STAT4

id: Q14765
gene_symbol: STAT4
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: STAT4 (Signal Transducer and Activator of Transcription 4) is a 
  latent cytoplasmic transcription factor of the STAT family (748 aa) that 
  serves as the canonical effector of interleukin-12 (IL-12) signaling. Upon 
  IL-12 binding to its receptor (IL12RB2), JAK2/TYK2 kinases phosphorylate STAT4
  at Tyr-693, enabling SH2-mediated homodimerization, nuclear translocation, and
  binding to STAT target sequences in IL-12-responsive genes (PMID:7638186, 
  PMID:10961885). Serine phosphorylation at Ser-721 by MKK6/p38 augments 
  transcriptional activity and is critical for IFN-gamma production 
  (PMID:12213961). STAT4 is essential for Th1 cell differentiation and IFN-gamma
  production, and also participates in T follicular regulatory (Tfr) cell 
  programming, NK cell function, and dendritic cell inflammatory programs via 
  IL-23 signaling. STAT4 can also be activated by type I IFNs (IFN-alpha/beta), 
  IL-23, IL-35, and IL-21. Two splice isoforms exist (STAT4a with TAD and STAT4b
  lacking TAD). Genetic variants in STAT4 (notably rs7574865) are strongly 
  associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis 
  (RA). Gain-of-function variants cause disabling pansclerotic morphea of 
  childhood (DPMC) (PMID:37256972).
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 is a latent cytoplasmic protein that resides in the cytoplasm
      prior to activation. This is well established from the deep research 
      review and UniProt subcellular location data. IBA annotation is consistent
      with all evidence.
    action: ACCEPT
    reason: STAT4 is cytoplasmic in its inactive (unphosphorylated) state. Upon 
      cytokine stimulation and tyrosine phosphorylation, it translocates to the 
      nucleus. The cytoplasmic localization is well supported by UniProt 
      annotation and multiple studies.
    supported_by:
    - reference_id: PMID:9284918
      supporting_text: STAT4 is phosphorylated following interleukin (IL)-12 
        stimulation and is essential for IL-12 signal transduction
- term:
    id: GO:0006952
    label: defense response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 plays a key role in innate and adaptive immune defense 
      responses through its role in Th1 differentiation, IFN-gamma production, 
      and NK cell function. The IBA annotation is phylogenetically well 
      supported across STAT family members.
    action: ACCEPT
    reason: STAT4 is essential for Th1-mediated defense responses including 
      IFN-gamma production, which is a critical cytokine for defense against 
      intracellular pathogens. The defense response annotation is appropriate at
      this level for a core immune signaling transcription factor. IBA 
      phylogenetic inference is consistent with the known biology.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: IL-12 induces STAT4 activation, which, in T cells, 
        promoted the acquisition of a T helper 1 (Th1) effector phenotype and 
        the subsequent production of IFN-gamma
- term:
    id: GO:0042127
    label: regulation of cell population proliferation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 has roles in cell proliferation regulation, particularly in 
      the context of T cell expansion during immune responses. IL-12/STAT4 
      signaling promotes T cell proliferation, and STAT4 serine phosphorylation 
      at S721 is required for IFN-gamma production but not for cell 
      proliferation. This is a known but non-core function.
    action: KEEP_AS_NON_CORE
    reason: While STAT4 participates in regulation of cell proliferation 
      (particularly T cell expansion in response to IL-12), this is a secondary 
      consequence of its role in cytokine signaling rather than a primary 
      function. The core function is transcriptional regulation downstream of 
      cytokine receptors.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: IL-12 induces STAT4 activation, which, in T cells, 
        promoted the acquisition of a T helper 1 (Th1) effector phenotype and 
        the subsequent production of IFN-gamma
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 translocates to the nucleus upon tyrosine phosphorylation and
      dimerization, where it binds DNA and regulates transcription. Nuclear 
      localization is a core aspect of STAT4 function.
    action: ACCEPT
    reason: Nuclear localization of activated STAT4 is central to its function 
      as a transcription factor. Phosphorylated STAT4 homodimerizes and migrates
      to the nucleus to bind STAT target sequences. This is supported by IDA 
      evidence (PMID:7638186) and UniProt subcellular location data.
    supported_by:
    - reference_id: PMID:9284918
      supporting_text: STAT4 is phosphorylated following interleukin (IL)-12 
        stimulation and is essential for IL-12 signal transduction
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 binds specific DNA sequences (STAT binding sites/GAS 
      elements) in the regulatory regions of target genes. IBA annotation is 
      well supported by the known DNA-binding domain structure and function of 
      STAT family members.
    action: ACCEPT
    reason: STAT4 contains a well-characterized DNA-binding domain (p53-like 
      fold) that recognizes GAS (Gamma-Activated Sequence) elements in the 
      promoters of target genes. The IBA annotation is appropriate and 
      consistent with the known biology of STAT family transcription factors. 
      This is the specific DNA-binding MF term that correctly describes what 
      STAT4 does.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: STAT dimers could then bind their target sequence, 
        recruit coactivators and effect transcription
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 regulates transcription by RNA polymerase II as a core 
      function. Upon activation, it dimerizes, translocates to the nucleus, and 
      binds to STAT binding sites in promoters to activate (or in some cases 
      repress) transcription of target genes.
    action: ACCEPT
    reason: This is a core biological process for STAT4. As a sequence-specific 
      DNA-binding transcription factor, STAT4 directly regulates Pol II-mediated
      transcription of target genes including IFNG and IL12RB2. The IBA 
      annotation is phylogenetically well supported and consistent with 
      experimental evidence.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: tyrosine phosphorylation of STAT proteins by receptor 
        binding and JAK activation could induce homodimerization of STAT 
        molecules... STAT dimers could then bind their target sequence, recruit 
        coactivators and effect transcription
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 is the canonical effector of the IL-12/JAK-STAT signaling 
      pathway. Upon IL-12 binding to IL12RB2, JAK2/TYK2 phosphorylate STAT4 at 
      Tyr-693.
    action: ACCEPT
    reason: This is the most specific and appropriate biological process for 
      STAT4. It is a central component of JAK-STAT signaling downstream of 
      multiple cytokine receptors (IL-12R, IL-23R, IFN-alpha/beta receptors). 
