---
id: P07321
gene_symbol: Epo
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: >-
  Epo encodes mouse erythropoietin, a secreted glycoprotein cytokine hormone of the EPO/TPO
  family. The mature ligand is produced mainly by kidney in adult mammals and liver in fetal
  or neonatal contexts, is induced by hypoxia-regulated HIF signaling, and circulates to erythroid
  progenitors where it binds EPOR and activates JAK2/STAT and MAPK-linked signaling. The core
  supported function is endocrine receptor-ligand control of definitive erythropoiesis: survival,
  proliferation, differentiation, maturation, and hemoglobinization of erythroid cells. Many
  automated response, neural, immune, cardiac-development, cell-surface, and generic transcription
  annotations reflect downstream or non-core contexts and should not obscure the primary EPOR
  ligand function.
existing_annotations:
- term:
    id: GO:0005128
    label: erythropoietin receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Epo directly functions as the ligand for the erythropoietin receptor.
    action: ACCEPT
    reason: >-
      EPOR binding is the precise molecular function that initiates Epo signaling and erythroid
      outcomes.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: Reactome:R-MMU-9006326
      supporting_text: >-
        Reactome models mouse Epo binding the Epor:JAK2-containing receptor complex as the
        initiating event in erythropoietin signaling.
      reference_section_type: RESULTS
- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Epo is a secreted endocrine hormone regulating erythrocyte mass.
    action: ACCEPT
    reason: >-
      Hormone activity accurately captures the circulating endocrine role of Epo, though receptor
      binding is the more precise MF.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Epo supports erythrocyte differentiation, especially definitive/stress erythropoiesis.
    action: ACCEPT
    reason: >-
      Erythroid differentiation is a direct biological outcome of Epo/EPOR signaling and is
      central to the gene function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0030295
    label: protein kinase activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Epo activates kinase cascades indirectly through EPOR, but protein kinase activator
      activity is not the best direct MF term.
    action: MODIFY
    reason: >-
      The ligand directly binds EPOR; kinase activation is a downstream BP consequence of
      receptor signaling rather than an independent protein kinase activator molecular activity.
      Positive regulation of protein kinase activity remains valid as pathway context, but
      it is a BP term and should not be proposed as a replacement for this MF annotation.
    proposed_replacement_terms:
    - id: GO:0005128
      label: erythropoietin receptor binding
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0038162
    label: erythropoietin-mediated signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Epo initiates the erythropoietin-mediated signaling pathway by binding EPOR.
    action: ACCEPT
    reason: >-
      This is the pathway named for the ligand and is the correct BP context for downstream
      JAK2/STAT, PI3K, RAS, and ERK events.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0097696
    label: cell surface receptor signaling pathway via STAT
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Epo/EPOR signaling activates STAT-family transcriptional signaling downstream
      of JAK2.
    action: ACCEPT
    reason: >-
      STAT signaling is a canonical immediate branch of Epo receptor activation and is part
      of the core pathway.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Epo is a hematopoietic cytokine ligand acting through EPOR.
    action: ACCEPT
    reason: >-
      Cytokine activity is supported by UniProt, Falcon, and Epo-dependent erythroid survival
      evidence.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: proliferation and survival of erythroid cells in response to Epo
      reference_section_type: ABSTRACT
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Epo is secreted and acts in the extracellular space.
    action: ACCEPT
    reason: Extracellular space is the appropriate core location for the circulating ligand.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005128
    label: erythropoietin receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Epo directly functions as the ligand for the erythropoietin receptor.
    action: ACCEPT
    reason: >-
      EPOR binding is the precise molecular function that initiates Epo signaling and erythroid
      outcomes.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: Reactome:R-MMU-9006326
      supporting_text: >-
        Reactome models mouse Epo binding the Epor:JAK2-containing receptor complex as the
        initiating event in erythropoietin signaling.
      reference_section_type: RESULTS
- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Epo is a secreted endocrine hormone regulating erythrocyte mass.
    action: ACCEPT
    reason: >-
      Hormone activity accurately captures the circulating endocrine role of Epo, though receptor
      binding is the more precise MF.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0006950
    label: response to stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Response to stress is too broad for the supported Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The stress connection is better captured by hypoxia-regulated Epo production and erythropoietic
      response rather than a generic response-to-stress annotation.
    supported_by:
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: PMID:17981124
      supporting_text: embryos show severe fetal anemia stemming from deficient erythropoietin
        (Epo)
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon emphasizes renal Epo induction by hypoxia through HIF signaling and renal EPO-producing
        interstitial cells.
      reference_section_type: RESULTS
- term:
    id: GO:0043249
    label: erythrocyte maturation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Epo promotes erythrocyte maturation as part of its erythropoietic hormone function.
    action: ACCEPT
    reason: >-
      Maturation is consistent with UniProt keyword evidence and the Falcon synthesis of Epo
      as the principal erythroid growth and maturation factor.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      Generic RNA polymerase II transcription regulation is downstream of receptor signaling
      and too broad for Epo.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Epo can induce transcriptional programs through EPOR/JAK/STAT, but the appropriate annotation
      is erythropoietin-mediated signaling or specific downstream erythroid outcomes.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Epo is a hematopoietic cytokine ligand acting through EPOR.
    action: ACCEPT
    reason: >-
      Cytokine activity is supported by UniProt, Falcon, and Epo-dependent erythroid survival
      evidence.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: proliferation and survival of erythroid cells in response to Epo
      reference_section_type: ABSTRACT
- term:
    id: GO:0005128
    label: erythropoietin receptor binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Epo directly functions as the ligand for the erythropoietin receptor.
    action: ACCEPT
    reason: >-
      EPOR binding is the precise molecular function that initiates Epo signaling and erythroid
      outcomes.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: Reactome:R-MMU-9006326
      supporting_text: >-
        Reactome models mouse Epo binding the Epor:JAK2-containing receptor complex as the
        initiating event in erythropoietin signaling.
      reference_section_type: RESULTS
- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Epo is a secreted endocrine hormone regulating erythrocyte mass.
    action: ACCEPT
    reason: >-
      Hormone activity accurately captures the circulating endocrine role of Epo, though receptor
      binding is the more precise MF.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Epo is secreted and acts in the extracellular space.
    action: ACCEPT
    reason: Extracellular space is the appropriate core location for the circulating ligand.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      Epo promotes proliferation of erythroid progenitors, but the term is broader than the
      core ligand function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The annotation is directionally correct as an erythroid outcome but should be interpreted
      in the erythropoietic context, not as generic proliferation across cell types.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Cell surface localization is not supported for Epo as a secreted ligand.
