id: Q92585
gene_symbol: MAML1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  MAML1 is a nuclear transcriptional coactivator in the canonical Notch
  transcription activation complex. It binds Notch intracellular domains with
  RBPJ/CSL to promote transcription of Notch target genes such as HES1, and can
  recruit additional coactivator machinery including CREBBP/EP300 and CDK8.
existing_annotations:
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        MAML1 is consistently described as a nuclear coactivator that functions
        in DNA-bound Notch transcription complexes.
      action: ACCEPT
      reason: >-
        Nucleoplasm/nucleus localization is the supported cellular context for
        the core transcriptional coactivator function.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            Here we clone MAML1, a human homologue of the Drosophila gene
            Mastermind, and show that it encodes a protein of 130 kD
            localizing to nuclear bodies.
        - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
          supporting_text: >-
            Nuclear localization is well supported; “nucleoplasm” is
            reasonable, but exact subnuclear assignment depends on assay
            context.
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        MAML1 is a transcriptional coactivator for Notch intracellular domain
        complexes and also has evidence for p53 coactivator activity.
      action: ACCEPT
      reason: >-
        The term captures the principal molecular role of MAML1. Direct
        experiments show MAML1 amplifies Notch-induced HES1 transcription and
        acts as a coactivator in p53-dependent transcription.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
        - reference_id: PMID:17317671
          supporting_text: >-
            Overexpression of wild-type MAML1 as well as a mutant, defective in
            Notch signaling, enhanced the p53-dependent gene induction in
            mammalian cells, whereas MAML1 knockdown reduced the p53-dependent
            gene expression.
  - term:
      id: GO:0007221
      label: positive regulation of transcription of Notch receptor target
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        MAML1 positively regulates transcription of Notch receptor target genes
        through the ICN-RBPJ/CSL-MAML transcriptional activation complex.
      action: ACCEPT
      reason: >-
        Direct reporter and complex-assembly evidence supports MAML1-dependent
        activation of HES1-class Notch target transcription.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
        - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
          supporting_text: >-
            The strongest direct evidence for MAML1 typically reads out
            **transcriptional activation** (HES/HES4/DTX1 reporters; chromatin
            templates; ChIP-linked acetylation changes), supporting specific
            transcriptional regulation terms rather than broad pathway-level
            terms (which can be context- and tissue-dependent).
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        MAML1's transcription coactivator activity is supported by direct
        experimental evidence and is not just an automated inference.
      action: ACCEPT
      reason: >-
        This is the core molecular function of MAML1 in Notch transcriptional
        activation.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        MAML1 participates in canonical Notch signaling through the nuclear
        transcriptional activation step.
      action: KEEP_AS_NON_CORE
      reason: >-
        The broad pathway term is defensible, but Falcon and the primary
        literature indicate the more precise curatable process is positive
        regulation of transcription of Notch target genes.
      supported_by:
        - reference_id: PMID:11390662
          supporting_text: >-
            hMam-1 stabilizes and participates in the DNA binding complex of
            the intracellular domain of human Notch1 and a CSL protein.
        - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
          supporting_text: >-
            **Prefer “Notch target gene transcription” over broad “Notch
            signaling pathway”** unless direct pathway-level phenotypes are
            tied specifically to human MAML1 (not dnMAML pan-inhibition, not
            paralog redundancy).
  - term:
      id: GO:0007221
      label: positive regulation of transcription of Notch receptor target
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        MAML1 positively regulates transcription of Notch receptor target genes
        through the ICN-RBPJ/CSL-MAML transcriptional activation complex.
      action: ACCEPT
      reason: >-
        This term is more specific than broad Notch signaling pathway and is
        directly supported by HES1 activation evidence.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Nuclear subcompartment localization has been reported, but Falcon
        cautions that nuclear-body/speck evidence is often overexpression-based.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        The broader nuclear/nucleoplasm localization is well supported, whereas
        nuclear speck is more specific than the strongest direct evidence
        warrants for a core annotation.
      supported_by:
        - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
          supporting_text: >-
            **Nuclear bodies/specks:** nuclear-body localization is supported
            but is **often overexpression-linked**; annotate cautiously at
            specific subnuclear compartments.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        MAML1 positively regulates RNA polymerase II transcription by acting as
        a coactivator in Notch and p53-responsive transcriptional complexes.
