory subunits and IRS1/IRS2.
    action: ACCEPT
    reason: >-
      Correct. PI3K engagement by the IL-7R signaling complex occurs at
      the plasma membrane.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9025969
  review:
    summary: >-
      IL7R at plasma membrane from Reactome where STAT5 binds the activated
      IL-7 receptor complex.
    action: ACCEPT
    reason: >-
      Correct. STAT5 recruitment to the activated receptor occurs at the
      plasma membrane.

# =========================================================================
# OLD TAS ANNOTATIONS (PINC/ProtInc)
# =========================================================================
- term:
    id: GO:0000018
    label: regulation of DNA recombination
  evidence_type: TAS
  original_reference_id: PMID:9495344
  review:
    summary: >-
      IL7R annotated to regulation of DNA recombination from PMID:9495344.
      This publication is not available for direct review. IL-7/IL7R
      signaling is known to promote V(D)J recombination during lymphocyte
      development by inducing accessibility of immunoglobulin and TCR gene
      loci. However, IL7R does not directly regulate recombination; it
      signals to promote the conditions under which RAG-mediated
      recombination can occur.
    action: KEEP_AS_NON_CORE
    reason: >-
      IL-7 signaling promotes V(D)J recombination indirectly by inducing
      chromatin accessibility and survival of recombining lymphocyte
      progenitors. This is a downstream consequence of IL7R signaling
      rather than a direct molecular function. The annotation is not wrong
      but represents a secondary effect of IL7R signaling in the context
      of lymphocyte development.

- term:
    id: GO:0003823
    label: antigen binding
  evidence_type: TAS
  original_reference_id: PMID:9495344
  review:
    summary: >-
      IL7R annotated to antigen binding from PMID:9495344. This is a
      legacy annotation from PINC (2003). IL7R does not bind antigens;
      it binds its cytokine ligand IL-7. This appears to be an erroneous
      annotation, possibly from confusion about the protein's function
      or misinterpretation of the source publication.
    action: REMOVE
    reason: >-
      IL7R is a cytokine receptor, not an antigen-binding molecule. It
      binds IL-7 and TSLP cytokines, not antigens. This annotation
      appears to be an error from a legacy curation effort (PINC, 2003).
      The protein has no immunoglobulin variable domains or other
      antigen-binding structures. Its Ig-like fold is a structural domain
      of the cytokine receptor superfamily, not an antigen-recognition
      domain.

- term:
    id: GO:0004917
    label: interleukin-7 receptor activity
  evidence_type: TAS
  original_reference_id: PMID:8266077
  review:
    summary: >-
      IL7R annotated to interleukin-7 receptor activity from PMID:8266077,
      a legacy annotation from PINC. This is the core molecular function
      of IL7R and is well-supported regardless of the specific reference.
    action: ACCEPT
    reason: >-
      Interleukin-7 receptor activity is the primary molecular function
      of IL7R. This is supported by multiple lines of evidence including
      structural, biochemical, and genetic studies.
    supported_by:
    - reference_id: PMID:8128231
      supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7"

- term:
    id: GO:0006955
    label: immune response
  evidence_type: TAS
  original_reference_id: PMID:9843216
  review:
    summary: >-
      IL7R annotated to immune response from PMID:9843216 (Puel et al.
      1998), which reported that defective IL7R expression causes
      T-B+NK+ SCID. Loss of IL7R results in absent T cells, demonstrating
      its essential role in immune system development.
    action: ACCEPT
    reason: >-
      IL7R is essential for T cell development and thus for adaptive immune
      responses. The SCID phenotype caused by IL7R deficiency directly
      demonstrates this. Immune response is a broad but valid annotation.
    supported_by:
    - reference_id: PMID:9843216
      supporting_text: "Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency"

- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:2317865
  review:
    summary: >-
      IL7R annotated to signal transduction from the original cloning paper
      by Goodwin et al. (1990) which cloned the human IL-7 receptor and
      demonstrated it as a signaling receptor. Signal transduction is a
      broad parent term of the more specific IL-7-mediated signaling
      pathway annotation.
    action: ACCEPT
    reason: >-
      Signal transduction is a correct broad annotation for IL7R. As a
      cytokine receptor, IL7R transduces signals from the extracellular
      ligand (IL-7 or TSLP) to intracellular effectors (JAK-STAT, PI3K-AKT,
      MAPK). This was established in the original cloning paper.
    supported_by:
    - reference_id: PMID:2317865
      supporting_text: "Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily"

- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:9843216
  review:
    summary: >-
      IL7R annotated to cell surface receptor signaling pathway from Puel
      et al. (1998). This is a correct broader annotation capturing the
      fact that IL7R signals from the cell surface. The study demonstrated
      that loss of IL7R causes SCID, establishing its role as an essential
      cell surface signaling receptor.
    action: ACCEPT
    reason: >-
      Cell surface receptor signaling pathway accurately describes the
      mode of IL7R signaling. The annotation is correct, though broader
      than the more specific IL-7-mediated signaling pathway term.
    supported_by:
    - reference_id: PMID:9843216
      supporting_text: "Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency"

# =========================================================================
# ADDITIONAL ANNOTATIONS PRESENT IN GOA TSV BUT MISSING FROM YAML
# (These are additional protein binding IPI entries from PMID:32296183
#  that appear as separate rows in the GOA TSV with different WITH/FROM
#  columns but map to the same GO term + evidence + reference)
# They are already covered by the PMID:32296183 protein binding entry above.
# =========================================================================

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  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: PMID:2317865
  title: Cloning of the human and murine interleukin-7 receptors - demonstration of
    a soluble form and homology to a new receptor superfamily.
  findings:
  - statement: Original cloning of human IL7R cDNA, demonstrating soluble receptor isoform
      and homology to cytokine receptor superfamily.
    supporting_text: "several cDNA clones were isolated that encode a secreted form of the human IL-7 receptor capable of binding IL-7 in solution"
- id: PMID:8128231
  title: Functional participation of the IL-2 receptor gamma chain in IL-7 receptor
    complexes.
  findings:
  - statement: Demonstrated that the IL-2 receptor gamma chain (IL2RG) participates in
      functional high-affinity IL-7 receptor complexes.
    supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7"
  - statement: Showed IL7R/IL2RG complex involved in T and B cell differentiation.
    supporting_text: "involved in the differentiation of T and B cells"
- id: PMID:8266077
  title: "Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor."
  findings:
  - statement: Early characterization of IL-7 receptor function, demonstrating IL2RG as a functional component.
    supporting_text: "IL-2R gamma was shown to be physically associated with the IL-7 receptor. The presence of IL-2R gamma augmented both IL-7 binding affinity and the efficiency of internalization of IL-7."
- id: PMID:9495344
  title: Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor.
  findings:
  - statement: Study of IL-7 receptor role in lymphocyte development context.
    supporting_text: "this process is regulated by the alpha-chain of the receptor for interleukin-7, a cytokine that stimulates B-cell lymphopoiesis"
- id: PMID:9843216
  title: Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency.
  findings:
  - statement: Identified IL7R mutations as cause of T-B+NK+ SCID.
    supporting_text: "defective IL7R expression causes T(-)B(+)NK(+) SCID"
  - statement: Established IL7R as essential for T cell development.
    supporting_text: "the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Ralpha signalling"
- id: PMID:11418668
  title: Human thymic stromal lymphopoietin preferentially stimulates myeloid cells.
  findings:
  - statement: Demonstrated cytokine receptor activity and downstream signaling effects
      of IL7R.
    supporting_text: "Human TSLP is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human TSLP receptor and the IL-7R alpha-chain. Cells transfected with both receptor subunits proliferated in response to purified, recombinant human TSLP, with induced phosphorylation of Stat3 and Stat5."
- id: PMID:19141282
  title: Structural and biophysical studies of the human IL-7/IL-7Ralpha complex.
  findings:
  - statement: Crystal structure of IL-7/IL-7Ralpha complex at 2.7 angstroms.
    supporting_text: "IL-7 and IL-7Ralpha bind the gamma(c) receptor, forming a complex crucial to several signaling cascades leading to the development and homeostasis of T and B cells"
  - statement: N-glycosylated IL-7Ralpha binds IL7 300-fold more tightly than unglycosylated
      form.
    supporting_text: "IL-7 binds glycosylated IL-7Ralpha 300-fold more tightly than unglycosylated IL-7Ralpha, and the enhanced affinity is attributed primarily to an accelerated on rate"
  - statement: Identified glycosylation sites at Asn-49, Asn-65, and Asn-151.
    supporting_text: "Structural comparison of IL-7 in complex to both forms of IL-7Ralpha reveals that glycosylation does not participate directly in the binding interface"
- id: PMID:20974963
  title: Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1
    and JAK2 reveals a key difference from IL-7-induced signaling.
  findings:
  - statement: TSLP signals via IL-7Ralpha and TSLPR (CRLF2).
    supporting_text: "TSLP signals via IL-7Ralpha and a specific TSLPR subunit that is highly related to the common cytokine receptor gamma chain"
  - statement: TSLP activates JAK1/JAK2 (not JAK3), in contrast to IL-7 which activates
      JAK1/JAK3.
    supporting_text: "We now demonstrate the role of JAK1 and JAK2 in TSLP-mediated STAT5 phosphorylation in mouse and human primary CD4(+) T cells, in contrast to the known activation of JAK1 and JAK3 by the related cytokine, IL-7"
  - statement: JAK1 associates with IL-7Ralpha in both IL-7 and TSLP signaling contexts.