    action: REMOVE
    reason: >-
      Epo acts on cell-surface EPOR after secretion, but the Epo protein itself is not a membrane
      or cell-surface resident protein in UniProt or Falcon.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0010523
    label: negative regulation of calcium ion transport into cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      negative regulation of calcium ion transport into cytosol is an osmotic/calcium-stress
      transfer that is not part of the core mouse Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      These annotations likely derive from context-specific non-erythroid or cellular-stress
      experiments in other species; they are not supported by the mouse UniProt/Falcon synthesis
      as primary Epo biology.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Epo supports erythrocyte differentiation, especially definitive/stress erythropoiesis.
    action: ACCEPT
    reason: >-
      Erythroid differentiation is a direct biological outcome of Epo/EPOR signaling and is
      central to the gene function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0038162
    label: erythropoietin-mediated signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Epo initiates the erythropoietin-mediated signaling pathway by binding EPOR.
    action: ACCEPT
    reason: >-
      This is the pathway named for the ligand and is the correct BP context for downstream
      JAK2/STAT, PI3K, RAS, and ERK events.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      Generic RNA polymerase II transcription regulation is downstream of receptor signaling
      and too broad for Epo.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Epo can induce transcriptional programs through EPOR/JAK/STAT, but the appropriate annotation
      is erythropoietin-mediated signaling or specific downstream erythroid outcomes.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0046579
    label: positive regulation of Ras protein signal transduction
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: RAS activation is a recognized downstream branch of Epo signaling.
    action: KEEP_AS_NON_CORE
    reason: >-
      This captures a downstream pathway module, whereas the core function remains EPOR ligand
      activity and erythropoietin-mediated signaling.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
    - reference_id: Reactome:R-MMU-9029152
      supporting_text: Reactome models Epo:Epor:JAK2-linked complexes mediating GDP-GTP exchange
        on Ras.
      reference_section_type: RESULTS
- term:
    id: GO:0071474
    label: cellular hyperosmotic response
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      cellular hyperosmotic response is an osmotic/calcium-stress transfer that is not part
      of the core mouse Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      These annotations likely derive from context-specific non-erythroid or cellular-stress
      experiments in other species; they are not supported by the mouse UniProt/Falcon synthesis
      as primary Epo biology.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0097696
    label: cell surface receptor signaling pathway via STAT
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Epo/EPOR signaling activates STAT-family transcriptional signaling downstream
      of JAK2.
    action: ACCEPT
    reason: >-
      STAT signaling is a canonical immediate branch of Epo receptor activation and is part
      of the core pathway.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:1902219
    label: >-
      negative regulation of intrinsic apoptotic signaling pathway in response to osmotic
      stress
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      negative regulation of intrinsic apoptotic signaling pathway in response to osmotic
      stress is an osmotic/calcium-stress transfer that is not part of the core mouse Epo
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      These annotations likely derive from context-specific non-erythroid or cellular-stress
      experiments in other species; they are not supported by the mouse UniProt/Falcon synthesis
      as primary Epo biology.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:1902251
    label: negative regulation of erythrocyte apoptotic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: Epo prevents apoptosis of erythroid cells during erythropoiesis.
    action: ACCEPT
    reason: Erythroid survival is a core biological effect of Epo/EPOR signaling.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Generic RNA polymerase II transcription regulation is downstream of receptor signaling
      and too broad for Epo.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Epo can induce transcriptional programs through EPOR/JAK/STAT, but the appropriate annotation
      is erythropoietin-mediated signaling or specific downstream erythroid outcomes.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Epo expression and systemic Epo response are hypoxia-regulated.
    action: KEEP_AS_NON_CORE
    reason: >-
      Hypoxia is a major upstream regulator and physiological context for Epo production,
      but the gene product function is the secreted hormone signal.
    supported_by:
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: PMID:17981124
      supporting_text: embryos show severe fetal anemia stemming from deficient erythropoietin
        (Epo)
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon emphasizes renal Epo induction by hypoxia through HIF signaling and renal EPO-producing
        interstitial cells.
      reference_section_type: RESULTS
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Epo is a hematopoietic cytokine ligand acting through EPOR.
    action: ACCEPT
    reason: >-
      Cytokine activity is supported by UniProt, Falcon, and Epo-dependent erythroid survival
      evidence.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: proliferation and survival of erythroid cells in response to Epo
      reference_section_type: ABSTRACT
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Epo is secreted and acts in the extracellular space.
    action: ACCEPT
    reason: Extracellular space is the appropriate core location for the circulating ligand.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0006953
    label: acute-phase response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      acute-phase response is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0007584
    label: response to nutrient
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to nutrient is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Epo promotes proliferation of erythroid progenitors, but the term is broader than the
      core ligand function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The annotation is directionally correct as an erythroid outcome but should be interpreted
      in the erythropoietic context, not as generic proliferation across cell types.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0009651
    label: response to salt stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to salt stress is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cell surface localization is not supported for Epo as a secreted ligand.
    action: REMOVE
    reason: >-
      Epo acts on cell-surface EPOR after secretion, but the Epo protein itself is not a membrane
      or cell-surface resident protein in UniProt or Falcon.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0010523
    label: negative regulation of calcium ion transport into cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      negative regulation of calcium ion transport into cytosol is an osmotic/calcium-stress
      transfer that is not part of the core mouse Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      These annotations likely derive from context-specific non-erythroid or cellular-stress
      experiments in other species; they are not supported by the mouse UniProt/Falcon synthesis
      as primary Epo biology.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0010976
    label: positive regulation of neuron projection development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      positive regulation of neuron projection development reflects non-erythroid neurotrophic
      contexts rather than the conserved core Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Falcon notes non-erythropoietic roles can occur in specific contexts, but the annotation
      is automated/orthology-derived and not supported as a primary mouse Epo function here.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Epo supports erythrocyte differentiation, especially definitive/stress erythropoiesis.
    action: ACCEPT
    reason: >-
      Erythroid differentiation is a direct biological outcome of Epo/EPOR signaling and is
      central to the gene function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0032496
    label: response to lipopolysaccharide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to lipopolysaccharide is a broad stimulus-response annotation transferred from
      automated evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0033189
    label: response to vitamin A
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to vitamin A is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0033574
    label: response to testosterone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to testosterone is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0038162
    label: erythropoietin-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Epo initiates the erythropoietin-mediated signaling pathway by binding EPOR.