      action: ACCEPT
      reason: >-
        The term is broad, but it is directly supported by MAML1-dependent
        activation of Notch target transcription and p53-dependent gene
        induction.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
        - reference_id: PMID:17317671
          supporting_text: >-
            Overexpression of wild-type MAML1 as well as a mutant, defective in
            Notch signaling, enhanced the p53-dependent gene induction in
            mammalian cells, whereas MAML1 knockdown reduced the p53-dependent
            gene expression.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12370315
    review:
      summary: >-
        Bare protein binding row from an IntAct interaction with RBPJ/CSL
        (UniProtKB:P46531). The underlying interaction is real, but the term is
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Per curation guidelines, bare protein binding (GO:0005515) is not
        informative about MAML1's molecular function. The biological substance
        of this RBPJ/CSL interaction (assembly of the Notch transcription
        activation complex) is captured by the accepted transcription
        coactivator activity (GO:0003713) and the MAML1-RBP-Jkappa-ICN1 complex
        (GO:0002193) annotations.
      supported_by:
        - reference_id: PMID:12370315
          supporting_text: >-
            Identification of a family of mastermind-like transcriptional
            coactivators for mammalian notch receptors.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16530044
    review:
      summary: >-
        Bare protein binding row from the crystal structure of the Notch
        transcription complex showing MAML recruitment to NICD-RBPJ. The
        interaction is well established but the term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        GO:0005515 protein binding is uninformative. The structurally
        characterized MAML1 recruitment to the NICD-RBPJ complex is captured by
        the accepted transcription coactivator activity and the
        MAML1-RBP-Jkappa-ICN1 complex annotations.
      supported_by:
        - reference_id: PMID:16530044
          supporting_text: >-
            Structural basis for cooperativity in recruitment of MAML
            coactivators to Notch transcription complexes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18427106
    review:
      summary: >-
        Bare protein binding row derived from an IntAct interaction with
        RBPJ/CSL (UniProtKB:P46531) catalogued in a Notch/hypoxia paper. The
        term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        GO:0005515 protein binding does not describe a molecular function. The
        MAML1-RBPJ interaction underlying these IntAct rows is already
        represented by the accepted Notch transcription coactivator and complex
        membership annotations.
      supported_by:
        - reference_id: PMID:18427106
          supporting_text: >-
            Notch signaling mediates hypoxia-induced tumor cell migration and
            invasion.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19907488
    review:
      summary: >-
        Bare protein binding row from the SAHM1 stapled-peptide study that
        targets the MAML1-NICD-RBPJ transcription complex. The interaction is
        genuine but the term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        GO:0005515 protein binding is uninformative; the functional content
        (MAML1 as a coactivator within the Notch transcription factor complex)
        is captured by accepted MF and complex annotations.
      supported_by:
        - reference_id: PMID:19907488
          supporting_text: >-
            Direct inhibition of the NOTCH transcription factor complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20972443
    review:
      summary: >-
        Bare protein binding row from a structural study of dimeric Notch
        transcription complexes that include MAML. The interaction is genuine
        but the term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        GO:0005515 protein binding adds no functional information beyond the
        accepted coactivator and Notch transcription complex annotations.
      supported_by:
        - reference_id: PMID:20972443
          supporting_text: >-
            Structural and mechanistic insights into cooperative assembly of
            dimeric Notch transcription complexes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22325781
    review:
      summary: >-
        Bare protein binding row from an X-ray/HX-MS structural study of the
        human MAML1/RAM/ANK/CSL/DNA Notch transcription complex. The interaction
        is well established but the term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        GO:0005515 protein binding is uninformative about molecular function.
        The structurally characterized MAML1 recruitment to the NICD-CSL complex
        is already captured by the accepted transcription coactivator activity
        (GO:0003713) and MAML1-RBP-Jkappa-ICN1 complex (GO:0002193) annotations.
      supported_by:
        - reference_id: PMID:22325781
          supporting_text: >-
            we report the X-ray structure of a human MAML1/RAM/ANK/CSL/DNA
            complex, and probe changes in component dynamics upon stepwise
            assembly of a MAML1/NICD/CSL complex using HX-MS.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23022380
    review:
      summary: >-
        Bare protein binding row derived from a NOTCH1 nuclear interactome study
        that confirms MAML1 as part of the core ICN1-CSL-MAML1 activation
        complex. The interaction is genuine but the term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        GO:0005515 protein binding does not describe a molecular function. The
        MAML1 membership in the Notch core activation complex described here is
        already captured by the accepted transcription coactivator activity and
        MAML1-RBP-Jkappa-ICN1 complex annotations.
      supported_by:
        - reference_id: PMID:23022380
          supporting_text: >-
            beyond the well-characterized core activation complex
            (ICN1-CSL-MAML1), NOTCH1 assembles a multifunctional complex
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        MAML1 is a nuclear protein with an NLS that functions in DNA-bound Notch
        transcription complexes; nuclear localization is well supported.
      action: ACCEPT
      reason: >-
        Nuclear localization is robustly supported by direct experimental
        evidence (PMID:11101851) and is consistent with the core transcriptional
        coactivator function. The IEA term is appropriate, if broader than the
        nucleoplasm assignment.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            Here we clone MAML1, a human homologue of the Drosophila gene
            Mastermind, and show that it encodes a protein of 130 kD
            localizing to nuclear bodies.