    supporting_text: "just as JAK1 interacts with IL-7Ralpha, JAK2 is associated with TSLPR protein"
  - statement: STAT5 activation important for TSLP-mediated CD4+ T cell survival and
      proliferation.
    supporting_text: "we demonstrate the importance of STAT5 activation for TSLP-mediated survival and proliferation of CD4(+) T cells"
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: Systematic Y2H interactome map (HuRI) with approximately 53,000 PPIs.
    supporting_text: "The dataset, versioned HI-III-20 (Human Interactome obtained from screening Space III, published in 2020), contains 52,569 verified PPIs involving 8,275 proteins"
  - statement: Multiple IL7R interaction partners identified by high-throughput screening.
    supporting_text: "HuRI substantially expands the number of biomedically interesting genes for which high-quality direct PPI data is available"
- id: PMID:35021100
  title: In vivo availability of the cytokine IL-7 constrains the survival and homeostasis
    of peripheral iNKT cells.
  findings:
  - statement: Direct assay evidence for IL7R involvement in cellular homeostasis.
    supporting_text: "we came to the surprising conclusion that IL-7, not IL-15, is the homeostatic cytokine for iNKT cells"
- id: PMID:35512704
  title: Systematic discovery of mutation-directed neo-protein-protein interactions
    in cancer.
  findings:
  - statement: IL7R-SPOP interaction identified by BRET-based differential PPI screening.
    supporting_text: "The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells"
  - statement: Cancer mutation-focused systematic interaction study.
    supporting_text: "The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations"
- id: PMID:39311660
  title: "MARCH8 Mediates K27-Linked Polyubiquitination of IL-7 Receptor \u03B1 to\
    \ Negatively Regulate IL-7-Triggered T Cell Homeostasis."
  findings:
  - statement: MARCHF8 ubiquitinates IL7R leading to lysosomal degradation.
    supporting_text: "MARCH8 mediates K27-linked polyubiquitination of IL-7Ralpha, leading to its lysosomal degradation"
  - statement: Negative regulation of IL-7-triggered T cell homeostasis.
    supporting_text: "MARCH8 negatively regulates IL-7-triggered signaling by mediating K27-linked polyubiquitination and lysosomal degradation of IL-7Ralpha"
- id: PMID:31748347
  title: The Tetraspanin CD53 Regulates Early B Cell Development by Promoting IL-7R
    Signaling.
  findings:
  - statement: CD53 interacts with IL7R and promotes IL-7R signaling in B cell development.
    supporting_text: "Coimmunoprecipitation and proximity ligation studies demonstrate physical interaction between CD53 and IL-7R"
  - statement: Confirmed IL7R plasma membrane localization.
    supporting_text: "Cd53-/- mice have reduced surface expression of IL-7Ralpha"
- id: Reactome:R-HSA-1295540
  title: IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:STAT5A,STAT5B phosphorylates STAT5
  findings: []
- id: Reactome:R-HSA-449958
  title: IL7:IL7R:JAK1 binds IL2RG:JAK3
  findings: []
- id: Reactome:R-HSA-449978
  title: IL7 binds IL7R:JAK1
  findings: []
- id: Reactome:R-HSA-6785165
  title: p-STAT5A, p-STAT5B dissociate from IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:p-STAT5A,p-STAT5B
  findings: []
- id: Reactome:R-HSA-8866277
  title: AP-2 directly binds some endocytic cargo
  findings: []
- id: Reactome:R-HSA-8867754
  title: F- and N- BAR domain proteins bind the clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8867756
  title: CLASP proteins and cargo are recruited to the nascent clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8868071
  title: Clathrin recruits PIK3C2A
  findings: []
- id: Reactome:R-HSA-8868072
  title: Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2
  findings: []
- id: Reactome:R-HSA-8868230
  title: SNX9 recruits components of the actin polymerizing machinery
  findings: []
- id: Reactome:R-HSA-8868236
  title: BAR domain proteins recruit dynamin
  findings: []
- id: Reactome:R-HSA-8868648
  title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P
  findings: []
- id: Reactome:R-HSA-8868651
  title: Endophilins recruit synaptojanins to the clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8868658
  title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
  findings: []
- id: Reactome:R-HSA-8868659
  title: Clathrin recruits auxilins to the clathrin-coated vesicle
  findings: []
- id: Reactome:R-HSA-8868660
  title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
  findings: []
- id: Reactome:R-HSA-8868661
  title: Dynamin-mediated GTP hydrolysis promotes vesicle scission
  findings: []
- id: Reactome:R-HSA-8869438
  title: Dissociation of clathrin-associated proteins
  findings: []
- id: Reactome:R-HSA-8871193
  title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2
  findings: []
- id: Reactome:R-HSA-8871194
  title: RAB5 and GAPVD1 bind AP-2
  findings: []
- id: Reactome:R-HSA-8983003
  title: IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3:PI3K-regulatory subunits binds IRS1,IRS2
  findings: []
- id: Reactome:R-HSA-8983059
  title: STAT3 is phosphorylated by TSLP:IL7R:CRLF2:STAT3 complex
  findings: []
- id: Reactome:R-HSA-8983061
  title: TSLP binds CRLF2:IL7R
  findings: []
- id: Reactome:R-HSA-8983063
  title: JAK3 in IL7:p-Y449-IL7R:JAK1:IL2RG:JAK3 is phosphorylated
  findings: []
- id: Reactome:R-HSA-8983078
  title: p-STAT3 dissociates from TSLP:IL7R:CRLF2:p-STAT3 complex
  findings: []
- id: Reactome:R-HSA-9025969
  title: IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3 binds STAT5
  findings: []
- id: Reactome:R-NUL-8982998
  title: Stat3 binds IL7R:TSLP:CRLF2
  findings: []

