id: P11308
gene_symbol: ERG
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ERG (ETS-related gene) encodes a member of the ETS family of transcription factors.
  ERG contains an N-terminal SAM/Pointed (PNT) domain involved in protein-protein
  interactions and a C-terminal ETS DNA-binding domain that mediates sequence-specific
  binding to the core consensus 5'-GGA(A/T)-3' (ETS binding site). ERG functions as
  both a transcriptional activator and repressor depending on context. In vascular
  endothelium, ERG is a key regulator of endothelial homeostasis, directly activating
  genes such as VE-cadherin (CDH5) and CLDN5 while repressing inflammatory adhesion
  molecules like E-selectin (SELE). ERG is essential for vascular development (Erg
  knockout is embryonic lethal in mice) and lymphatic vessel formation. ERG also
  interacts with chromatin-modifying enzymes including SETDB1 and KDM4A. Clinically,
  ERG is highly significant in oncology due to the recurrent TMPRSS2-ERG fusion found
  in approximately 50% of prostate cancers, where aberrant ERG expression drives
  oncogenic transcriptional programs. ERG fusions are also found in Ewing sarcoma
  (EWSR1-ERG) and acute myeloid leukemia (FUS-ERG, ELF4-ERG). Loss-of-function
  variants in ERG cause primary lymphedema (LMPHM14).
existing_annotations:
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ERG is a well-established ETS-family transcription factor with RNA polymerase
        II-specific activity. IBA annotation is well supported by phylogenetic
        conservation across the ETS family and extensive experimental evidence from
        multiple publications demonstrating ERG binds specific DNA sequences and
        activates/represses Pol II-dependent transcription [PMID:18195090, PMID:23093599].
      action: ACCEPT
      reason: >-
        Core function of ERG as an ETS-family transcription factor is unambiguously
        established. The IBA annotation is at the appropriate level of specificity.
      supported_by:
        - reference_id: PMID:18195090
          supporting_text: >-
            Erg binds to the VE-cadherin promoter. Furthermore, Erg was found to
            enhance VE-cadherin promoter activity in a transactivation assay.
        - reference_id: PMID:23093599
          supporting_text: >-
            The minimal EBS core is the consensus 5′-GGA(A/T)-3′ known to be
            recognized by the ETS family of transcription factors through their
            highly conserved winged helix-turn-helix DNA-binding domain (ETS-domain) (13,14)

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ERG is a nuclear transcription factor. Nuclear localization is essential for
        its DNA-binding and transcriptional activity. PMID:8502479 describes ERG-2 as
        a "nuclear phosphoprotein." UniProt also confirms nuclear localization.
      action: ACCEPT
      reason: >-
        Nuclear localization is a core aspect of ERG function as a transcription
        factor, well supported by IBA and multiple experimental studies.
      supported_by:
        - reference_id: PMID:8502479
          supporting_text: >-
            ERG-2 is a nuclear phosphoprotein and binds to purine-rich sequences

  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ERG regulates Pol II-dependent transcription of multiple target genes including
        VE-cadherin (CDH5), CLDN5, E-selectin, Wnt genes, and YAP1 [PMID:18195090,
        PMID:22235125, PMID:23913826, PMID:27109047]. This is a core biological
        process for ERG.
      action: ACCEPT
      reason: >-
        ERG's role in regulation of Pol II transcription is its primary biological
        process. The IBA annotation is at an appropriate level.
      supported_by:
        - reference_id: PMID:18195090
          supporting_text: >-
            Erg binds to the VE-cadherin promoter. Furthermore, Erg was found to
            enhance VE-cadherin promoter activity in a transactivation assay.