  - term:
      id: GO:0010831
      label: positive regulation of myotube differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        MAML1 promotes myotube formation as a coactivator for MEF2C, an activity
        documented in mouse and transferred to human by ortholog inference.
      action: KEEP_AS_NON_CORE
      reason: >-
        Maml1-null fibroblasts fail MyoD-induced differentiation and MAML1
        overexpression enhances myotube formation, supporting positive
        regulation of myotube differentiation. This is a genuine Notch-
        independent (MEF2C) function but is peripheral to the core Notch
        coactivator role.
      supported_by:
        - reference_id: PMID:16510869
          supporting_text: >-
            overexpression of MAML1 in C2C12 cells dramatically enhanced myotube
            formation and increased the expression of muscle-specific genes,
            while RNA interference (RNAi)-mediated MAML1 knockdown abrogated
            differentiation.
  - term:
      id: GO:0045445
      label: myoblast differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        MAML1 is required for myogenic differentiation, documented in mouse and
        transferred to human by ortholog inference.
      action: KEEP_AS_NON_CORE
      reason: >-
        Maml1-null embryonic fibroblasts fail to undergo MyoD-induced myogenic
        differentiation, supporting a role in myoblast/muscle differentiation.
        This is a genuine but non-core (MEF2C-mediated, Notch-independent)
        process relative to the core Notch coactivator function.
      supported_by:
        - reference_id: PMID:16510869
          supporting_text: >-
            In vitro, Maml1-null embryonic fibroblasts failed to undergo
            MyoD-induced myogenic differentiation, further suggesting that Maml1
            is required for muscle development.
  - term:
      id: GO:0051149
      label: positive regulation of muscle cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        MAML1 positively regulates muscle cell differentiation via MEF2C
        coactivation, documented in mouse and transferred by ortholog inference.
      action: KEEP_AS_NON_CORE
      reason: >-
        MAML1 enhances muscle-specific gene expression and myotube formation and
        is required for myogenesis. This supports positive regulation of muscle
        cell differentiation, a genuine but non-core function relative to the
        core Notch coactivator role.
      supported_by:
        - reference_id: PMID:16510869
          supporting_text: >-
            overexpression of MAML1 in C2C12 cells dramatically enhanced myotube
            formation and increased the expression of muscle-specific genes
  - term:
      id: GO:0060928
      label: atrioventricular node cell development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Cardiac/atrioventricular node development is attributed to MAML1 via
        Notch-pathway roles in the mouse ortholog and transferred to human by
        automated ortholog inference.
      action: KEEP_AS_NON_CORE
      reason: >-
        AV node development is a plausible developmental output of MAML-dependent
        Notch signaling, but direct attribution to human MAML1 is indirect
        (ortholog/pathway-based, with potential MAML paralog redundancy). Keep as
        a non-core developmental annotation rather than a core function.
      supported_by:
        - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
          supporting_text: >-
            Avoid over-broad human MAML1 developmental annotations unless
            supported by direct gene-specific experiments; dnMAML affects
            multiple MAML paralogs/pathway output.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Direct immunofluorescence localization (Human Protein Atlas) places
        MAML1 in the nucleoplasm, consistent with its nuclear coactivator role.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the supported subnuclear compartment for MAML1's
        DNA-bound transcriptional coactivator function, corroborated by direct
        experimental nuclear localization in the primary literature.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            Here we clone MAML1, a human homologue of the Drosophila gene
            Mastermind, and show that it encodes a protein of 130 kD
            localizing to nuclear bodies.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:32601208
    review:
      summary: >-
        MAML1 acts as part of the nuclear Notch transcription factor complex, the
        target of the small-molecule inhibitor characterized in this study.
      action: ACCEPT
      reason: >-
        Nuclear localization is the supported cellular context for MAML1's
        function within the Notch transcription activation complex.
      supported_by:
        - reference_id: PMID:32601208
          supporting_text: >-
            the use of drug-like small molecules to target the downstream
            mediators of Notch signaling, the Notch transcription activation
            complex
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:32601208
    review:
      summary: >-
        MAML1 is a component of the Notch transcription activation complex whose
        pharmacological disruption inhibits Notch signaling output.