      The IBA annotation is fully consistent with the well-established role of 
      STAT4.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: Most cytokines predominantly transmit signals via Janus 
        kinase (just another kinase, or JAK)-signal transducer and activator of 
        transcription (STAT) pathways
- term:
    id: GO:0019221
    label: cytokine-mediated signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 is activated by multiple cytokines including IL-12, IL-23, 
      IL-35, IL-21, and type I interferons. The cytokine-mediated signaling 
      pathway annotation is appropriate as a broader characterization of STAT4 
      function.
    action: ACCEPT
    reason: STAT4 is a bona fide cytokine signal transducer. While GO:0007259 
      (JAK-STAT) is more specific, this broader term captures the fact that 
      STAT4 participates in signaling from multiple cytokine families. The IBA 
      annotation is phylogenetically well supported.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: Most cytokines predominantly transmit signals via Janus 
        kinase (just another kinase, or JAK)-signal transducer and activator of 
        transcription (STAT) pathways
- 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: STAT4 is a DNA-binding transcription factor that activates 
      transcription by RNA polymerase II. This MF annotation is the correct 
      specific term for STAT4 molecular function. The IBA inference is well 
      supported by the known domain architecture and function.
    action: ACCEPT
    reason: This is the core molecular function of STAT4. It contains a 
      DNA-binding domain, SH2 domain for dimerization, and transactivation 
      domain. Upon activation it binds specific DNA sequences and activates Pol 
      II-dependent transcription. The IBA annotation is appropriate and 
      consistent with ISA and IDA evidence.
    supported_by:
    - reference_id: PMID:9284918
      supporting_text: STAT4 is phosphorylated following interleukin (IL)-12 
        stimulation and is essential for IL-12 signal transduction
- term:
    id: GO:0090575
    label: RNA polymerase II transcription regulator complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 forms homodimers and heterodimers (with STAT1 or STAT3) that 
      function as transcription regulator complexes. ComplexPortal documents 
      STAT4 homodimer (CPX-6050), STAT1/STAT4 complex (CPX-6042), and 
      STAT3/STAT4 complex (CPX-6046).
    action: ACCEPT
    reason: STAT4 functions as part of transcription regulator complexes. It 
      forms homodimers (the primary functional unit downstream of IL-12) as well
      as heterodimers with STAT1 (downstream of IL-35) and STAT3 (downstream of 
      IL-23). The IBA annotation is consistent with ComplexPortal data and 
      experimental evidence.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: IL-12 works mainly through inducing mostly STAT4 
        homodimers... IL-23 was shown to activate STAT3 and STAT4 downstream of 
        these receptors
- term:
    id: GO:0043434
    label: response to peptide hormone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: STAT4 responds to cytokines including interleukins (IL-12, IL-23), 
      which are peptide signaling molecules. However, cytokines are typically 
      classified separately from peptide hormones in GO. This annotation may be 
      overly broad.
    action: KEEP_AS_NON_CORE
    reason: While interleukins are technically peptide signaling molecules, the 
      standard GO annotation for STAT4 activation is more precisely captured by 
      the cytokine-mediated signaling pathway and JAK-STAT pathway terms. The 
      response to peptide hormone term is not wrong (some STATs respond to 
      growth hormone, prolactin, etc.) but is a secondary characterization for 
      STAT4.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: Most cytokines predominantly transmit signals via Janus 
        kinase (just another kinase, or JAK)-signal transducer and activator of 
        transcription (STAT) pathways
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: STAT4 binds DNA through its DNA-binding domain (p53-like fold). 
      This is a correct but general annotation. More specific terms (GO:0000978)
      are available.
    action: ACCEPT
    reason: DNA binding is a fundamental property of STAT4 supported by its 
      domain architecture (IPR013801). While this IEA annotation is broader than
      the IBA annotation for GO:0000978, it is not incorrect and provides 
      appropriate coverage from the InterPro-based pipeline.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: STAT4 is a DNA-binding transcription factor. This IEA annotation 
      from InterPro/ARBA is consistent with the IBA (GO:0000981) and multiple 
      IDA annotations for the same or more specific terms.
    action: ACCEPT
    reason: Correct annotation consistent with experimental evidence. The IEA is
      broader than GO:0000981 but captures the essential molecular function of 
      STAT4.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Nuclear localization of STAT4 inferred from UniProt subcellular 
      location. Consistent with experimental data showing nuclear translocation 
      upon activation.
    action: ACCEPT
    reason: Correct. STAT4 translocates to the nucleus upon phosphorylation. 
      This IEA from UniProt subcellular location vocabulary is consistent with 
      IDA (PMID:7638186) and IBA evidence for the same term.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Cytoplasmic localization of STAT4 inferred from UniProt subcellular
      location. Consistent with experimental data showing STAT4 is cytoplasmic 
      before activation.
    action: ACCEPT
    reason: Correct. STAT4 resides in the cytoplasm in its inactive state. This 
      IEA from UniProt subcellular location vocabulary is consistent with IBA 
      evidence for the same term.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Cytosolic localization from ARBA machine learning. Consistent with 
      Reactome TAS annotations and the established biology of STAT proteins 
      being cytosolic before activation.
    action: ACCEPT
    reason: Correct. STAT4 is cytosolic in resting cells. This is a more 
      specific sub-compartment of cytoplasm, consistent with multiple Reactome 
      TAS annotations for the same term.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Regulation of transcription from InterPro domain mapping. This is a
      broader parent of the more specific IBA annotation (GO:0006357, regulation
      of transcription by RNA polymerase II).
    action: ACCEPT
    reason: Correct but general. The IEA from InterPro captures the 
      transcription regulation function of STAT4. The more specific term 
      GO:0006357 is annotated via IBA. This broader IEA annotation is 
      acceptable.