  - term:
      id: GO:0030154
      label: cell differentiation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ERG plays roles in cell differentiation, particularly endothelial and
        hematopoietic differentiation. ERG expression is enriched in endothelial cells
        and restricted to specific cell types including early myeloid cells
        [PMID:8502479]. ERG regulates endothelial differentiation programs and
        lymphatic endothelial identity. This is a broad term but appropriate for IBA.
      action: ACCEPT
      reason: >-
        Cell differentiation is a well-supported biological role for ERG across
        endothelial and hematopoietic lineages. The IBA annotation is appropriate
        as a general term capturing the ETS family's conserved role in differentiation.
      supported_by:
        - reference_id: PMID:8502479
          supporting_text: >-
            The expression of ERG-2 protein is restricted to few cell types and is
            high in early myeloid cells, indicating that it may function at an early
            stage of hematopoietic lineage determination.

  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        ERG binds DNA through its ETS domain. This IEA annotation from UniProt
        keyword mapping is correct but less specific than the IBA and IDA annotations
        for sequence-specific DNA binding.
      action: ACCEPT
      reason: >-
        Correct but general. More specific terms (GO:0000978, GO:1990837) are also
        present. As an IEA annotation it is acceptable to keep alongside more
        specific experimental annotations.

  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        ERG is a DNA-binding transcription factor. This IEA annotation from InterPro
        domain mapping is correct. It is slightly less specific than the Pol
        II-specific annotation (GO:0000981) but acceptable as an IEA.
      action: ACCEPT
      reason: >-
        Correct annotation from InterPro mapping of the ETS domain. The more specific
        Pol II-specific term is also present via IBA and ISA evidence.

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate of the IBA nucleus annotation. IEA annotation is consistent with
        known nuclear localization of ERG.
      action: ACCEPT
      reason: >-
        Correct. Duplicates with different evidence codes are acceptable. ERG is
        clearly a nuclear protein.

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        UniProt records that ERG localizes to cytoplasm, specifically in cytoplasmic
        mRNP granules containing untranslated mRNAs [PMID:17289661]. This is not the
        primary localization but is supported by the IMP1 RNP granule study.
      action: ACCEPT
      reason: >-
        While ERG is primarily nuclear, its presence in cytoplasmic mRNP granules
        has been documented by mass spectrometry [PMID:17289661]. The IEA annotation
        from UniProt subcellular location mapping is therefore correct.
      supported_by:
        - reference_id: PMID:17289661
          supporting_text: >-
            We isolated the IMP1-containing RNP granules and found that they
            represent a unique RNP entity

  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        ERG regulates DNA-templated transcription as an ETS-family transcription
        factor. This IEA from InterPro is correct and is a parent term of the more
        specific Pol II regulation annotation.
      action: ACCEPT
      reason: >-
        Correct but more general than the Pol II-specific annotation. Acceptable
        as an IEA annotation.

  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Duplicate of the IBA annotation for this term. IEA from InterPro domain
        mapping is consistent with known function.
      action: ACCEPT
      reason: >-
        Correct. Duplicates with different evidence codes are acceptable.

  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        ERG binds DNA in a sequence-specific manner via its ETS domain, recognizing
        the core 5'-GGA(A/T)-3' motif [PMID:8502479, PMID:23093599]. IEA from
        InterPro mapping is correct.
      action: ACCEPT
      reason: >-
        Well supported by experimental evidence. ERG binds purine-rich sequences
        with the consensus (C/G)(C/a)GG-AA(G/a)T [PMID:8502479].
      supported_by:
        - reference_id: PMID:8502479
          supporting_text: >-
            ERG-2 is a nuclear phosphoprotein and binds to purine-rich sequences
            (C/G)(C/a)GG-AA(G/a)T

  - term:
      id: GO:1990837
      label: sequence-specific double-stranded DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        ERG binds double-stranded DNA in a sequence-specific manner. This IEA from
        ARBA machine learning is consistent with the IDA annotation for the same
        term from PMID:28473536.
      action: ACCEPT
      reason: >-
        Correct annotation. The same term is also supported by direct experimental
        evidence (IDA from PMID:28473536).