      action: KEEP_AS_NON_CORE
      reason: >-
        The broad pathway term is defensible as context, but the more precise
        curatable process for MAML1's direct role is positive regulation of
        transcription of Notch target genes. Keep this as non-core.
      supported_by:
        - reference_id: PMID:32601208
          supporting_text: >-
            we describe a pharmacological strategy that interferes with Notch
            signaling by disrupting the Notch transcription complex
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:32601208
    review:
      summary: >-
        As a component of the Notch transcription activation complex, MAML1
        positively regulates transcription of Notch target genes.
      action: ACCEPT
      reason: >-
        Positive regulation of DNA-templated transcription is supported by
        MAML1's coactivator role in the Notch transcription complex; disrupting
        the complex reduces this transcriptional output. The more specific
        RNA Pol II and Notch-target-gene terms are also annotated.
      supported_by:
        - reference_id: PMID:32601208
          supporting_text: >-
            we describe a pharmacological strategy that interferes with Notch
            signaling by disrupting the Notch transcription complex
  - term:
      id: GO:0003162
      label: atrioventricular node development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Atrioventricular node development is inferred for MAML1 by curator
        sequence-similarity transfer (ISS) from Notch pathway components, not
        from direct human MAML1 experiments.
      action: KEEP_AS_NON_CORE
      reason: >-
        AV node development is a plausible developmental consequence of
        MAML-dependent Notch signaling, but the attribution to human MAML1 is
        indirect (ISS from NOTCH/ortholog) and subject to MAML paralog
        redundancy. Retain as a non-core developmental annotation.
      supported_by:
        - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
          supporting_text: >-
            Avoid over-broad human MAML1 developmental annotations unless
            supported by direct gene-specific experiments; dnMAML affects
            multiple MAML paralogs/pathway output.
  - term:
      id: GO:0060928
      label: atrioventricular node cell development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Atrioventricular node cell development is inferred for MAML1 by curator
        sequence-similarity transfer (ISS) from the mouse Maml1 ortholog, not
        from direct human MAML1 experiments.
      action: KEEP_AS_NON_CORE
      reason: >-
        This duplicates the IEA AV node cell development annotation and rests on
        ortholog-based Notch developmental roles rather than direct human MAML1
        evidence. Retain as a non-core developmental annotation.
      supported_by:
        - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
          supporting_text: >-
            Avoid over-broad human MAML1 developmental annotations unless
            supported by direct gene-specific experiments; dnMAML affects
            multiple MAML paralogs/pathway output.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1912394
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        the NICD-RBPJ coactivator complex assembly reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-212356
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2197588
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2220957
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2220964
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2220971
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2976742
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4396371
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4396379
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4396392
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4396393
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4396401
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-4396402
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8878220
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8878237
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9017835
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9018542
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9021406
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9021451
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9021480
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-2064916
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-2065178
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-4396363
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-9013647
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-9013660
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-9013699
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-NUL-9604511
    review:
      summary: >-
        Reactome traceable assertion placing MAML in the nucleoplasm as part of
        a NICD-RBPJ-MAML Notch coactivator complex reaction.
      action: ACCEPT
      reason: >-
        Nucleoplasm is the correct subnuclear compartment for MAML1's role in
        the Notch transcription activation complex, consistent with direct
        experimental nuclear localization. One of many redundant Reactome rows.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0002193
      label: MAML1-RBP-Jkappa- ICN1 complex
    evidence_type: IDA
    original_reference_id: PMID:16510869
    review:
      summary: >-
        MAML1 is a component of the Notch intracellular domain-RBPJ/CSL
        transcriptional activation complex.
      action: ACCEPT
      reason: >-
        The term is a specific cellular component representation of the
        canonical Notch transcription activation complex. The original cited
        PMID is myogenesis-focused, so the support should rely on the direct
        Notch complex papers.
      supported_by:
        - reference_id: PMID:11390662
          supporting_text: >-
            hMam-1 stabilizes and participates in the DNA binding complex of
            the intracellular domain of human Notch1 and a CSL protein.
        - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
          supporting_text: >-
            Specific complex membership: NICD–RBPJ–MAML1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16510869
    review:
      summary: >-
        Bare protein binding rows from the myogenesis paper capturing the MAML1
        interactions with MEF2C and RBPJ. The interactions are real but the term
        is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        GO:0005515 protein binding is uninformative about molecular function.