- term:
    id: GO:0006955
    label: immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: STAT4 participates in immune responses, particularly Th1-mediated 
      immunity. This broad annotation from ARBA is correct but very general.
    action: ACCEPT
    reason: Correct but general. STAT4 is essential for Th1 immunity, IFN-gamma 
      production, and defense against intracellular pathogens. The term is very 
      broad but not incorrect for an IEA annotation.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Signal transduction annotation from InterPro. STAT4 is a signal 
      transducer by definition. This is a very broad parent of the more specific
      JAK-STAT pathway term.
    action: ACCEPT
    reason: Correct but very general. STAT4 is literally named "Signal 
      Transducer and Activator of Transcription 4." The more specific term 
      GO:0007259 (JAK-STAT pathway) is annotated via IBA and other evidence 
      types. This broad IEA is acceptable.
- term:
    id: GO:0019221
    label: cytokine-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Cytokine-mediated signaling from ARBA. Consistent with the IBA 
      annotation for the same term and the well-established role of STAT4 in 
      cytokine signaling.
    action: ACCEPT
    reason: Correct. Duplicates the IBA annotation for the same term. STAT4 is 
      activated by multiple cytokines (IL-12, IL-23, IL-35, type I IFNs). The 
      IEA is consistent with experimental evidence.
- term:
    id: GO:0090575
    label: RNA polymerase II transcription regulator complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: STAT4 forms transcription regulator complexes. This IEA from ARBA 
      is consistent with the IBA annotation for the same term and ComplexPortal 
      data.
    action: ACCEPT
    reason: Correct. Duplicates the IBA annotation. STAT4 forms homodimers and 
      heterodimers that function as Pol II transcription regulator complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22740693
  review:
    summary: Protein binding to LAMTOR5 detected by IntAct. PMID:22740693 is not
      available in the publications cache. This is a high-throughput interactome
      study. The interaction with LAMTOR5 (a lysosomal adaptor) is of unclear 
      biological significance for STAT4 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is an uninformative MF term that does not describe 
      STAT4's actual molecular function. The interaction with LAMTOR5 likely 
      comes from a high-throughput screen and its biological relevance to STAT4 
      function is unclear. More informative MF terms (GO:0000981, DNA-binding TF
      activity) are available.
    supported_by:
    - reference_id: PMID:22740693
      supporting_text: HBXIP is able to activate S100A4 promoter via interacting
        with STAT4 in breast cancer cells, leading to the up-regulation of 
        S100A4
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: Protein binding detected in a neurodegenerative disease interactome
      mapping study (Haenig et al. 2020). The interacting partners are KLF11 and
      NUP58. This is a high-throughput yeast two-hybrid screen focused on 
      neurodegeneration, and the relevance to STAT4 biology is unclear.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is an uninformative MF term. The interactions 
      detected in this neurodegenerative disease-focused interactome mapping 
      study (yeast two-hybrid) are of uncertain physiological relevance for 
      STAT4. STAT4's primary molecular function is sequence-specific DNA-binding
      transcription factor activity.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Here, we report on an interactome map that focuses on 
        neurodegenerative disease (ND), connects ∼5,000 human proteins via 
        ∼30,000 candidate interactions and is generated by systematic yeast 
        two-hybrid interaction screening of ∼500 ND-related proteins and 
        integration of literature interactions
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18591661
  review:
    summary: STAT4 homodimerization detected by IntAct. This is biologically 
      relevant as STAT4 homodimers are the primary functional unit downstream of
      IL-12 signaling. ComplexPortal documents the STAT4 homodimer (CPX-6050). 
      PMID:18591661 is not available in the publications cache but UniProt 
      records the homodimer interaction.
    action: ACCEPT
    reason: STAT4 homodimerization is a well-established and functionally 
      important aspect of its biology. Upon Tyr-693 phosphorylation, STAT4 forms
      SH2-mediated homodimers that translocate to the nucleus and activate 
      transcription. This is documented in ComplexPortal (CPX-6050) and is the 
      canonical signaling mechanism downstream of IL-12.
    supported_by:
    - reference_id: PMID:18591661
      supporting_text: the N-domain dissociation constants of STAT1, STAT3, and 
        STAT4 differed by more than three orders of magnitude
    - reference_id: PMID:24058793
      supporting_text: tyrosine phosphorylation of STAT proteins by receptor 
        binding and JAK activation could induce homodimerization of STAT 
        molecules... IL-12 works mainly through inducing mostly STAT4 homodimers
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Nucleoplasm localization from HPA immunofluorescence curation. 
      STAT4 enters the nucleoplasm upon activation, which is consistent with its
      function as a nuclear transcription factor.
    action: ACCEPT
    reason: Correct. STAT4 translocates to the nucleus (specifically the 
      nucleoplasm) upon phosphorylation. HPA immunofluorescence data supports 
      this localization.
- term:
    id: GO:0016604
    label: nuclear body
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Nuclear body localization from HPA immunofluorescence curation. 
      Nuclear bodies are subnuclear structures. STAT4 may localize to nuclear 
      bodies in some contexts, but this is not a well-characterized aspect of 
      its biology.
    action: KEEP_AS_NON_CORE
    reason: While HPA immunofluorescence data may show nuclear body 
      localization, this is not a well-characterized or central aspect of STAT4 
      function. The primary nuclear localization (nucleoplasm) is more 
      informative. Keeping as non-core since the HPA data is generally reliable 
      but this does not represent a core localization.