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20478527
    review:
      summary: >-
        PMID:20478527 demonstrates ERG interaction with androgen receptor (AR, P10275)
        in prostate cancer. ChIP-seq showed ERG binds to and inhibits AR activity at
        gene-specific loci. The term "protein binding" is uninformative; a more
        specific term describing the functional interaction would be preferable.
      action: MODIFY
      reason: >-
        The interaction between ERG and AR is functionally relevant in prostate
        cancer biology. However, "protein binding" is too vague. ERG acts as a
        transcriptional co-regulator with AR. A more informative term would be
        appropriate.
      proposed_replacement_terms:
        - id: GO:0003714
          label: transcription corepressor activity
      supported_by:
        - reference_id: PMID:20478527
          supporting_text: >-
            ERG disrupts androgen receptor (AR) signaling by inhibiting AR
            expression, binding to and inhibiting AR activity at gene-specific loci

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21575865
    review:
      summary: >-
        PMID:21575865 reports ERG interaction with PARP1 (P09874). ETS gene fusions
        including ERG interact with PARP1 and induce DNA damage. The interaction
        with PARP1 is relevant to the prostate cancer oncogenic context of TMPRSS2-ERG
        fusion. "Protein binding" is uninformative.
      action: MODIFY
      reason: >-
        The ERG-PARP1 interaction has functional significance. However, "protein
        binding" is too vague. A more specific term would better capture the
        biology.
      proposed_replacement_terms:
        - id: GO:0140693
          label: molecular condensate scaffold activity
      supported_by:
        - reference_id: PMID:21575865
          supporting_text: >-
            Recurrent fusions of ETS genes are considered driving mutations in a
            diverse array of cancers

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22531786
    review:
      summary: >-
        PMID:22531786 demonstrates ERG interaction with AR (P10275) via ChIP-seq
        in prostate cancer cells. ERG, HDACs, and EZH2 form a transcriptional
        repressor network modulating AR-regulated transcription. "Protein binding"
        is uninformative.
      action: MODIFY
      reason: >-
        ERG functions as a transcriptional co-regulator with AR. "Protein binding"
        is not informative enough.
      proposed_replacement_terms:
        - id: GO:0003714
          label: transcription corepressor activity
      supported_by:
        - reference_id: PMID:22531786
          supporting_text: >-
            ERG, HDACs, and EZH2 are directly involved in androgen-regulated
            transcription and wired into an AR centric transcriptional network

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22722839
    review:
      summary: >-
        PMID:22722839 is a genomic landscape study of castration-resistant prostate
        cancer. The IPI annotation for ERG-AR interaction is from a large-scale
        genomics study context. "Protein binding" is uninformative.
      action: MODIFY
      reason: >-
        While the ERG-AR interaction is real, "protein binding" does not capture
        the functional significance. Better annotated with a more specific term.
      proposed_replacement_terms:
        - id: GO:0003714
          label: transcription corepressor activity
      supported_by:
        - reference_id: PMID:22722839
          supporting_text: >-
            ETS gene family fusions, PTEN loss and androgen receptor (AR)
            amplification, which drive

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27109047
    review:
      summary: >-
        PMID:27109047 demonstrates that ERG directly binds KDM4A (O75164), a histone
        H3K9 demethylase. ERG and KDM4A cooperate to upregulate YAP1 transcription.
        GST pulldown showed direct binding. "Protein binding" is uninformative.
      action: MODIFY
      reason: >-
        The ERG-KDM4A interaction is functionally characterized - ERG recruits
        KDM4A to modify chromatin at target promoters. "Protein binding" should
        be replaced with a more informative term.
      proposed_replacement_terms:
        - id: GO:0003713
          label: transcription coactivator activity
      supported_by:
        - reference_id: PMID:27109047
          supporting_text: >-
            ERG can directly bind to KDM4A (also known as JMJD2A), a histone
            demethylase that particularly demethylates lysine 9 on histone H3. ERG
            and KDM4A cooperated in upregulating the promoter of Yes-associated
            protein 1 (YAP1)