        The functional content (MAML1 coactivation of MEF2C-mediated muscle
        transcription, and Notch complex membership) is captured by the
        transcription coactivator activity and muscle-differentiation
        annotations.
      supported_by:
        - reference_id: PMID:16510869
          supporting_text: >-
            we determined that MAML1 interacts with MEF2C (myocyte enhancer
            factor 2C), functioning as its potent co-transcriptional regulator.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:16510869
    review:
      summary: >-
        MAML1 functions as a nuclear coactivator (for MEF2C and Notch), placing
        it in the nucleus.
      action: ACCEPT
      reason: >-
        Nuclear localization is the supported cellular context for MAML1's
        coactivator function, consistent across the Notch and MEF2C literature.
      supported_by:
        - reference_id: PMID:16510869
          supporting_text: >-
            we determined that MAML1 interacts with MEF2C (myocyte enhancer
            factor 2C), functioning as its potent co-transcriptional regulator.
  - term:
      id: GO:0006468
      label: protein phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:16510869
    review:
      summary: >-
        MISANNOTATION: MAML1 is a transcriptional coactivator, not a kinase,
        and the cited PMID:16510869 supports MEF2C coactivation/myogenesis
        rather than protein phosphorylation.
      action: REMOVE
      reason: >-
        The essence of the annotation is not sound: MAML1 does not catalyze
        protein phosphorylation in this paper. MAML1's non-catalytic CDK8
        recruitment role is already captured separately by the accepted
        GO:0019901 protein kinase binding row based on PMID:15546612.
      supported_by:
        - reference_id: PMID:16510869
          supporting_text: >-
            Our study thus reveals novel and nonredundant functions for MAML1:
            It acts as a coactivator for MEF2C transcription and is essential
            for proper muscle development.
  - term:
      id: GO:0010831
      label: positive regulation of myotube differentiation
    evidence_type: IGI
    original_reference_id: PMID:16510869
    review:
      summary: >-
        MAML1 promotes myotube differentiation as a MEF2C coactivator,
        demonstrated by gain- and loss-of-function in C2C12 cells and Maml1-null
        fibroblasts.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a directly supported (IGI, MyoD genetic interaction) muscle
        differentiation function, but it is a Notch-independent MEF2C-mediated
        activity peripheral to MAML1's core Notch coactivator role.
      supported_by:
        - reference_id: PMID:16510869
          supporting_text: >-
            overexpression of MAML1 in C2C12 cells dramatically enhanced myotube
            formation and increased the expression of muscle-specific genes,
            while RNA interference (RNAi)-mediated MAML1 knockdown abrogated
            differentiation.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:16510869
    review:
      summary: >-
        MAML1 positively regulates RNA polymerase II transcription as a
        coactivator for MEF2C-mediated muscle-specific gene expression.
      action: ACCEPT
      reason: >-
        Direct evidence that MAML1 acts as a potent co-transcriptional regulator
        of MEF2C and increases muscle-specific gene expression supports positive
        regulation of RNA Pol II transcription.
      supported_by:
        - reference_id: PMID:16510869
          supporting_text: >-
            we determined that MAML1 interacts with MEF2C (myocyte enhancer
            factor 2C), functioning as its potent co-transcriptional regulator.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11101851
    review:
      summary: >-
        Bare protein binding rows from the founding MAML1 paper capturing
        interactions with NOTCH intracellular domains and RBPJ. The interactions
        are central but the term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        GO:0005515 protein binding does not describe MAML1's molecular function.
        The functionally meaningful content (binding the Notch ANK domain to
        assemble the ICN-RBPJ-MAML transcription complex) is captured by the
        accepted transcription coactivator activity and MAML1-RBP-Jkappa-ICN1
        complex annotations.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11390662
    review:
      summary: >-
        Bare protein binding row from a paper showing hMam-1 coordinates nuclear
        Notch and CSL into a transcriptional activator complex. The interaction
        is real but the term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        GO:0005515 protein binding is uninformative. The substance of this
        MAML1-Notch-CSL interaction (assembly/stabilization of the DNA-bound
        Notch transcription activation complex) is already captured by the
        accepted coactivator and complex-membership annotations.
      supported_by:
        - reference_id: PMID:11390662
          supporting_text: >-
            hMam-1 stabilizes and participates in the DNA binding complex of
            the intracellular domain of human Notch1 and a CSL protein.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:9874765
    review:
      summary: >-
        Nucleus localization annotation; the cited PMID:9874765 is a CIR/CBF1
        corepressor paper only tangentially related to MAML1, but nuclear
        localization of MAML1 is independently well established.
      action: ACCEPT
      reason: >-
        Although the original reference is principally about the CBF1/CSL
        corepressor CIR rather than direct MAML1 localization, the nucleus
        assignment is correct and robustly supported by direct MAML1
        experiments (PMID:11101851).
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            Here we clone MAML1, a human homologue of the Drosophila gene
            Mastermind, and show that it encodes a protein of 130 kD
            localizing to nuclear bodies.