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: NAS
  original_reference_id: PMID:15864272
  review:
    summary: JAK-STAT pathway annotation from ComplexPortal, citing Platanias 
      2005 review on interferon-mediated signaling. The review discusses 
      JAK-STAT signaling including STAT4 activation by type I and type II 
      interferons.
    action: ACCEPT
    reason: Correct. STAT4 is a canonical component of JAK-STAT signaling. The 
      Platanias review is an authoritative source on interferon/JAK-STAT 
      signaling. This duplicates the IBA and TAS annotations for the same term.
    supported_by:
    - reference_id: PMID:15864272
      supporting_text: the classical JAK (Janus activated kinase)-STAT (signal 
        transducer and activator of transcription) pathway of signalling
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: NAS
  original_reference_id: PMID:24058793
  review:
    summary: JAK-STAT pathway annotation from ComplexPortal, citing Delgoffe & 
      Vignali 2013 review on STAT heterodimers in immunity. The review discusses
      STAT4 activation by IL-12 and formation of homodimers and heterodimers.
    action: ACCEPT
    reason: Correct. The review explicitly discusses STAT4 as part of JAK-STAT 
      signaling downstream of IL-12, IL-23, and IL-35. Duplicates other evidence
      for this term.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: Most cytokines predominantly transmit signals via Janus 
        kinase (just another kinase, or JAK)-signal transducer and activator of 
        transcription (STAT) pathways... IL-12 induces STAT4 activation
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: NAS
  original_reference_id: PMID:15864272
  review:
    summary: Positive regulation of transcription from ComplexPortal, citing the
      Platanias interferon signaling review. STAT4 primarily acts as a 
      transcriptional activator upon phosphorylation and nuclear translocation.
    action: ACCEPT
    reason: Correct. STAT4 is primarily a transcriptional activator. Upon 
      activation, STAT4 dimers bind target sequences and recruit coactivators to
      drive transcription of genes such as IFNG and IL12RB2. While STAT4 can 
      also act as a transcriptional repressor in some contexts (e.g., IL5 
      repression via IFN-alpha, PMID:26990433), its primary role is 
      transcriptional activation.
    supported_by:
    - reference_id: PMID:15864272
      supporting_text: the classical JAK (Janus activated kinase)-STAT (signal 
        transducer and activator of transcription) pathway of signalling
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: NAS
  original_reference_id: PMID:24058793
  review:
    summary: Positive regulation of transcription from ComplexPortal, citing the
      STAT heterodimer review. Consistent with STAT4's role as a transcriptional
      activator in immune cells.
    action: ACCEPT
    reason: Correct. Duplicates the annotation from PMID:15864272. STAT4 
      activates transcription of target genes including IFNG.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: STAT dimers could then bind their target sequence, 
        recruit coactivators and effect transcription
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IMP
  original_reference_id: PMID:37256972
  review:
    summary: DNA-binding transcription factor activity demonstrated by mutant 
      phenotype analysis in Baghdassarian et al. 2023 (NEJM). Gain-of-function 
      STAT4 variants (H623Y, A635V, A650D) in the SH2 domain cause DPMC with 
      constitutive STAT4 activation. Abrogation of TF activity by Y693A mutation
      confirms the transcription factor function.
    action: ACCEPT
    reason: Strong evidence from characterization of gain-of-function disease 
      variants. The Y693A mutation abolishes phosphorylation and transcriptional
      activity, confirming that STAT4 functions as a DNA-binding transcription 
      factor. The gain-of-function variants show increased JAK-STAT signaling, 
      further supporting this molecular function.
    supported_by:
    - reference_id: PMID:37256972
      supporting_text: Genome sequencing revealed three novel heterozygous 
        missense gain-of-function variants in STAT4
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IMP
  original_reference_id: PMID:37256972
  review:
    summary: Nuclear localization demonstrated by mutant phenotype analysis. 
      Gain-of-function STAT4 variants show constitutive nuclear localization 
      consistent with constitutive activation of the transcription factor.
    action: ACCEPT
    reason: The gain-of-function STAT4 variants in DPMC show enhanced nuclear 
      localization, consistent with constitutive STAT4 activation. This IMP 
      evidence complements the IDA evidence from PMID:7638186 for the same term.
    supported_by:
    - reference_id: PMID:37256972
      supporting_text: Inhibition of Janus kinase (JAK)-STAT signaling with 
        ruxolitinib led to improvement in the hyperinflammatory fibroblast 
        phenotype in vitro and resolution of inflammatory markers and clinical 
        symptoms in treated patients, without adverse effects
- term:
    id: GO:0070741
    label: response to interleukin-6
  evidence_type: IMP
  original_reference_id: PMID:37256972
  review:
    summary: Response to IL-6 from the DPMC study. STAT4 gain-of-function 
      variants show enhanced signaling in the context of IL-6 family cytokines. 
      However, STAT4 is not traditionally considered a primary effector of IL-6 
      signaling (STAT3 is the canonical IL-6 effector). This annotation may 
      reflect the gain-of-function variant context rather than normal STAT4 
      biology.
    action: UNDECIDED
    reason: PMID:37256972 is now available. The paper shows that 
      gain-of-function STAT4 variants in DPMC fibroblasts exhibit enhanced 
      interleukin-6 secretion, supporting a response to IL-6 annotation. 
      However, this appears to be a consequence of the gain-of-function variant 
      rather than normal STAT4 biology, as STAT3 is the canonical effector of 
      IL-6 signaling. The annotation may reflect the disease context where 
      gain-of-function STAT4 drives an IL-6-related inflammatory phenotype.
    supported_by:
    - reference_id: PMID:37256972
      supporting_text: primary skin fibroblasts showed enhanced interleukin-6 
        secretion, with impaired wound healing, contraction of the collagen 
        matrix, and matrix secretion
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:7638186
  review:
    summary: Nuclear localization of STAT4 demonstrated by Bacon et al. 1995 
      (PNAS). This seminal paper showed that IL-12 induces tyrosine 
      phosphorylation and activation of STAT4 in human lymphocytes, with nuclear
      translocation of the activated protein.
    action: ACCEPT
    reason: Key foundational paper establishing STAT4 activation by IL-12. 
      Nuclear localization is a core aspect of STAT4 function as a transcription
      factor. UniProt cites this as evidence for FUNCTION and PHOSPHORYLATION.
    supported_by:
    - reference_id: PMID:7638186
      supporting_text: IL-12 induces tyrosine phosphorylation of a recently 
        identified STAT family member, STAT4, and show that STAT4 expression is 
        regulated by T-cell activation. Furthermore, we show that IL-12 
        stimulates formation of a DNA-binding complex that recognizes a DNA 
        sequence previously shown to bind STAT proteins and that this complex 
        contains STAT4
    - reference_id: PMID:9284918
      supporting_text: STAT4 is phosphorylated following interleukin (IL)-12 
        stimulation and is essential for IL-12 signal transduction
- term:
    id: GO:0035722
    label: interleukin-12-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:7638186
  review:
    summary: IL-12-mediated signaling pathway from the seminal Bacon et al. 1995
      paper demonstrating IL-12 induces STAT4 tyrosine phosphorylation and 
      activation in human lymphocytes.
    action: ACCEPT
    reason: This is the most important and specific biological process 
      annotation for STAT4. STAT4 is the canonical effector of IL-12 signaling. 