  - term:
      id: GO:0003682
      label: chromatin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        ERG binds chromatin at regulatory elements across the genome. ChIP-seq studies
        show ERG occupancy at approximately 50% of promoters and 44% of active enhancers
        in endothelial cells. ERG also recruits chromatin-modifying enzymes like SETDB1
        and KDM4A. This IEA from Ensembl ortholog transfer is well supported.
      action: ACCEPT
      reason: >-
        Chromatin binding is well supported by ChIP-seq data from multiple studies
        including PMID:20478527 and deep research evidence showing extensive ERG
        chromatin occupancy.
      supported_by:
        - reference_id: PMID:27109047
          supporting_text: >-
            ERG expression reduced histone H3 lysine 9 trimethylation at the YAP1
            gene promoter, consistent with its epigenetic regulation through the ERG
            interaction partner, KDM4A

  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        ERG localizes to the nucleoplasm as demonstrated by immunofluorescence data
        curated by HPA. As a nuclear transcription factor, nucleoplasm localization
        is expected and consistent with its function.
      action: ACCEPT
      reason: >-
        Nucleoplasm localization is consistent with ERG's role as a nuclear
        transcription factor. IDA from HPA immunofluorescence data.

  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        HPA immunofluorescence data indicates ERG presence in the cytosol. While ERG
        is primarily nuclear, some cytoplasmic presence has been noted, and ERG has been
        identified in cytoplasmic mRNP granules [PMID:17289661]. However, cytosol
        localization may represent incomplete nuclear import or antibody cross-reactivity.
      action: ACCEPT
      reason: >-
        Supported by HPA immunofluorescence data and consistent with the cytoplasmic
        mRNP granule finding from PMID:17289661. While not the primary localization,
        the evidence is present.

  - term:
      id: GO:1990837
      label: sequence-specific double-stranded DNA binding
    evidence_type: IDA
    original_reference_id: PMID:28473536
    review:
      summary: >-
        PMID:28473536 is a systematic analysis of DNA binding specificities of 542
        human TFs using methylation-sensitive SELEX. ERG was included in this study
        and its sequence-specific double-stranded DNA binding was confirmed. This
        is consistent with the well-established ETS domain-mediated DNA binding.
      action: ACCEPT
      reason: >-
        IDA evidence from a high-quality systematic study of TF binding specificities.
        Confirms ERG's sequence-specific dsDNA binding activity.
      supported_by:
        - reference_id: PMID:28473536
          supporting_text: >-
            By analysis of 542 human TFs with methylation-sensitive SELEX (systematic
            evolution of ligands by exponential enrichment)

  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase
        II-specific
    evidence_type: IMP
    original_reference_id: PMID:18195090
    review:
      summary: >-
        PMID:18195090 demonstrates that ERG directly activates the VE-cadherin (CDH5)
        promoter. ChIP showed ERG binding to the VE-cadherin promoter, and
        transactivation assays confirmed ERG enhances promoter activity. Inhibition
        of ERG decreased VE-cadherin expression.
      action: ACCEPT
      reason: >-
        ERG acts as a transcriptional activator of VE-cadherin and other endothelial
        genes. This is a core molecular function of ERG, directly demonstrated by
        ChIP and reporter assays.
      supported_by:
        - reference_id: PMID:18195090
          supporting_text: >-
            Using chromatin immunoprecipitation, we showed that Erg binds to the
            VE-cadherin promoter. Furthermore, Erg was found to enhance VE-cadherin
            promoter activity in a transactivation assay.

  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: ISA
    original_reference_id: GO_REF:0000113
    review:
      summary: >-
        ERG localizes to chromatin as expected for a DNA-binding transcription factor.
        ISA from TFClass database annotation is consistent with ChIP-seq data showing
        extensive ERG chromatin occupancy.
      action: ACCEPT
      reason: >-
        Consistent with ERG's role as a chromatin-bound transcription factor. Well
        supported by multiple ChIP studies.

  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    evidence_type: ISA
    original_reference_id: GO_REF:0000113
    review:
      summary: >-
        ISA annotation from TFClass database. Duplicates the IBA annotation for the
        same term. Consistent with ERG's established function.
      action: ACCEPT
      reason: >-
        Correct annotation. Duplicates with different evidence codes are acceptable.