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IPI
    original_reference_id: PMID:15546612
    review:
      summary: >-
        MAML1 binds/recruits CDK8 in the Notch transcription complex to promote
        Notch intracellular domain phosphorylation and turnover.
      action: ACCEPT
      reason: >-
        This is a specific and informative interaction term supported by the
        CDK8 recruitment paper, unlike generic protein binding rows.
      supported_by:
        - reference_id: PMID:15546612
          supporting_text: >-
            MAM interacts directly with CDK8 and can cause it to localize to
            subnuclear foci.
        - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
          supporting_text: >-
            Mediator kinase module recruitment and NICD phosphorylation/turnover.
  - term:
      id: GO:0042605
      label: peptide antigen binding
    evidence_type: IPI
    original_reference_id: PMID:17317671
    review:
      summary: >-
        The cited paper shows MAML1 interaction with p53 and transcriptional
        coactivator activity, not peptide antigen binding.
      action: REMOVE
      reason: >-
        Peptide antigen binding is unsupported and appears to be an erroneous
        interpretation of a p53 interaction/coactivator paper.
      supported_by:
        - reference_id: PMID:17317671
          supporting_text: >-
            MAML1-p53 interaction involves the N-terminal region of MAML1 and
            the DNA-binding domain of p53, and we use a chromatin
            immunoprecipitation assay to show that MAML1 is part of the
            activator complex that binds to native p53-response elements within
            the promoter of the p53 target genes.
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IDA
    original_reference_id: PMID:11101851
    review:
      summary: >-
        MAML1 is a transcriptional coactivator for Notch receptor intracellular
        domains and RBPJ/CSL.
      action: ACCEPT
      reason: >-
        This direct experimental annotation captures the principal molecular
        function of MAML1.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:11101851
    review:
      summary: >-
        MAML1 is a nuclear protein that acts in nuclear Notch transcription
        complexes.
      action: ACCEPT
      reason: >-
        Nuclear localization is the supported cellular context for the core
        transcriptional coactivator function.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:11101851
    review:
      summary: >-
        MAML1 acts in the nuclear transcriptional arm of the Notch signaling
        pathway.
      action: KEEP_AS_NON_CORE
      reason: >-
        The broad pathway term is acceptable as context, but the more specific
        curated process is activation of Notch target gene transcription.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:11101851
    review:
      summary: >-
        MAML1 positively regulates RNA polymerase II transcription as a Notch
        transcriptional coactivator.
      action: ACCEPT
      reason: >-
        Reporter and complex-assembly evidence support MAML1-dependent
        activation of Notch target transcription.
      supported_by:
        - reference_id: PMID:11101851
          supporting_text: >-
            MAML1 binds to the ankyrin repeat domain of all four mammalian
            NOTCH receptors, forms a DNA-binding complex with ICN and
            RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    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:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:11101851
    title: MAML1, a human homologue of Drosophila mastermind, is a 
      transcriptional co-activator for NOTCH receptors.
    findings:
      - statement: >-
          MAML1 binds Notch intracellular domains, forms a DNA-binding complex
          with ICN and RBP-Jkappa, and amplifies Notch-induced HES1
          transcription.
        supporting_text: >-
          MAML1 binds to the ankyrin repeat domain of all four mammalian NOTCH
          receptors, forms a DNA-binding complex with ICN and RBP-Jkappa, and
          amplifies NOTCH-induced transcription of HES1.
  - id: PMID:11390662
    title: A human protein with sequence similarity to Drosophila mastermind 
      coordinates the nuclear form of notch and a CSL protein to build a 
      transcriptional activator complex on target promoters.
    findings:
      - statement: >-
          Human MAML1 stabilizes and participates in the DNA-binding complex of
          intracellular Notch1 and CSL.
        supporting_text: >-
          hMam-1 stabilizes and participates in the DNA binding complex of the
          intracellular domain of human Notch1 and a CSL protein.
  - id: PMID:12370315
    title: Identification of a family of mastermind-like transcriptional 
      coactivators for mammalian notch receptors.
    findings: []
  - id: PMID:15546612
    title: Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and 
      coordinate activation with turnover.
    findings:
      - statement: >-
          Mastermind/MAML binds CDK8 and helps recruit the kinase machinery that
          phosphorylates Notch intracellular domain.
        supporting_text: >-
          MAM interacts directly with CDK8 and can cause it to localize to
          subnuclear foci.