      The Bacon et al. paper was the first to demonstrate IL-12-induced STAT4 
      phosphorylation and activation. This is a core function annotation.
    supported_by:
    - reference_id: PMID:7638186
      supporting_text: IL-12 induces tyrosine phosphorylation of a recently 
        identified STAT family member, STAT4
    - reference_id: PMID:9284918
      supporting_text: STAT4 is phosphorylated following interleukin (IL)-12 
        stimulation and is essential for IL-12 signal transduction
- term:
    id: GO:0045063
    label: T-helper 1 cell differentiation
  evidence_type: IDA
  original_reference_id: PMID:14688310
  review:
    summary: Th1 cell differentiation annotation. PMID:14688310 is not in the 
      publications cache, but STAT4's role in Th1 differentiation is one of the 
      best-established aspects of its biology. STAT4-deficient mice fail to 
      generate Th1 responses.
    action: ACCEPT
    reason: Th1 cell differentiation is a core biological process for STAT4. 
      IL-12/STAT4 signaling is essential for programming naive CD4+ T cells 
      toward the Th1 fate and IFN-gamma production. This is supported by 
      extensive literature including knockout studies and is a defining feature 
      of STAT4 biology.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: IL-12 induces STAT4 activation, which, in T cells, 
        promoted the acquisition of a T helper 1 (Th1) effector phenotype and 
        the subsequent production of IFN-gamma
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IDA
  original_reference_id: PMID:31562212
  review:
    summary: DNA-binding transcription factor activity from direct assay 
      evidence. PMID:31562212 is not in the publications cache. The annotation 
      is consistent with STAT4's well-established function as a TF.
    action: ACCEPT
    reason: Correct. STAT4 is a bona fide DNA-binding transcription factor with 
      a well- characterized DNA-binding domain. This IDA evidence complements 
      IMP (PMID:37256972), IBA, ISA, and TAS evidence for the same molecular 
      function.
    supported_by:
    - reference_id: PMID:31562212
      supporting_text: the transcription factor STAT4 is required for the 
        proliferative and IFN-γ effector response by ILC1s and ILC3s
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  review:
    summary: Chromatin localization inferred from TFClass database (ISA from 
      NTNU_SB). STAT4 binds chromatin at target gene loci. Recent studies show 
      STAT4 cooperates with SWI/SNF-like BAF chromatin remodeling complexes 
      during Th1 differentiation.
    action: ACCEPT
    reason: Correct. As a sequence-specific transcription factor, STAT4 binds 
      chromatin at STAT binding sites in target gene promoters. The deep 
      research review notes that STAT4 cooperates with SWI/SNF-like BAF 
      chromatin remodeling to induce IL12RB2 during Th1 differentiation. The ISA
      from TFClass is appropriate for a validated STAT-family transcription 
      factor.
- 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: Pol II-specific TF activity from TFClass (ISA from NTNU_SB). STAT4 
      is classified as TFClass 6.2.1, a STAT-family transcription factor.
    action: ACCEPT
    reason: Correct. STAT4 is a validated DNA-binding transcription factor 
      (TFClass 6.2.1). This ISA annotation is consistent with IBA and IDA 
      evidence for the same term.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950269
  review:
    summary: Cytosol localization from Reactome IL-23 signaling pathway (STAT4 
      phosphorylation by JAK2/TYK2 in IL23 receptor complex).
    action: ACCEPT
    reason: Correct. STAT4 is cytosolic before being recruited to the IL-23 
      receptor complex for phosphorylation. Reactome pathway annotation is well 
      curated.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950448
  review:
    summary: Cytosol localization from Reactome (STAT4 binds IL12RB2 in IL-12 
      receptor complex).
    action: ACCEPT
    reason: Correct. STAT4 is recruited from the cytosol to the IL-12 receptor 
      complex by binding IL12RB2.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950453
  review:
    summary: Cytosol localization from Reactome (JAK1/JAK2 phosphorylates STAT1 
      and STAT4 at IL12RB2:IL6ST receptor).
    action: ACCEPT
    reason: Correct. STAT4 is phosphorylated at the receptor complex in the 
      cytosol before translocating to the nucleus.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950522
  review:
    summary: Cytosol localization from Reactome (p-STAT1:p-STAT4 translocates to
      the nucleus). This Reactome event represents the starting point (cytosol) 
      of the translocation.
    action: ACCEPT
    reason: Correct. The STAT1:STAT4 heterodimer starts in the cytosol before 
      nuclear translocation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952749
  review:
    summary: Cytosol localization from Reactome (STAT4 binds p-Y-IL23R in IL23 
      receptor complex).
    action: ACCEPT
    reason: Correct. STAT4 is recruited from cytosol to the IL-23 receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983872
  review:
    summary: Cytosol localization from Reactome (JAK2 phosphorylates STAT4 at 
      IL12RB2 homodimer).
    action: ACCEPT
    reason: Correct. STAT4 is phosphorylated by JAK2 at the IL12RB2 homodimeric 
      receptor in the cytosol.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983876
  review:
    summary: Cytosol localization from Reactome (STAT4 binds IL12RB2 homodimer).
    action: ACCEPT
    reason: Correct. STAT4 is recruited from cytosol to bind the IL12RB2 
      homodimer receptor (IL-35 signaling context).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983878
  review:
    summary: Cytosol localization from Reactome (p-STAT4 dissociates from 
      IL12RB2 homodimer).
    action: ACCEPT
    reason: Correct. After phosphorylation, STAT4 dissociates from the receptor 
      in the cytosol before dimerization and nuclear translocation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983983
  review:
    summary: Cytosol localization from Reactome (p-STAT1 and p-STAT4 dissociate 
      from IL12RB2:IL6ST receptor).