  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA
        binding
    evidence_type: IDA
    original_reference_id: PMID:23093599
    review:
      summary: >-
        PMID:23093599 demonstrates ERG binding to specific DNA sequences using EMSA,
        DNase I footprinting, and cellular luciferase assays. ERG binds the ETS
        binding site (5'-GGA(A/T)-3') in cis-regulatory regions including the
        osteopontin promoter and synthetic EBS constructs linked to the SV40 minimal
        promoter. This confirms ERG binds Pol II cis-regulatory regions in a
        sequence-specific manner.
      action: ACCEPT
      reason: >-
        Strong direct experimental evidence (IDA) demonstrating ERG binds
        cis-regulatory regions in a sequence-specific manner. Core molecular
        function of ERG.
      supported_by:
        - reference_id: PMID:23093599
          supporting_text: >-
            ERG, an ETS-family transcription factor, is commonly over-expressed or
            translocated in leukaemia and prostate carcinoma. In this work, we
            selected the di-(thiophene-phenyl-amidine) compound DB1255 as an
            ERG/DNA binding inhibitor

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:18195090
    review:
      summary: >-
        PMID:18195090 shows ERG directly activates VE-cadherin transcription.
        ChIP demonstrated ERG binding to the VE-cadherin promoter, and
        transactivation assays confirmed positive regulation.
      action: ACCEPT
      reason: >-
        Direct experimental evidence of ERG positively regulating Pol II transcription
        at the VE-cadherin locus. Core function.
      supported_by:
        - reference_id: PMID:18195090
          supporting_text: >-
            Using chromatin immunoprecipitation, we showed that Erg binds to the
            VE-cadherin promoter. Furthermore, Erg was found to enhance VE-cadherin
            promoter activity in a transactivation assay.

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:18195090
    review:
      summary: >-
        Same study as above (PMID:18195090). IMP evidence from mutant phenotype:
        inhibition of ERG expression resulted in decreased VE-cadherin expression,
        supporting its role as a positive regulator.
      action: ACCEPT
      reason: >-
        IMP evidence complements the IDA evidence from the same study. ERG knockdown
        reduces VE-cadherin expression, confirming positive transcriptional regulation.
      supported_by:
        - reference_id: PMID:18195090
          supporting_text: >-
            Inhibition of Erg expression in human umbilical vein endothelial cells
            (HUVECs), using antisense oligonucleotides, resulted in detachment of
            cell-cell contacts and increased cell death. Inhibition of Erg expression
            by antisense in HUVECs also lowered expression of the adhesion molecule
            vascular endothelial (VE)-cadherin

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:22235125
    review:
      summary: >-
        PMID:22235125 identifies CLDN5 (claudin 5) as a downstream target of ERG
        in endothelial cells. ERG knockdown results in reduced CLDN5 expression and
        increased EC permeability, supporting ERG as a positive transcriptional
        regulator.
      action: ACCEPT
      reason: >-
        Additional IMP evidence for ERG's role as a positive transcriptional
        regulator, here at the CLDN5 locus. Consistent with ERG's endothelial
        regulatory functions.
      supported_by:
        - reference_id: PMID:22235125
          supporting_text: >-
            ERG knockdown results in marked increases in EC permeability. This is
            associated with a significant increase of stress fiber and gap formation
            in EC. Furthermore, we identify CLDN5 as a downstream target of ERG in EC.

  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:23913826
    review:
      summary: >-
        PMID:23913826 demonstrates ERG directly activates Wnt/LEF1 signaling in
        prostate cancer. ERG bound to promoters of Wnt genes and LEF1, directly
        increasing their expression.
      action: KEEP_AS_NON_CORE
      reason: >-
        While ERG clearly activates transcription of Wnt pathway genes, this occurs
        in the context of aberrant TMPRSS2-ERG fusion expression in prostate cancer
        rather than normal ERG physiology. The positive transcriptional regulation
        by ERG is core, but the specific Wnt/LEF1 activation in prostate cancer is
        a disease context.
      supported_by:
        - reference_id: PMID:23913826
          supporting_text: >-
            ERG activates Wnt/LEF1 signaling cascade through multiple mechanisms.
            ERG bound to the promoters of various Wnt genes to directly increase
            ligand expression.