  - id: PMID:16510869
    title: The Notch coactivator, MAML1, functions as a novel coactivator for 
      MEF2C-mediated transcription and is required for normal myogenesis.
    findings: []
  - id: PMID:16530044
    title: Structural basis for cooperativity in recruitment of MAML 
      coactivators to Notch transcription complexes.
    findings: []
  - id: PMID:17317671
    title: The notch regulator MAML1 interacts with p53 and functions as a 
      coactivator.
    findings:
      - statement: >-
          MAML1 interacts with p53 and acts as a transcriptional coactivator on
          p53 target genes, supporting coactivator activity but not peptide
          antigen binding.
        supporting_text: >-
          MAML1-p53 interaction involves the N-terminal region of MAML1 and the
          DNA-binding domain of p53, and we use a chromatin immunoprecipitation
          assay to show that MAML1 is part of the activator complex that binds
          to native p53-response elements within the promoter of the p53 target
          genes.
  - id: PMID:18427106
    title: Notch signaling mediates hypoxia-induced tumor cell migration and 
      invasion.
    findings: []
  - id: PMID:19907488
    title: Direct inhibition of the NOTCH transcription factor complex.
    findings: []
  - id: PMID:20972443
    title: Structural and mechanistic insights into cooperative assembly of 
      dimeric Notch transcription complexes.
    findings: []
  - id: PMID:22325781
    title: Conformational locking upon cooperative assembly of notch 
      transcription complexes.
    findings: []
  - id: PMID:23022380
    title: NOTCH1 nuclear interactome reveals key regulators of its 
      transcriptional activity and oncogenic function.
    findings: []
  - id: PMID:32601208
    title: Pharmacological disruption of the Notch transcription factor complex.
    findings: []
  - id: PMID:9874765
    title: CIR, a corepressor linking the DNA binding factor CBF1 to the histone
      deacetylase complex.
    findings: []
  - id: file:human/MAML1/MAML1-deep-research-falcon.md
    title: Falcon deep research on MAML1 GO-relevant functions
    findings:
      - statement: >-
          MAML1 is best modeled as a Notch transcription coactivator and
          complex-associated regulator rather than a generic protein-binding
          protein.
        supporting_text: >-
          MAML1 is better captured by Notch transcription
          coactivator/complex-associated terms than by a broad “protein
          binding” annotation alone.
      - statement: >-
          Notch target-gene transcription terms are more precise than broad
          Notch pathway terms for MAML1's direct role.
        supporting_text: >-
          **Prefer “Notch target gene transcription” over broad “Notch
          signaling pathway”** unless direct pathway-level phenotypes are tied
          specifically to human MAML1 (not dnMAML pan-inhibition, not paralog
          redundancy).
      - statement: >-
          Nuclear speck/nuclear body annotations should be curated cautiously.
        supporting_text: >-
          **Nuclear bodies/specks:** nuclear-body localization is supported but
          is **often overexpression-linked**; annotate cautiously at specific
          subnuclear compartments.
  - id: Reactome:R-HSA-1912394
    title: NICD1 in complex with RBPJ (CSL) recruits MAML
    findings: []
  - id: Reactome:R-HSA-212356
    title: Formation of CSL-NICD coactivator complex
    findings: []
  - id: Reactome:R-HSA-2197588
    title: NICD2 binds RBPJ and MAML in the nucleus
    findings: []
  - id: Reactome:R-HSA-2220957
    title: NOTCH1 PEST domain mutants coactivator complex binds CDK8:CCNC
    findings: []
  - id: Reactome:R-HSA-2220964
    title: NICD1 PEST domain mutants in complex with RBPJ (CSL) bind MAML
    findings: []
  - id: Reactome:R-HSA-2220971
    title: CDK8 phosphorylates NICD1 PEST domain mutants
    findings: []
  - id: Reactome:R-HSA-2976742
    title: NOTCH2 coactivator complex binds FCER2 promoter
    findings: []
  - id: Reactome:R-HSA-4396371
    title: NOTCH1 Coactivator Complex binds MYC promoter
    findings: []
  - id: Reactome:R-HSA-4396379
    title: NOTCH1 Coactivator Complex binds HES5 promoter
    findings: []
  - id: Reactome:R-HSA-4396392
    title: NOTCH1 PEST domain mutants bind HES1 promoter
    findings: []
  - id: Reactome:R-HSA-4396393
    title: NOTCH1 PEST domain mutants bind MYC promoter
    findings: []
  - id: Reactome:R-HSA-4396401
    title: NOTCH1 PEST domain mutants bind HES5 promoter
    findings: []
  - id: Reactome:R-HSA-4396402
    title: NOTCH1 PEST domain mutants bind promoters of HEY genes
    findings: []
  - id: Reactome:R-HSA-8878220