    action: ACCEPT
    reason: Correct. Phosphorylated STATs dissociate from the receptor complex 
      in the cytosol.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983996
  review:
    summary: Cytosol localization from Reactome (STAT1 and STAT4 associate with 
      IL12RB2:IL6ST receptor).
    action: ACCEPT
    reason: Correct. STAT4 is recruited from the cytosol to the receptor 
      complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8986985
  review:
    summary: 'Cytosol localization from Reactome (IFN-lambda signaling: STAT4 among
      STATs phosphorylated by the IFNLR complex).'
    action: ACCEPT
    reason: Correct. STAT4 can be phosphorylated in the context of IFN-lambda 
      signaling, consistent with its cytosolic pre-activation localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8987033
  review:
    summary: Cytosol localization from Reactome (p-STAT4 dissociates from 
      IFN-lambda receptor complex).
    action: ACCEPT
    reason: Correct. Phosphorylated STAT4 dissociates in the cytosol after 
      IFN-lambda receptor signaling.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8987266
  review:
    summary: Cytosol localization from Reactome (STAT4 among STATs binding to 
      IFN-lambda receptor complex).
    action: ACCEPT
    reason: Correct. STAT4 is recruited from cytosol to the IFN-lambda receptor.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9006870
  review:
    summary: Cytosol localization from Reactome (IL-21 receptor STAT 
      phosphorylation).
    action: ACCEPT
    reason: Correct. STAT4 can be phosphorylated in the context of IL-21 
      signaling, consistent with cytosolic localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9006873
  review:
    summary: Cytosol localization from Reactome (IL-21 receptor STAT binding).
    action: ACCEPT
    reason: Correct. STAT4 binds the IL-21 receptor complex in the cytosol.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950181
  review:
    summary: Nucleoplasm localization from Reactome (p-Y693-STAT4 dimer 
      translocates to the nucleus).
    action: ACCEPT
    reason: Correct. The phosphorylated STAT4 dimer translocates from cytosol to
      nucleoplasm to regulate transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950522
  review:
    summary: Nucleoplasm localization from Reactome (p-STAT1:p-STAT4 
      translocates to the nucleus). The STAT1:STAT4 heterodimer enters the 
      nucleoplasm.
    action: ACCEPT
    reason: Correct. The STAT1:STAT4 heterodimer translocates to the nucleoplasm
      to regulate transcription.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950724
  review:
    summary: Nucleoplasm localization from Reactome (p-Y705-STAT3:p-Y693-STAT4 
      translocates to the nucleus). The STAT3:STAT4 heterodimer enters the 
      nucleoplasm.
    action: ACCEPT
    reason: Correct. The STAT3:STAT4 heterodimer (formed downstream of IL-23 
      signaling) translocates to the nucleoplasm.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950181
  review:
    summary: Cytosol localization from Reactome (p-Y693-STAT4 dimer translocates
      to the nucleus - starting compartment is cytosol).
    action: ACCEPT
    reason: Correct. The STAT4 dimer originates in the cytosol before nuclear 
      translocation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950724
  review:
    summary: Cytosol localization from Reactome (STAT3:STAT4 heterodimer 
      translocation - starting compartment).
    action: ACCEPT
    reason: Correct. The STAT3:STAT4 heterodimer originates in the cytosol.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950778
  review:
    summary: Cytosol localization from Reactome (p-Y693-STAT4 dimerizes in the 
      cytosol).
    action: ACCEPT
    reason: Correct. STAT4 homodimerization occurs in the cytosol before nuclear
      translocation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950780
  review:
    summary: Cytosol localization from Reactome (p-STAT3 binds p-STAT4 in the 
      cytosol to form the STAT3:STAT4 heterodimer).
    action: ACCEPT
    reason: Correct. STAT3:STAT4 heterodimerization occurs in the cytosol.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952807
  review:
    summary: Cytosol localization from Reactome (p-STAT4 dissociates after 
      IL12:IL12R interaction).
    action: ACCEPT
    reason: Correct. Phosphorylated STAT4 dissociates from the IL-12 receptor 
      complex in the cytosol.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952823
  review:
    summary: Cytosol localization from Reactome (p-STAT4, p-STAT3 dissociate 
      from IL23 receptor).
    action: ACCEPT
    reason: Correct. Phosphorylated STAT4 and STAT3 dissociate from the IL-23 
      receptor in the cytosol before dimerization.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: TAS
  original_reference_id: PMID:9284918
  review:
    summary: TF activity from the Yamamoto et al. 1997 paper on STAT4 cDNA 
      cloning and expression. The paper describes STAT4 as a transcription 
      factor activated by IL-12 phosphorylation.
    action: ACCEPT
    reason: Correct. The original cloning paper describes STAT4 as a STAT-family
      transcription factor essential for IL-12 signal transduction. This TAS 
      annotation is consistent with all other evidence types for this term.
    supported_by:
    - reference_id: PMID:9284918
      supporting_text: a family of proteins that serve as signal transducers and
        activators of transcription (STAT). STAT4 is phosphorylated following 
        interleukin (IL)-12 stimulation and is essential for IL-12 signal 
        transduction
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: TAS
  original_reference_id: PMID:9284918
  review:
    summary: JAK-STAT pathway from the Yamamoto et al. 1997 cloning paper. STAT4
      is described as part of the JAK-STAT signaling cascade activated by IL-12.
    action: ACCEPT
    reason: Correct. The paper describes STAT4 as a STAT-family member essential
      for IL-12 signal transduction, which occurs via the JAK-STAT pathway. This
      TAS annotation is consistent with IBA and NAS evidence for the same term.
    supported_by:
    - reference_id: PMID:9284918
      supporting_text: Studies of transcriptional activation by interferons and 
        a variety of cytokines have led to the identification of a family of 
        proteins that serve as signal transducers and activators of 
        transcription (STAT)
- term:
    id: GO:0034097
    label: response to cytokine
  evidence_type: IDA
  original_reference_id: PMID:7638186
  review:
    summary: STAT4 responds to multiple cytokines including IL-12 (the primary 
      activator), IL-23, IL-35, IL-21, and type I interferons. This broader term
      captures the multi-cytokine responsiveness of STAT4 beyond just IL-12. 