  - term:
      id: GO:1990904
      label: ribonucleoprotein complex
    evidence_type: IDA
    original_reference_id: PMID:17289661
    review:
      summary: >-
        PMID:17289661 identified ERG as a component of IMP1-containing mRNP granules
        by mass spectrometry. ERG was found in cytoplasmic ribonucleoprotein granules
        containing untranslated mRNAs. This is not a core function of ERG as a
        transcription factor; ERG mRNA (or protein) may be present in these
        granules for regulatory purposes.
      action: KEEP_AS_NON_CORE
      reason: >-
        ERG was identified in RNP granules by mass spectrometry in a large-scale
        proteomics study. While the finding is real, it likely reflects ERG mRNA
        being transported in mRNP granules or incidental co-purification, rather
        than a core functional role of ERG in ribonucleoprotein complexes. This is
        peripheral to ERG's primary function as a transcription factor.
      supported_by:
        - reference_id: PMID:17289661
          supporting_text: >-
            We isolated the IMP1-containing RNP granules and found that they
            represent a unique RNP entity distinct from neuronal hStaufen and/or
            fragile X mental retardation protein granules, processing bodies, and
            stress granules.

  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: TAS
    original_reference_id: PMID:8502479
    review:
      summary: >-
        PMID:8502479 directly demonstrates that ERG-2 is a DNA-binding protein using
        random oligonucleotide selection and EMSA. ERG-2 binds purine-rich sequences
        with consensus (C/G)(C/a)GG-AA(G/a)T. This is a core molecular function.
      action: ACCEPT
      reason: >-
        Well-supported TAS annotation from a primary study demonstrating ERG's
        DNA-binding activity. While more specific terms exist, this is acceptable
        as legacy evidence.
      supported_by:
        - reference_id: PMID:8502479
          supporting_text: >-
            ERG-2 is a nuclear phosphoprotein and binds to purine-rich sequences
            (C/G)(C/a)GG-AA(G/a)T

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: TAS
    original_reference_id: PMID:8502479
    review:
      summary: >-
        PMID:8502479 identifies ERG-2 as a nuclear phosphoprotein. TAS evidence
        for nuclear localization.
      action: ACCEPT
      reason: >-
        Consistent with all other evidence for ERG nuclear localization. Additional
        evidence code for the same correct annotation.
      supported_by:
        - reference_id: PMID:8502479
          supporting_text: >-
            ERG-2 is a nuclear phosphoprotein

  - term:
      id: GO:0006468
      label: protein phosphorylation
    evidence_type: TAS
    original_reference_id: PMID:8502479
    review:
      summary: >-
        MISANNOTATION: ERG is a SUBSTRATE of protein phosphorylation, not an enzyme
        that catalyzes phosphorylation. PMID:8502479 explicitly states "ERG-2 is a
        nuclear phosphoprotein" and that "ERG-2 protein is phosphorylated by activation
        of protein kinase C." ERG has no kinase activity; it is a transcription factor
        whose activity is regulated by phosphorylation.
      action: REMOVE
      reason: >-
        ERG does not catalyze protein phosphorylation. The annotation confuses
        ERG being a phosphorylation substrate with ERG being involved in the process
        of phosphorylation. The GO term "protein phosphorylation" (GO:0006468) means
        the process of phosphorylating a protein, which requires kinase activity
        that ERG does not possess. ERG is phosphorylated BY protein kinase C
        [PMID:8502479].
      supported_by:
        - reference_id: PMID:8502479
          supporting_text: >-
            ERG-2 is a nuclear phosphoprotein and binds to purine-rich sequences
            (C/G)(C/a)GG-AA(G/a)T. ERG-2 protein, with a half-life of 21 h, is
            considerably more stable than the short-lived ETS-1 or ETS-2 proteins.
            Its phosphorylation is stimulated by phorbol myristate acetate (PMA)