    title: RUNX3 binds the NOTCH1 coactivator complex
    findings: []
  - id: Reactome:R-HSA-8878237
    title: RUNX3:NOTCH1 coactivator complex binds the HES1 gene promoter
    findings: []
  - id: Reactome:R-HSA-9017835
    title: NOTCH1 coactivator complex binds NOTCH3 gene
    findings: []
  - id: Reactome:R-HSA-9018542
    title: NOTCH3 coactivator complex binds DLGAP5 gene promoter
    findings: []
  - id: Reactome:R-HSA-9021406
    title: NOTCH3 coactivator complex binds PBX1 gene promoter
    findings: []
  - id: Reactome:R-HSA-9021451
    title: NOTCH1,NOTCH3 coactivator complex binds PLXND1 gene promoter
    findings: []
  - id: Reactome:R-HSA-9021480
    title: NOTCH3 coactivator complex binds WWC1 (Kibra) gene promoter
    findings: []
  - id: Reactome:R-NUL-2064916
    title: MAML recruits CDK8:CCNC to xNICD1
    findings: []
  - id: Reactome:R-NUL-2065178
    title: CDK8 phosphorylates xNICD1
    findings: []
  - id: Reactome:R-NUL-4396363
    title: mNICD1 Chimeric Enhancer Complex binds Hes1 promoter
    findings: []
  - id: Reactome:R-NUL-9013647
    title: NICD3 binds RBPJ and MAML in the nucleus
    findings: []
  - id: Reactome:R-NUL-9013660
    title: Notch3 coactivator complex binds Hes1 gene promoter
    findings: []
  - id: Reactome:R-NUL-9013699
    title: NICD4 binds RBPJ and MAML in the nucleus
    findings: []
  - id: Reactome:R-NUL-9604511
    title: Notch4 binds FLT4 gene promoter
    findings: []
core_functions:
  - molecular_function:
      id: GO:0003713
      label: transcription coactivator activity
    description: >-
      MAML1 is a nuclear transcriptional coactivator for Notch intracellular
      domain-RBPJ/CSL complexes. It forms a DNA-bound transcriptional activation
      complex that promotes HES1-class Notch target gene transcription, and it
      also has direct evidence for p53 coactivator activity.
    directly_involved_in:
      - id: GO:0007221
        label: positive regulation of transcription of Notch receptor target
      - id: GO:0045944
        label: positive regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0005634
        label: nucleus
      - id: GO:0005654
        label: nucleoplasm
    supported_by:
      - reference_id: PMID:11101851
        supporting_text: >-
          MAML1 binds to the ankyrin repeat domain of all four mammalian NOTCH
          receptors, forms a DNA-binding complex with ICN and RBP-Jkappa, and
          amplifies NOTCH-induced transcription of HES1.
      - reference_id: PMID:17317671
        supporting_text: >-
          Overexpression of wild-type MAML1 as well as a mutant, defective in
          Notch signaling, enhanced the p53-dependent gene induction in
          mammalian cells, whereas MAML1 knockdown reduced the p53-dependent
          gene expression.
      - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
        supporting_text: >-
          MAML1 is better captured by Notch transcription
          coactivator/complex-associated terms than by a broad “protein
          binding” annotation alone.
  - molecular_function:
      id: GO:0019901
      label: protein kinase binding
    description: >-
      MAML1 directly binds/recruits CDK8 in the Notch transcription complex,
      coupling Notch transcriptional activation to Notch intracellular domain
      phosphorylation and turnover. This is a specific binding function and
      should not be collapsed into generic protein binding.
    locations:
      - id: GO:0005634
        label: nucleus
      - id: GO:0005654
        label: nucleoplasm
    supported_by:
      - reference_id: PMID:15546612
        supporting_text: >-
          MAM interacts directly with CDK8 and can cause it to localize to
          subnuclear foci.
      - reference_id: file:human/MAML1/MAML1-deep-research-falcon.md
        supporting_text: >-
          Mediator kinase module recruitment and NICD phosphorylation/turnover.
proposed_new_terms: []
suggested_questions:
  - question: >-
      Which MAML1 developmental annotations are directly supported by human
      MAML1-specific experiments rather than pan-MAML or Notch pathway
      perturbation?
  - question: >-
      Are endogenous MAML1 nuclear bodies equivalent to nuclear specks in the
      contexts represented by GOA annotations?
suggested_experiments:
  - description: >-
      Use endogenous-tagged MAML1 with Notch activation time courses to map
      nuclear subcompartment localization and distinguish nucleoplasm, nuclear
      body, and nuclear speck assignments.
  - description: >-
      Perform MAML1-specific rescue after knockout at representative Notch,
      p53, and myogenic target genes to separate direct MAML1 functions from
      broader Notch pathway or paralog-redundant effects.