    action: ACCEPT
    reason: >-
      This is the pathway named for the ligand and is the correct BP context for downstream
      JAK2/STAT, PI3K, RAS, and ERK events.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0042104
    label: positive regulation of activated T cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Activated T cell proliferation is not supported as a core mouse Epo function in the
      reviewed evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This transferred immune term is outside the canonical EPOR ligand role in erythropoiesis
      and lacks direct support in UniProt/Falcon/local publications.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0043627
    label: response to estrogen
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to estrogen is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0044297
    label: cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cell body localization is not a supported core location for mouse Epo.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The core location is extracellular/secreted; cell body appears to be transferred from
      non-canonical contexts and should not be treated as a general Epo localization.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0045666
    label: positive regulation of neuron differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      positive regulation of neuron differentiation reflects non-erythroid neurotrophic contexts
      rather than the conserved core Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Falcon notes non-erythropoietic roles can occur in specific contexts, but the annotation
      is automated/orthology-derived and not supported as a primary mouse Epo function here.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Generic RNA polymerase II transcription regulation is downstream of receptor signaling
      and too broad for Epo.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Epo can induce transcriptional programs through EPOR/JAK/STAT, but the appropriate annotation
      is erythropoietin-mediated signaling or specific downstream erythroid outcomes.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0046579
    label: positive regulation of Ras protein signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: RAS activation is a recognized downstream branch of Epo signaling.
    action: KEEP_AS_NON_CORE
    reason: >-
      This captures a downstream pathway module, whereas the core function remains EPOR ligand
      activity and erythropoietin-mediated signaling.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
    - reference_id: Reactome:R-MMU-9029152
      supporting_text: Reactome models Epo:Epor:JAK2-linked complexes mediating GDP-GTP exchange
        on Ras.
      reference_section_type: RESULTS
- term:
    id: GO:0048678
    label: response to axon injury
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to axon injury is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0051602
    label: response to electrical stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to electrical stimulus is a broad stimulus-response annotation transferred
      from automated evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0055093
    label: response to hyperoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to hyperoxia is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      ERK1/2 activation can occur downstream of Epo signaling but is not the primary annotation
      level for Epo.
    action: KEEP_AS_NON_CORE
    reason: >-
      MAPK/ERK is a downstream branch of Epo/EPOR signaling, best retained as non-core rather
      than as the defining function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0070555
    label: response to interleukin-1
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to interleukin-1 is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0071474
    label: cellular hyperosmotic response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      cellular hyperosmotic response is an osmotic/calcium-stress transfer that is not part
      of the core mouse Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      These annotations likely derive from context-specific non-erythroid or cellular-stress
      experiments in other species; they are not supported by the mouse UniProt/Falcon synthesis
      as primary Epo biology.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0071548
    label: response to dexamethasone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      response to dexamethasone is a broad stimulus-response annotation transferred from automated
      evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The review evidence supports hypoxia-regulated Epo production and erythropoietic signaling,
      not this broad stimulus-response term as an Epo function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0097696
    label: cell surface receptor signaling pathway via STAT
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Epo/EPOR signaling activates STAT-family transcriptional signaling downstream
      of JAK2.
    action: ACCEPT
    reason: >-
      STAT signaling is a canonical immediate branch of Epo receptor activation and is part
      of the core pathway.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:1902219
    label: >-
      negative regulation of intrinsic apoptotic signaling pathway in response to osmotic
      stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      negative regulation of intrinsic apoptotic signaling pathway in response to osmotic
      stress is an osmotic/calcium-stress transfer that is not part of the core mouse Epo
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      These annotations likely derive from context-specific non-erythroid or cellular-stress
      experiments in other species; they are not supported by the mouse UniProt/Falcon synthesis
      as primary Epo biology.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:1902251
    label: negative regulation of erythrocyte apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Epo prevents apoptosis of erythroid cells during erythropoiesis.
    action: ACCEPT
    reason: Erythroid survival is a core biological effect of Epo/EPOR signaling.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Epo is secreted and acts in the extracellular space.
    action: ACCEPT
    reason: Extracellular space is the appropriate core location for the circulating ligand.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: >-
      Epo promotes proliferation of erythroid progenitors, but the term is broader than the
      core ligand function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The annotation is directionally correct as an erythroid outcome but should be interpreted
      in the erythropoietic context, not as generic proliferation across cell types.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0010976
    label: positive regulation of neuron projection development
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: >-
      positive regulation of neuron projection development reflects non-erythroid neurotrophic
      contexts rather than the conserved core Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Falcon notes non-erythropoietic roles can occur in specific contexts, but the annotation
      is automated/orthology-derived and not supported as a primary mouse Epo function here.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0042104
    label: positive regulation of activated T cell proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: >-
      Activated T cell proliferation is not supported as a core mouse Epo function in the
      reviewed evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This transferred immune term is outside the canonical EPOR ligand role in erythropoiesis
      and lacks direct support in UniProt/Falcon/local publications.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0044297
    label: cell body
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: Cell body localization is not a supported core location for mouse Epo.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The core location is extracellular/secreted; cell body appears to be transferred from
      non-canonical contexts and should not be treated as a general Epo localization.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0045666
    label: positive regulation of neuron differentiation
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: >-
      positive regulation of neuron differentiation reflects non-erythroid neurotrophic contexts
      rather than the conserved core Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Falcon notes non-erythropoietic roles can occur in specific contexts, but the annotation
      is automated/orthology-derived and not supported as a primary mouse Epo function here.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: >-
      ERK1/2 activation can occur downstream of Epo signaling but is not the primary annotation
      level for Epo.
    action: KEEP_AS_NON_CORE
    reason: >-
      MAPK/ERK is a downstream branch of Epo/EPOR signaling, best retained as non-core rather
      than as the defining function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: >-
      Proteasome-mediated ubiquitin-dependent protein catabolism is not a supported Epo function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This appears to be an indirect transferred pathway context, not a process performed
      or directly controlled by the secreted Epo ligand.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        The UniProt function statement centers Epo on EPOR binding, JAK2 activation, erythrocyte
        proliferation and differentiation, and secreted localization.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies the best-supported function as secreted endocrine EPOR ligand activity
        in definitive erythropoiesis, while non-erythroid response and development terms are
        context-specific or less directly supported.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9006326
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9006327
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9006329
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9012652
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9012653
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9012656
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9027266
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9027268
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9027429
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9027436
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9029146
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9029147
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9029152
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9029162
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9030346
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9030353
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-MMU-9032476
  review:
    summary: Epo is an extracellular secreted ligand.