  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: TAS
    original_reference_id: PMID:8502479
    review:
      summary: >-
        PMID:8502479 suggests ERG-2 is involved in signal transduction based on its
        phosphorylation by PKC and its role in downstream gene regulation. However,
        ERG is a downstream effector (transcription factor) rather than a signal
        transduction molecule per se. The annotation is overly broad.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        While ERG is regulated by signal transduction (phosphorylated by PKC) and
        its transcriptional targets include signaling pathway components, ERG itself
        is not a signal transduction molecule. It is a transcription factor that
        responds to signaling inputs. The GO term "signal transduction" is too broad
        and over-represents ERG's actual role, which is transcriptional regulation
        downstream of signaling pathways.
      supported_by:
        - reference_id: PMID:8502479
          supporting_text: >-
            ERG-2 protein is phosphorylated by activation of protein kinase C,
            suggesting their involvement in distinct signal transduction mechanisms.

references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
      Location vocabulary mapping, accompanied by conservative changes to GO
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000113
    title: Gene Ontology annotation of human sequence-specific DNA binding
      transcription factors (DbTFs) based on the TFClass database
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:3299708
    title: "erg, a human ets-related gene on chromosome 21: alternative splicing,
      polyadenylation, and translation."
    findings:
      - statement: Original cloning and characterization of human ERG gene.
  - id: PMID:8502479
    title: Human ERG-2 protein is a phosphorylated DNA-binding protein--a
      distinct member of the ets family.
    findings:
      - statement: ERG-2 is a nuclear phosphoprotein that binds purine-rich DNA sequences with consensus (C/G)(C/a)GG-AA(G/a)T.
      - statement: ERG-2 is phosphorylated by protein kinase C activation.
      - statement: ERG-2 expression is high in early myeloid cells, suggesting role in early hematopoietic differentiation.
  - id: PMID:17289661
    title: Molecular composition of IMP1 ribonucleoprotein granules.
    findings:
      - statement: ERG was identified as a component of IMP1-containing cytoplasmic mRNP granules by mass spectrometry.
  - id: PMID:18195090
    title: Transcription factor Erg regulates angiogenesis and endothelial
      apoptosis through VE-cadherin.
    findings:
      - statement: ERG binds to the VE-cadherin (CDH5) promoter and enhances its activity in transactivation assays.
      - statement: ERG inhibition results in decreased VE-cadherin expression, cell detachment, and increased endothelial apoptosis.
      - statement: ERG is required for endothelial tube formation and angiogenesis in vivo.
  - id: PMID:20478527
    title: An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG
      gene fusions in prostate cancer progression.
    findings:
      - statement: TMPRSS2-ERG fusion disrupts AR signaling by inhibiting AR expression and binding to AR-regulated loci.
      - statement: ERG directly activates the H3K27 methyltransferase EZH2.
  - id: PMID:21575865
    title: Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase
      in ETS gene fusion-positive prostate cancer.
    findings:
      - statement: ERG interacts with PARP1 in ETS gene fusion-positive prostate cancer cells.
  - id: PMID:22235125
    title: ETS-related gene (ERG) controls endothelial cell permeability via
      transcriptional regulation of the claudin 5 (CLDN5) gene.
    findings:
      - statement: ERG is a positive regulator of CLDN5 expression in endothelial cells.
      - statement: ERG knockdown increases endothelial permeability.
      - statement: ERG is a positive regulator of EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor.
      - statement: ERG is a negative regulator of IL-8 and ICAM-1.
  - id: PMID:22531786
    title: A transcriptional repressor co-regulatory network governing androgen
      response in prostate cancers.
    findings:
      - statement: ERG interacts with AR, HDACs, and EZH2 in a transcriptional repressor network in prostate cancer.
      - statement: ERG, EZH2, and HDACs cooperate to repress cytoskeletal genes including Vinculin.
  - id: PMID:22722839
    title: The mutational landscape of lethal castration-resistant prostate
      cancer.
    findings:
      - statement: Large-scale genomic characterization of castration-resistant prostate cancer identifying ETS gene fusions.
  - id: PMID:23093599
    title: Targeting the DNA-binding activity of the human ERG transcription
      factor using new heterocyclic dithiophene diamidines.
    findings:
      - statement: ERG binds the ETS binding site (EBS) consensus 5'-GGA(A/T)-3' through its conserved ETS domain.
      - statement: ERG/DNA binding can be inhibited by heterocyclic diamidines targeting the DNA minor groove.
      - statement: ERG regulates the osteopontin promoter through direct EBS binding.
  - id: PMID:23913826
    title: ERG is a critical regulator of Wnt/LEF1 signaling in prostate cancer.
    findings:
      - statement: ERG directly activates Wnt ligand genes and LEF1 in TMPRSS2-ERG fusion prostate cancers.
      - statement: LEF1 is a critical mediator of ERG-induced tumorigenesis.
  - id: PMID:27109047
    title: ETS transcription factor ERG cooperates with histone demethylase
      KDM4A.
    findings:
      - statement: ERG directly binds KDM4A histone demethylase.
      - statement: ERG and KDM4A cooperate to upregulate YAP1 transcription.
      - statement: ERG expression reduces H3K9me3 at the YAP1 promoter.
  - id: PMID:28473536
    title: Impact of cytosine methylation on DNA binding specificities of human
      transcription factors.
    findings:
      - statement: Systematic SELEX analysis confirming ERG sequence-specific DNA binding specificity.
  - id: PMID:36928819
    title: Genetic association analysis of 77,539 genomes reveals rare disease
      etiologies.
    findings:
      - statement: ERG loss-of-function variants cause lymphatic malformation 14 (LMPHM14), an autosomal dominant form of primary lymphedema.