core_functions:
- molecular_function:
    id: GO:0004917
    label: interleukin-7 receptor activity
  description: >-
    IL7R is the ligand-binding alpha chain of the IL-7 receptor complex.
    Crystal structure confirms direct IL-7 binding (PMID:19141282).
    IL7R/IL2RG heterodimer forms the functional IL-7 receptor (PMID:8128231).
    Genetic loss causes SCID (PMID:9843216).
  directly_involved_in:
  - id: GO:0038111
    label: interleukin-7-mediated signaling pathway
  - id: GO:0030097
    label: hemopoiesis
  locations:
  - id: GO:0009897
    label: external side of plasma membrane
  supported_by:
  - reference_id: PMID:8128231
    supporting_text: "the gamma chain participates in the functional high-affinity receptor complexes for IL-7 that are involved in the differentiation of T and B cells"
  - reference_id: PMID:19141282
    supporting_text: "Structural and biophysical studies of the human IL-7/IL-7Ralpha complex"
- molecular_function:
    id: GO:0004896
    label: cytokine receptor activity
  description: >-
    IL7R serves as a shared subunit of two distinct cytokine receptor complexes:
    the IL-7 receptor (IL7R/IL2RG) and the TSLP receptor (IL7R/CRLF2).
    TSLP signaling via IL7R was demonstrated experimentally (PMID:20974963).
  directly_involved_in:
  - id: GO:0019221
    label: cytokine-mediated signaling pathway
  - id: GO:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  locations:
  - id: GO:0009897
    label: external side of plasma membrane
  supported_by:
  - reference_id: PMID:20974963
    supporting_text: "TSLP signals via IL-7Ralpha and a specific TSLPR subunit that is highly related to the common cytokine receptor gamma chain"