    action: ACCEPT
    reason: >-
      Extracellular region is correct, although extracellular space is the more specific location
      used for the core function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
- term:
    id: GO:0005128
    label: erythropoietin receptor binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Epo directly functions as the ligand for the erythropoietin receptor.
    action: ACCEPT
    reason: >-
      EPOR binding is the precise molecular function that initiates Epo signaling and erythroid
      outcomes.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: Reactome:R-MMU-9006326
      supporting_text: >-
        Reactome models mouse Epo binding the Epor:JAK2-containing receptor complex as the
        initiating event in erythropoietin signaling.
      reference_section_type: RESULTS
- term:
    id: GO:0038162
    label: erythropoietin-mediated signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Epo initiates the erythropoietin-mediated signaling pathway by binding EPOR.
    action: ACCEPT
    reason: >-
      This is the pathway named for the ligand and is the correct BP context for downstream
      JAK2/STAT, PI3K, RAS, and ERK events.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0033033
    label: negative regulation of myeloid cell apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:17981124
  review:
    summary: >-
      The SENP1/HIF paper supports deficient Epo production causing fetal anemia, not broad
      myeloid apoptosis as a direct Epo annotation.
    action: MODIFY
    reason: >-
      The defensible Epo terms are erythroid differentiation and negative regulation of erythrocyte
      apoptosis, not broad myeloid apoptosis.
    proposed_replacement_terms:
    - id: GO:0030218
      label: erythrocyte differentiation
    - id: GO:1902251
      label: negative regulation of erythrocyte apoptotic process
    supported_by:
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: PMID:17981124
      supporting_text: embryos show severe fetal anemia stemming from deficient erythropoietin
        (Epo)
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon emphasizes renal Epo induction by hypoxia through HIF signaling and renal EPO-producing
        interstitial cells.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0018105
    label: peptidyl-serine phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:21095239
  review:
    summary: >-
      Epo does not catalyze peptidyl-serine phosphorylation; it stimulates kinases that phosphorylate
      substrates such as Bad.
    action: MODIFY
    reason: >-
      PMID:21095239 attributes Bad phosphorylation to Epo-activated JNK1, not to Epo as an
      enzyme. The correct curation is positive regulation of kinase activity and erythroid
      cell survival.
    proposed_replacement_terms:
    - id: GO:0045860
      label: positive regulation of protein kinase activity
    - id: GO:1902251
      label: negative regulation of erythrocyte apoptotic process
    supported_by:
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: Binds to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
- term:
    id: GO:0030295
    label: protein kinase activator activity
  evidence_type: IDA
  original_reference_id: PMID:21095239
  review:
    summary: >-
      Epo activates kinase cascades indirectly through EPOR, but protein kinase activator
      activity is not the best direct MF term.
    action: MODIFY
    reason: >-
      The ligand directly binds EPOR; kinase activation is a downstream BP consequence of
      receptor signaling rather than an independent protein kinase activator molecular activity.
      Positive regulation of protein kinase activity remains valid as pathway context, but
      it is a BP term and should not be proposed as a replacement for this MF annotation.
    proposed_replacement_terms:
    - id: GO:0005128
      label: erythropoietin receptor binding
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:21095239
  review:
    summary: >-
      Epo has anti-apoptotic effects, but the broad apoptotic-process term should be narrowed
      to erythroid survival where supported.
    action: MODIFY
    reason: >-
      The strongest supported context is negative regulation of apoptosis in Epo-dependent
      erythroid cells, already represented by the more specific erythrocyte apoptotic-process
      term.
    proposed_replacement_terms:
    - id: GO:1902251
      label: negative regulation of erythrocyte apoptotic process
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0045860
    label: positive regulation of protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:21095239
  review:
    summary: Epo signaling positively regulates downstream kinase activity after EPOR engagement.
    action: ACCEPT
    reason: JAK2, JNK1, and MAPK-family activation are supported downstream of Epo/EPOR signaling.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
        signaling that coordinate erythroid survival, proliferation, and differentiation.
      reference_section_type: RESULTS
- term:
    id: GO:0005128
    label: erythropoietin receptor binding
  evidence_type: TAS
  original_reference_id: PMID:20299672
  review:
    summary: Epo directly functions as the ligand for the erythropoietin receptor.
    action: ACCEPT
    reason: >-
      EPOR binding is the precise molecular function that initiates Epo signaling and erythroid
      outcomes.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: Reactome:R-MMU-9006326
      supporting_text: >-
        Reactome models mouse Epo binding the Epor:JAK2-containing receptor complex as the
        initiating event in erythropoietin signaling.
      reference_section_type: RESULTS
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: TAS
  original_reference_id: PMID:20299672
  review:
    summary: >-
      Angiogenic effects of Epo are plausible but secondary and not the defining mouse Epo
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The cached source is review-level and Falcon treats non-erythroid tissue effects as
      context-dependent; retain only as non-core pending stronger direct mouse evidence.
    supported_by:
    - reference_id: PMID:20299672
      supporting_text: mediated in part by secreted growth factors
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon treats non-erythropoietic tissue outcomes as context-dependent and secondary
        to the core endocrine erythropoiesis function.
      reference_section_type: RESULTS
- term:
    id: GO:0003007
    label: heart morphogenesis
  evidence_type: TAS
  original_reference_id: PMID:20299672
  review:
    summary: >-
      heart morphogenesis is too specific and developmental for the evidence available in
      this review.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The locally cached PMID:20299672 abstract does not provide direct Epo-specific evidence
      for these heart/coronary/pericardial morphogenesis terms, and Falcon identifies erythropoiesis
      as the supported core function.
    supported_by:
    - reference_id: PMID:20299672
      supporting_text: mediated in part by secreted growth factors
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon treats non-erythropoietic tissue outcomes as context-dependent and secondary
        to the core endocrine erythropoiesis function.
      reference_section_type: RESULTS
- term:
    id: GO:0055008
    label: cardiac muscle tissue morphogenesis
  evidence_type: TAS
  original_reference_id: PMID:20299672
  review:
    summary: >-
      cardiac muscle tissue morphogenesis is too specific and developmental for the evidence
      available in this review.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The locally cached PMID:20299672 abstract does not provide direct Epo-specific evidence
      for these heart/coronary/pericardial morphogenesis terms, and Falcon identifies erythropoiesis
      as the supported core function.