core_functions:
  - description: >-
      ERG functions as an ETS-family DNA-binding transcription factor that both
      activates and represses RNA polymerase II-dependent transcription of target
      genes by binding to ETS binding sites (5'-GGA(A/T)-3') in promoters and
      enhancers.
    molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    directly_involved_in:
      - id: GO:0006357
        label: regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0005634
        label: nucleus
    supported_by:
      - reference_id: PMID:18195090
      - reference_id: PMID:23093599
  - description: >-
      ERG is a key transcriptional regulator of endothelial cell homeostasis,
      directly activating expression of endothelial genes (VE-cadherin/CDH5,
      CLDN5, endoglin, von Willebrand factor) and repressing inflammatory
      adhesion molecules (E-selectin, ICAM-1, IL-8), thereby maintaining
      vascular integrity and controlling endothelial permeability.
    molecular_function:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase II-specific
    directly_involved_in:
      - id: GO:0045944
        label: positive regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0005634
        label: nucleus
    supported_by:
      - reference_id: PMID:18195090
      - reference_id: PMID:22235125
  - description: >-
      ERG binds chromatin at regulatory regions genome-wide, occupying
      approximately 50% of promoters and 44% of active enhancers in endothelial
      cells, and recruits chromatin-modifying enzymes (SETDB1, KDM4A) to
      modulate local chromatin structure and regulate gene expression.
    molecular_function:
      id: GO:0003682
      label: chromatin binding
    locations:
      - id: GO:0005634
        label: nucleus
      - id: GO:0000785
        label: chromatin
    supported_by:
      - reference_id: PMID:27109047

suggested_questions:
  - question: >-
      What are the relative contributions of ERG's transcriptional activation
      versus repression activities in endothelial homeostasis?
  - question: >-
      Does ERG have distinct target gene programs in blood vascular versus
      lymphatic endothelial cells?
  - question: >-
      Are there isoform-specific functional differences among the six known
      ERG splice variants?

suggested_experiments:
  - description: >-
      ChIP-seq comparison of ERG binding sites in blood endothelial cells versus
      lymphatic endothelial cells to define tissue-specific regulatory programs.
  - description: >-
      Isoform-specific expression and functional analysis of ERG splice variants
      to determine if different isoforms have distinct transcriptional activities
      or target gene preferences.