      While specific cytokine response terms exist (GO:0035722 for IL-12), a 
      broader annotation would capture the full scope.
    action: NEW
    reason: STAT4 is activated by multiple cytokines beyond IL-12, including 
      IL-23, IL-35, type I IFNs, and IL-21. The existing annotations capture 
      IL-12 specifically (GO:0035722) and cytokine-mediated signaling 
      (GO:0019221), but a direct response to cytokine annotation would 
      complement these. However, this may be redundant with GO:0019221.
    supported_by:
    - reference_id: PMID:24058793
      supporting_text: IL-12 works mainly through inducing mostly STAT4 
        homodimers... IL-23 was shown to activate STAT3 and STAT4 downstream of 
        these receptors
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:26990433
  review:
    summary: STAT4 also functions as a transcriptional repressor. In response to
      IFN-alpha/beta signaling, STAT4 suppresses IL5 and IL13 mRNA expression 
      during TCR activation (PMID:26990433, cited in UniProt). This repressor 
      function is not captured by any existing annotation.
    action: NEW
    reason: UniProt documents that STAT4 acts as a transcriptional repressor of 
      IL5 and IL13 in response to IFN-alpha/beta signaling (PMID:26990433). This
      is a biologically significant function not captured by existing 
      annotations, which focus on transcriptional activation. Adding negative 
      regulation of transcription would provide a more complete picture of STAT4
      function.
    supported_by:
    - reference_id: PMID:26990433
      supporting_text: IFN-α/β-mediated STAT4 activation was required for 
        repressing the human IL5 gene, and disrupting STAT4 dimerization 
        reversed this effect. This is the first demonstration of STAT4 acting as
        a transcriptional repressor in response to IFN-α/β signaling
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping, accompanied by conservative changes to GO terms
    applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF: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:7638186
  title: Interleukin 12 induces tyrosine phosphorylation and activation of STAT4
    in human lymphocytes.
  findings:
  - statement: IL-12 induces tyrosine phosphorylation and nuclear translocation 
      of STAT4 in human T and NK cells.
    supporting_text: IL-12 induces tyrosine phosphorylation of a recently 
      identified STAT family member, STAT4, and show that STAT4 expression is 
      regulated by T-cell activation. Furthermore, we show that IL-12 stimulates
      formation of a DNA-binding complex that recognizes a DNA sequence 
      previously shown to bind STAT proteins and that this complex contains 
      STAT4
- id: PMID:9284918
  title: 'cDNA cloning, expression and chromosome mapping of the human STAT4 gene:
    both STAT4 and STAT1 genes are mapped to 2q32.2-->q32.3.'
  findings:
  - statement: STAT4 is a STAT-family transcription factor essential for IL-12 
      signal transduction, expressed in spleen, heart, brain, peripheral blood 
      cells, and testis.
    supporting_text: STAT4 is phosphorylated following interleukin (IL)-12 
      stimulation and is essential for IL-12 signal transduction... human STAT4 
      is expressed in several tissues including spleen, heart, brain, peripheral
      blood cells, and testis
- id: PMID:10961885
  title: Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 
    serine phosphorylation and transcriptional activity.
  findings:
  - statement: MAP2K6/p38 phosphorylates STAT4 at Ser-721, which is required for
      full transcriptional activity but not DNA binding.
    supporting_text: IL-12 induces STAT4 phosphorylation on serine 721 and that 
      mutation of serine 721 interferes with STAT4 transcriptional activity
- id: PMID:12213961
  title: STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma 
    production but not for cell proliferation.
  findings:
  - statement: STAT4 Ser-721 phosphorylation is critical for IFN-gamma 
      production but not for cell proliferation.
    supporting_text: expression of wild-type STAT4, but not the S721A mutant, 
      restored normal T(H)1 differentiation and IFN-gamma synthesis
- id: PMID:14688310
  title: Sustained IL-12 signaling is required for Th1 development.
  findings:
  - statement: STAT4 is required for Th1 cell differentiation.
    supporting_text: STAT4 is an essential transcription factor for Th1 cell 
      development
- id: PMID:15864272
  title: Mechanisms of type-I- and type-II-interferon-mediated signalling.
  findings:
  - statement: Review of JAK-STAT signaling in interferon responses including 
      STAT4 activation.
    supporting_text: the classical JAK (Janus activated kinase)-STAT (signal 
      transducer and activator of transcription) pathway of signalling
- id: PMID:18591661
  title: Tyrosine phosphorylation regulates the partitioning of STAT1 between 
    different dimer conformations.
  findings:
  - statement: STAT4 forms homodimers detected by IntAct.
    supporting_text: the N-domain dissociation constants of STAT1, STAT3, and 
      STAT4 differed by more than three orders of magnitude
- id: PMID:22740693
  title: The oncoprotein HBXIP uses two pathways to up-regulate S100A4 in 
    promotion of growth and migration of breast cancer cells.
  findings:
  - statement: STAT4 interacts with LAMTOR5 detected by IntAct.
    supporting_text: HBXIP is able to activate S100A4 promoter via interacting 
      with STAT4 in breast cancer cells, leading to the up-regulation of S100A4
- id: PMID:24058793
  title: 'STAT heterodimers in immunity: A mixed message or a unique signal?'
  findings:
  - statement: IL-12 induces mostly STAT4 homodimers; IL-23 promotes STAT3:STAT4
      heterodimers; IL-35 induces STAT1:STAT4 heterodimers.
    supporting_text: IL-12 works mainly through inducing mostly STAT4 
      homodimers... IL-23 was shown to activate STAT3 and STAT4 downstream of 
      these receptors... IL-35 utilizes three receptors... the gp130:IL-12Rbeta2
      heterodimeric receptor is essential for induced expression of IL-35, which
      is initiated by a STAT1:STAT4 heterodimer
- id: PMID:26990433
  title: STAT4-mediated transcriptional repression of the IL5 gene in human 
    memory Th2 cells.
  findings:
  - statement: STAT4 acts as a transcriptional repressor of IL5 in response to 
      IFN-alpha/beta signaling.