    supported_by:
    - reference_id: PMID:20299672
      supporting_text: mediated in part by secreted growth factors
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon treats non-erythropoietic tissue outcomes as context-dependent and secondary
        to the core endocrine erythropoiesis function.
      reference_section_type: RESULTS
- term:
    id: GO:0055010
    label: ventricular cardiac muscle tissue morphogenesis
  evidence_type: TAS
  original_reference_id: PMID:20299672
  review:
    summary: >-
      ventricular cardiac muscle tissue morphogenesis is too specific and developmental for
      the evidence available in this review.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The locally cached PMID:20299672 abstract does not provide direct Epo-specific evidence
      for these heart/coronary/pericardial morphogenesis terms, and Falcon identifies erythropoiesis
      as the supported core function.
    supported_by:
    - reference_id: PMID:20299672
      supporting_text: mediated in part by secreted growth factors
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon treats non-erythropoietic tissue outcomes as context-dependent and secondary
        to the core endocrine erythropoiesis function.
      reference_section_type: RESULTS
- term:
    id: GO:0060979
    label: vasculogenesis involved in coronary vascular morphogenesis
  evidence_type: TAS
  original_reference_id: PMID:20299672
  review:
    summary: >-
      vasculogenesis involved in coronary vascular morphogenesis is too specific and developmental
      for the evidence available in this review.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The locally cached PMID:20299672 abstract does not provide direct Epo-specific evidence
      for these heart/coronary/pericardial morphogenesis terms, and Falcon identifies erythropoiesis
      as the supported core function.
    supported_by:
    - reference_id: PMID:20299672
      supporting_text: mediated in part by secreted growth factors
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon treats non-erythropoietic tissue outcomes as context-dependent and secondary
        to the core endocrine erythropoiesis function.
      reference_section_type: RESULTS
- term:
    id: GO:0061032
    label: visceral serous pericardium development
  evidence_type: TAS
  original_reference_id: PMID:20299672
  review:
    summary: >-
      visceral serous pericardium development is too specific and developmental for the evidence
      available in this review.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The locally cached PMID:20299672 abstract does not provide direct Epo-specific evidence
      for these heart/coronary/pericardial morphogenesis terms, and Falcon identifies erythropoiesis
      as the supported core function.
    supported_by:
    - reference_id: PMID:20299672
      supporting_text: mediated in part by secreted growth factors
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon treats non-erythropoietic tissue outcomes as context-dependent and secondary
        to the core endocrine erythropoiesis function.
      reference_section_type: RESULTS
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:17300687
  review:
    summary: >-
      Epo signaling can regulate hemoglobin-related gene expression in decidual cells, but
      this broad transcription term overstates the direct function.
    action: MODIFY
    reason: >-
      The PMID:17300687 evidence is better represented as Epo-dependent hemoglobin biosynthesis
      and decidual survival, downstream of receptor signaling.
    proposed_replacement_terms:
    - id: GO:0042541
      label: hemoglobin biosynthetic process
    - id: GO:0007566
      label: embryo implantation
    supported_by:
    - reference_id: PMID:17300687
      supporting_text: destroyed Hb-containing cells and resulted in apoptosis
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies erythropoietin-mediated erythroid survival and hemoglobin accumulation
        as a downstream biological outcome of EPOR signaling.
      reference_section_type: RESULTS
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:17300687
  review:
    summary: >-
      The decidual evidence concerns apoptosis after Epo signaling blockade, so the direction
      should be anti-apoptotic rather than generic apoptotic process.
    action: MODIFY
    reason: >-
      Epo signaling supports survival; use negative regulation of apoptotic process instead
      of the broad apoptotic process term.
    proposed_replacement_terms:
    - id: GO:0043066
      label: negative regulation of apoptotic process
    supported_by:
    - reference_id: PMID:17300687
      supporting_text: destroyed Hb-containing cells and resulted in apoptosis
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies erythropoietin-mediated erythroid survival and hemoglobin accumulation
        as a downstream biological outcome of EPOR signaling.
      reference_section_type: RESULTS
- term:
    id: GO:0007566
    label: embryo implantation
  evidence_type: IDA
  original_reference_id: PMID:17300687
  review:
    summary: >-
      Epo contributes to mouse implantation through decidual-cell hemoglobin synthesis and
      survival.
    action: KEEP_AS_NON_CORE
    reason: >-
      The PMID:17300687 evidence supports this developmental context, but it is not the core
      conserved function of Epo.
    supported_by:
    - reference_id: PMID:17300687
      supporting_text: destroyed Hb-containing cells and resulted in apoptosis
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies erythropoietin-mediated erythroid survival and hemoglobin accumulation
        as a downstream biological outcome of EPOR signaling.
      reference_section_type: RESULTS
- term:
    id: GO:0042541
    label: hemoglobin biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:17300687
  review:
    summary: Epo signaling promotes hemoglobin synthesis in erythroid and decidual contexts.
    action: KEEP_AS_NON_CORE
    reason: >-
      Hemoglobin synthesis is a downstream outcome of Epo signaling, not a molecular function
      of Epo itself.
    supported_by:
    - reference_id: PMID:17300687
      supporting_text: destroyed Hb-containing cells and resulted in apoptosis
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon identifies erythropoietin-mediated erythroid survival and hemoglobin accumulation
        as a downstream biological outcome of EPOR signaling.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0030218
    label: erythrocyte differentiation
  evidence_type: IDA
  original_reference_id: PMID:15591122
  review:
    summary: Epo supports erythrocyte differentiation, especially definitive/stress erythropoiesis.
    action: ACCEPT
    reason: >-
      Erythroid differentiation is a direct biological outcome of Epo/EPOR signaling and is
      central to the gene function.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
        and the maintenance of a physiological level of circulating erythrocyte mass. Binds
        to EPOR leading to EPOR dimerization and JAK2 activation.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
        binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
        for survival and terminal differentiation in definitive erythropoiesis.
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
        severe anemia, and embryonic lethality around E13-E13.5.
      reference_section_type: RESULTS
    - reference_id: PMID:15591122
      supporting_text: mobilization and differentiation of erythroid progenitors in the adult
        spleen
      reference_section_type: ABSTRACT
    - reference_id: PMID:21095239
      supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
      reference_section_type: ABSTRACT
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IDA
  original_reference_id: PMID:15016652
  review:
    summary: Epo expression and systemic Epo response are hypoxia-regulated.
    action: KEEP_AS_NON_CORE
    reason: >-
      Hypoxia is a major upstream regulator and physiological context for Epo production,
      but the gene product function is the secreted hormone signal.
    supported_by:
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: PMID:17981124
      supporting_text: embryos show severe fetal anemia stemming from deficient erythropoietin
        (Epo)
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon emphasizes renal Epo induction by hypoxia through HIF signaling and renal EPO-producing
        interstitial cells.
      reference_section_type: RESULTS
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:15016652
  review:
    summary: Epo is secreted and acts in the extracellular space.
    action: ACCEPT
    reason: Extracellular space is the appropriate core location for the circulating ligand.
    supported_by:
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted.'
      reference_section_type: RESULTS
    - reference_id: file:mouse/Epo/Epo-uniprot.txt
      supporting_text: >-
        TISSUE SPECIFICITY: Produced by kidney or liver of adult mammals and by liver of fetal
        or neonatal mammals.
      reference_section_type: RESULTS
    - reference_id: PMID:15016652
      supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
      reference_section_type: ABSTRACT
    - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
      supporting_text: >-
        Falcon describes Epo as secreted into circulation from renal interstitial EPO-producing
        cells to act on marrow erythroid precursors.
      reference_section_type: RESULTS
references:
- id: GO_REF:0000024
  title: >-
    Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
    judgment of sequence similarity
  findings:
  - statement: >-
      Manual orthology transfer supports receptor binding and Epo-mediated signaling from
      experimentally characterized erythropoietin orthologs.
    supporting_text: >-
      GOA ISS rows transfer erythropoietin receptor binding and erythropoietin-mediated signaling
      from human EPO.
    reference_section_type: RESULTS
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: >-
      IBA annotations correctly recover conserved Epo receptor-ligand function and erythroid
      signaling, but protein kinase activator activity is better represented as downstream
      kinase regulation.
    supporting_text: >-
      GOA IBA rows include EPOR binding, hormone activity, cytokine activity, erythrocyte
      differentiation, Epo-mediated signaling, STAT signaling, and protein kinase activator
      activity.
    reference_section_type: RESULTS
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings:
  - statement: UniProt keyword mapping supports erythrocyte maturation as an Epo outcome.
    supporting_text: GOA maps the UniProt erythrocyte maturation keyword to GO:0043249 for
      Epo.
    reference_section_type: RESULTS
- id: GO_REF:0000096
  title: >-
    Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs
  findings:
  - statement: >-
      Mouse-rat transfer includes plausible downstream proliferation and ERK/neural terms,
      but these are non-core or over-extended relative to mouse Epo erythropoiesis.
    supporting_text: >-
      GOA ISO rows from rat include extracellular space, proliferation, neuron projection
      development, T cell proliferation, cell body, neuron differentiation, and ERK cascade
      terms.
    reference_section_type: RESULTS
- id: GO_REF:0000107
  title: >-
    Automatic transfer of experimentally verified manual GO annotation data to orthologs using
    Ensembl Compara
  findings:
  - statement: >-
      Ensembl Compara transfer contributes many broad response and neural/immune annotations
      that should not be treated as core mouse Epo biology.
    supporting_text: >-
      GOA IEA rows include response to nutrient, salt stress, lipopolysaccharide, vitamin
      A, testosterone, estrogen, axon injury, electrical stimulus, hyperoxia, interleukin-1,
      and dexamethasone.
    reference_section_type: RESULTS
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings:
  - statement: >-
      ARBA assigns a generic response-to-stress annotation that is less informative than hypoxia-regulated
      Epo production and erythropoietic signaling.
    supporting_text: GOA includes an ARBA response to stress annotation for Epo.
    reference_section_type: RESULTS
- id: GO_REF:0000119
  title: >-
    Automated transfer of experimentally-verified manual GO annotation data to mouse-human
    orthologs
  findings:
  - statement: >-
      Mouse-human transfer captures conserved receptor binding, cytokine/hormone activity,
      secreted localization, erythropoiesis, Epo signaling, STAT signaling, and erythroid
      anti-apoptosis, but also transfers broad transcription, cell surface, osmotic, Ras,
      and proteasome terms requiring restraint.
    supporting_text: >-
      GOA ISO rows from human EPO include both canonical Epo signaling terms and many broad
      downstream response annotations.
    reference_section_type: RESULTS
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
  - statement: >-
      Combined IEA methods support receptor binding, hormone activity, extracellular localization,
      and proliferation as broad Epo outcomes.
    supporting_text: >-
      GOA IEA rows include erythropoietin receptor binding, hormone activity, extracellular
      region/space, and positive regulation of cell population proliferation.
    reference_section_type: RESULTS
- id: file:mouse/Epo/Epo-uniprot.txt
  title: UniProtKB record for mouse Epo (P07321)
  findings:
  - statement: >-
      UniProt describes Epo as a hormone that binds EPOR, activates JAK2, and regulates erythrocyte
      proliferation/differentiation and circulating erythrocyte mass.
    supporting_text: >-
      FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
      and the maintenance of a physiological level of circulating erythrocyte mass. Binds
      to EPOR leading to EPOR dimerization and JAK2 activation.
    reference_section_type: RESULTS
  - statement: UniProt localizes mouse Epo as secreted and notes kidney/liver production contexts.
    supporting_text: >-
      SUBCELLULAR LOCATION: Secreted. TISSUE SPECIFICITY: Produced by kidney or liver of adult
      mammals and by liver of fetal or neonatal mammals.
    reference_section_type: RESULTS
- id: file:mouse/Epo/Epo-deep-research-falcon.md
  title: Falcon deep research report for mouse Epo
  findings:
  - statement: >-
      Falcon verifies the target as mouse erythropoietin P07321 and identifies the core function
      as a secreted endocrine cytokine required for definitive erythropoiesis.
    supporting_text: >-
      The most strongly supported functional annotation for mouse Epo (UniProt P07321) is
      a secreted, hypoxia-inducible endocrine cytokine produced primarily by renal cortical
      interstitial REP cells that binds EPOR on erythroid progenitors to activate JAK2-dependent
      signaling required for survival and terminal differentiation in definitive erythropoiesis.
    reference_section_type: RESULTS
  - statement: >-
      Falcon summarizes mouse genetic evidence that Epo/Epor loss causes severe anemia and
      embryonic lethality around E13-E13.5 due to impaired definitive erythropoiesis.
    supporting_text: >-
      Mouse Epo and EpoR loss-of-function causes defective definitive erythropoiesis, severe
      anemia, and embryonic lethality around E13-E13.5.
    reference_section_type: RESULTS
  - statement: >-
      Falcon highlights hypoxia/HIF regulation of renal Epo production and context-dependent
      non-erythropoietic tissue effects as secondary to the core erythropoietic function.
    supporting_text: >-
      A central regulatory principle is that Epo expression is strongly induced by hypoxia
      through the HIF system in renal EPO-producing cells.
    reference_section_type: RESULTS
- id: PMID:15016652
  title: Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia.
  full_text_unavailable: true
  findings:
  - statement: >-
      Mouse renal EPO mRNA induction by hypoxia is attenuated in SOD3 knockout mice, supporting
      hypoxia-regulated Epo production.
    supporting_text: hypoxic activation of HIF-1 alpha and its target gene EPO in mouse
    reference_section_type: ABSTRACT
- id: PMID:15591122
  title: BMP4 and Madh5 regulate the erythroid response to acute anemia.
  full_text_unavailable: true
  findings:
  - statement: >-
      Acute anemia/hypoxia mobilizes and differentiates erythroid progenitors in mouse spleen,
      supporting the stress erythropoiesis context for Epo action.
    supporting_text: mobilization and differentiation of erythroid progenitors in the adult
      spleen
    reference_section_type: ABSTRACT
- id: PMID:17300687
  title: >-
    Erythropoietin contributes to implantation: ectopic hemoglobin synthesis in decidual cells
    of mice.
  full_text_unavailable: true
  findings:
  - statement: >-
      Epo signaling in mouse decidua supports implantation through hemoglobin synthesis and
      decidual-cell survival.
    supporting_text: destroyed Hb-containing cells and resulted in apoptosis
    reference_section_type: ABSTRACT
- id: PMID:17981124
  title: SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia.
  findings:
  - statement: >-
      SENP1 regulates hypoxia-induced Epo production through HIF1alpha stability; defective
      Epo production causes severe fetal anemia.
    supporting_text: embryos show severe fetal anemia stemming from deficient erythropoietin
      (Epo)
    reference_section_type: ABSTRACT
- id: PMID:20299672
  title: Epicardial-myocardial signaling directing coronary vasculogenesis.
  full_text_unavailable: true
  findings:
  - statement: >-
      The cached abstract supports a broad role for secreted growth factors in coronary development
      but does not itself provide direct Epo-specific evidence for the narrow cardiac GO terms.
    supporting_text: mediated in part by secreted growth factors
    reference_section_type: ABSTRACT
- id: PMID:21095239
  title: >-
    Phosphorylation of Bcl-associated death protein (Bad) by erythropoietin-activated c-Jun
    N-terminal protein kinase 1 contributes to survival of erythropoietin-dependent cells.
  findings:
  - statement: >-
      Epo supports survival of immature erythroid cells and Epo-dependent murine cells through
      JNK1-dependent Bad phosphorylation.
    supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
    reference_section_type: ABSTRACT
  - statement: >-
      The phosphorylation event is performed by JNK1, so Epo should be annotated as regulating
      kinase activity and erythroid survival rather than catalyzing phosphorylation.
    supporting_text: proliferation and survival of erythroid cells in response to Epo
    reference_section_type: ABSTRACT
- id: Reactome:R-MMU-9006326
  title: Epo binds Epor:Jak2:Lyn:Irs2
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Epo binds Epor:Jak2:Lyn:Irs2
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9006327
  title: Phospho-Jak2 phosphorylates Epor
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Phospho-Jak2 phosphorylates Epor
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9006329
  title: Jak2 transphosphorylates and is activated in response to Erythropoietin
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Jak2 transphosphorylates and is activated in response to Erythropoietin
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9012652
  title: p-Stat5 dissociates from Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: p-Stat5 dissociates from Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9012653
  title: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2 phosphorylates Stat5
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2 phosphorylates Stat5
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9012656
  title: phospho-Epor:phospho-Jak2:Lyn:Irs2 binds Stat5
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: phospho-Epor:phospho-Jak2:Lyn:Irs2 binds Stat5
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9027266
  title: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2:p-Crkl:Rapgef1 binds Shc1
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2:p-Crkl:Rapgef1 binds Shc1
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9027268
  title: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2 binds Pi3k
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2 binds Pi3k
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9027429
  title: Lyn phosphorylates Plcg1,2 in Epo receptor complex
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Lyn phosphorylates Plcg1,2 in Epo receptor complex
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9027436
  title: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2 binds Plcg1,2
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Epo:p-8Y-Epor:p-12Y-Jak2:Lyn:Irs2 binds Plcg1,2
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9029146
  title: Epo receptor complex binds Grb2:Sos1
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Epo receptor complex binds Grb2:Sos1
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9029147
  title: Jak2 phosphorylates Shc1 in Epo receptor complex
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Jak2 phosphorylates Shc1 in Epo receptor complex
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9029152
  title: Epo receptor complex mediates exchange of GDP for GTP bound to Ras
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Epo receptor complex mediates exchange of GDP for GTP bound to Ras
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9029162
  title: Jak2 phosphorylates Vav1 in Epo receptor complex
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Jak2 phosphorylates Vav1 in Epo receptor complex
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9030346
  title: Epo receptor complex binds Crkl:Rapgef1
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Epo receptor complex binds Crkl:Rapgef1
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9030353
  title: Lyn phosphorylates Crkl in Epo receptor complex
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Lyn phosphorylates Crkl in Epo receptor complex
    reference_section_type: RESULTS
- id: Reactome:R-MMU-9032476
  title: Epor-associated Plcg hydrolyzes phosphatidylinositol bisphosphate
  findings:
  - statement: >-
      Reactome places secreted Epo in extracellular receptor-signaling complexes that activate
      EPOR/JAK2-linked pathways.
    supporting_text: Epor-associated Plcg hydrolyzes phosphatidylinositol bisphosphate
    reference_section_type: RESULTS
core_functions:
- description: >-
    Secreted endocrine cytokine/hormone ligand that binds erythropoietin receptor (EPOR) on
    erythroid progenitors, initiating EPOR dimerization and JAK2-dependent signaling. This
    receptor-ligand function is the specific core molecular activity of Epo and is responsible
    for downstream STAT, RAS/MAPK, and survival signaling.
  molecular_function:
    id: GO:0005128
    label: erythropoietin receptor binding
  directly_involved_in:
  - id: GO:0038162
    label: erythropoietin-mediated signaling pathway
  - id: GO:0097696
    label: cell surface receptor signaling pathway via STAT
  locations:
  - id: GO:0005615
    label: extracellular space
  supported_by:
  - reference_id: file:mouse/Epo/Epo-uniprot.txt
    supporting_text: >-
      FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
      and the maintenance of a physiological level of circulating erythrocyte mass. Binds
      to EPOR leading to EPOR dimerization and JAK2 activation.
    reference_section_type: RESULTS
  - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
    supporting_text: >-
      Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
      binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
      for survival and terminal differentiation in definitive erythropoiesis.
    reference_section_type: RESULTS
  - reference_id: Reactome:R-MMU-9006326
    supporting_text: >-
      Reactome models mouse Epo binding the Epor:JAK2-containing receptor complex as the initiating
      event in erythropoietin signaling.
    reference_section_type: RESULTS
  - reference_id: file:mouse/Epo/Epo-uniprot.txt
    supporting_text: >-
      FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
      and the maintenance of a physiological level of circulating erythrocyte mass. Binds
      to EPOR leading to EPOR dimerization and JAK2 activation.
    reference_section_type: RESULTS
  - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
    supporting_text: >-
      Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
      binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
      for survival and terminal differentiation in definitive erythropoiesis.
    reference_section_type: RESULTS
  - reference_id: PMID:21095239
    supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
    reference_section_type: ABSTRACT
  - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
    supporting_text: >-
      Falcon summarizes canonical EPO/EPOR downstream modules as JAK2/STAT5 and RAS/MEK/ERK
      signaling that coordinate erythroid survival, proliferation, and differentiation.
    reference_section_type: RESULTS
- description: >-
    Physiological erythropoietic hormone function: Epo promotes definitive and stress erythropoiesis
    by supporting erythroid progenitor survival, proliferation, differentiation, maturation,
    and hemoglobin accumulation. This is the core biological outcome of the EPOR ligand activity,
    whereas broader transcription, stress, neural, immune, cardiac, and osmotic annotations
    are secondary or over-extended.
  molecular_function:
    id: GO:0005179
    label: hormone activity
  directly_involved_in:
  - id: GO:0030218
    label: erythrocyte differentiation
  - id: GO:0043249
    label: erythrocyte maturation
  - id: GO:1902251
    label: negative regulation of erythrocyte apoptotic process
  locations:
  - id: GO:0005615
    label: extracellular space
  supported_by:
  - reference_id: file:mouse/Epo/Epo-uniprot.txt
    supporting_text: >-
      FUNCTION: Hormone involved in the regulation of erythrocyte proliferation and differentiation
      and the maintenance of a physiological level of circulating erythrocyte mass. Binds
      to EPOR leading to EPOR dimerization and JAK2 activation.
    reference_section_type: RESULTS
  - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
    supporting_text: >-
      Falcon synthesizes mouse Epo as a secreted hypoxia-inducible endocrine cytokine that
      binds EPOR on erythroid progenitors and activates JAK2-dependent signaling required
      for survival and terminal differentiation in definitive erythropoiesis.
    reference_section_type: RESULTS
  - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
    supporting_text: >-
      Falcon reports that mouse Epo and Epor null mutants have impaired definitive erythropoiesis,
      severe anemia, and embryonic lethality around E13-E13.5.
    reference_section_type: RESULTS
  - reference_id: PMID:15591122
    supporting_text: mobilization and differentiation of erythroid progenitors in the adult
      spleen
    reference_section_type: ABSTRACT
  - reference_id: PMID:21095239
    supporting_text: Epo-activated JNK1 phosphorylated Bad at threonine 201
    reference_section_type: ABSTRACT
  - reference_id: PMID:17300687
    supporting_text: destroyed Hb-containing cells and resulted in apoptosis
    reference_section_type: ABSTRACT
  - reference_id: file:mouse/Epo/Epo-deep-research-falcon.md
    supporting_text: >-
      Falcon identifies erythropoietin-mediated erythroid survival and hemoglobin accumulation
      as a downstream biological outcome of EPOR signaling.
    reference_section_type: RESULTS
proposed_new_terms: []
suggested_questions:
- question: >-
    Which non-erythroid Epo annotations in mouse have direct endogenous-ligand evidence strong
    enough to keep in GO, and which should be retired as orthology-transfer over-annotations?
  experts:
  - erythropoietin signaling curators
  - mouse developmental biology curators
- question: >-
    Should GO annotation for Epo use erythropoietin receptor binding plus Epo-mediated signaling
    instead of protein kinase activator activity for ligand-driven JAK2 activation?
  experts:
  - GO molecular function curators
  - cytokine signaling experts
- question: >-
    Can the cardiac/coronary developmental TAS annotations from PMID:20299672 be traced to
    direct Epo-specific statements in full text, or should they be replaced by broader non-core
    angiogenesis context only?
  experts:
  - cardiovascular development curators
  - MGI/Reactome curators
suggested_experiments:
- experiment_type: Endogenous ligand-receptor signaling assay
  description: >-
    In primary mouse erythroid progenitors, perturb endogenous Epo or EPOR and measure JAK2,
    STAT5, ERK, and Bad phosphorylation together with survival and differentiation readouts.
  hypothesis: >-
    Epo core function is EPOR ligand activity that drives JAK2/STAT and survival signaling
    in erythroid progenitors.
- experiment_type: Context-specific non-erythroid validation
  description: >-
    Use Epo conditional loss or neutralization in candidate neural, immune, and cardiac contexts
    represented by transferred annotations, with rescue by physiological Epo, to test whether
    endogenous Epo is required for the annotated process.
  hypothesis: >-
    Most broad non-erythroid transferred annotations will not show a direct endogenous Epo
    requirement comparable to erythropoiesis.
- experiment_type: Secreted versus cell-surface localization check
  description: >-
    Use endogenous tagging or validated antibodies in renal Epo-producing cells and erythroid
    target cells to distinguish intracellular production/secretory pathway signal from extracellular
    ligand and cell-surface receptor localization.
  hypothesis: >-
    Epo protein is secreted/extracellular, and cell-surface signal in GOA reflects EPOR-bound
    ligand or receptor localization rather than Epo as a membrane-resident protein.