    supporting_text: IFN-α/β-mediated STAT4 activation was required for 
      repressing the human IL5 gene, and disrupting STAT4 dimerization reversed 
      this effect. This is the first demonstration of STAT4 acting as a 
      transcriptional repressor in response to IFN-α/β signaling
- id: PMID:31562212
  title: STAT4 Directs a Protective Innate Lymphoid Cell Response to 
    Gastrointestinal Infection.
  findings:
  - statement: Direct assay evidence for STAT4 DNA-binding transcription factor 
      activity.
    supporting_text: the transcription factor STAT4 is required for the 
      proliferative and IFN-γ effector response by ILC1s and ILC3s, and loss of 
      STAT4 signaling in the innate immune compartment results in an inability 
      to control bacterial growth and dissemination. Interestingly, STAT4 acts 
      acutely as a transcription factor to promote IFN-γ production
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
    Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings:
  - statement: High-throughput yeast two-hybrid interactome mapping detecting 
      STAT4 interactions with KLF11 and NUP58.
    supporting_text: Here, we report on an interactome map that focuses on 
      neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000
      candidate interactions and is generated by systematic yeast two-hybrid 
      interaction screening of ∼500 ND-related proteins and integration of 
      literature interactions
- id: PMID:35614130
  title: Acetylation licenses Th1 cell polarization to constrain Listeria 
    monocytogenes infection.
  findings:
  - statement: Acetylation of STAT4 at Lys-667 is required for JAK2-mediated 
      phosphorylation and activation.
    supporting_text: Acetylation of STAT4-K667 is required for JAK2-mediated 
      phosphorylation and activation of STAT4
- id: PMID:37256972
  title: Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory 
    Syndrome.
  findings:
  - statement: Gain-of-function STAT4 SH2 domain variants (H623Y, A635V, A650D) 
      cause disabling pansclerotic morphea of childhood (DPMC) with constitutive
      JAK-STAT signaling.
    supporting_text: Genome sequencing revealed three novel heterozygous 
      missense gain-of-function variants in STAT4
- id: Reactome:R-HSA-8950181
  title: p-Y693-STAT4 dimer translocates to the nucleus
  findings: []
- id: Reactome:R-HSA-8950269
  title: STAT3, STAT4 are phosphorylated by p-JAK2, p-TYK2 in IL23:IL23 receptor
  findings: []
- id: Reactome:R-HSA-8950448
  title: STAT4 binds to IL12RB2 in Interleukin-12 receptor complex
  findings: []
- id: Reactome:R-HSA-8950453
  title: JAK1/JAK2 bound to IL12RB2:IL6ST receptor phosphorylates STAT1 and 
    STAT4
  findings: []
- id: Reactome:R-HSA-8950522
  title: p-STAT1:p-STAT4 translocates to the nucleus
  findings: []
- id: Reactome:R-HSA-8950724
  title: p-Y705-STAT3:p-Y693-STAT4 translocates to the nucleus
  findings: []
- id: Reactome:R-HSA-8950778
  title: p-Y693-STAT4 dimerizes
  findings: []
- id: Reactome:R-HSA-8950780
  title: p-Y705-STAT3 binds p-Y693-STAT4
  findings: []
- id: Reactome:R-HSA-8952749
  title: STAT4 binds p-Y-IL23R in IL23:IL23 receptor
  findings: []
- id: Reactome:R-HSA-8952807
  title: p-Y693-STAT4 dissociates after IL12:IL12R interaction
  findings: []
- id: Reactome:R-HSA-8952823
  title: p-Y693-STAT4, p-Y705-STAT3 dissociate from IL23:IL23 receptor
  findings: []
- id: Reactome:R-HSA-8983872
  title: JAK2 bound to IL12RB2:IL12RB2 phosphorylate STAT4
  findings: []
- id: Reactome:R-HSA-8983876
  title: STAT4 binds IL12RB2:IL12RB2
  findings: []
- id: Reactome:R-HSA-8983878
  title: p-STAT4 dissociates from IL12RB2:IL12RB2 receptor
  findings: []
- id: Reactome:R-HSA-8983983
  title: p-STAT1 and p-STAT4 dissociate from IL12RB2:IL6ST receptor
  findings: []
- id: Reactome:R-HSA-8983996
  title: STAT1 and STAT4 associate with IL12RB2:IL6ST receptor
  findings: []
- id: Reactome:R-HSA-8986985
  title: IFNL1:p-Y343,Y517-IFNLR1:p-JAK1:IL10RB:p-TYK2:STAT1 phosphorylates 
    STAT1, STAT2, STAT3, STAT4 and STAT5
  findings: []
- id: Reactome:R-HSA-8987033
  title: p-STAT1, p-Y-STAT2, p-STAT3, p-STAT4, p-STAT5 dissociates from IFNL 
    receptor complex
  findings: []
- id: Reactome:R-HSA-8987266
  title: IFNL1:p-Y434,Y517-IFNLR1:p-JAK1:IL10RB:p-TYK2 binds STAT1, STAT2, 
    STAT3, STAT4, STAT5
  findings: []
- id: Reactome:R-HSA-9006870
  title: IL21 receptor STAT phosphorylation
  findings: []
- id: Reactome:R-HSA-9006873
  title: IL21 receptor STAT binding
  findings: []
core_functions:
- description: STAT4 functions as a DNA-binding transcription factor that is the
    canonical effector of IL-12 signaling in the JAK-STAT pathway. Upon IL-12 
    binding to IL12RB2, JAK2/TYK2 phosphorylate STAT4 at Tyr-693, enabling 
    SH2-mediated homodimerization and nuclear translocation. In the nucleus, 
    STAT4 dimers bind GAS elements in target gene promoters to activate 
    transcription of Th1-associated genes including IFNG and IL12RB2. Serine 
    phosphorylation at Ser-721 by MKK6/p38 is required for full transcriptional 
    activity and IFN-gamma production.
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0035722
    label: interleukin-12-mediated signaling pathway
  - id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005654
    label: nucleoplasm
  supported_by:
  - reference_id: PMID:7638186
    supporting_text: STAT4 is phosphorylated following interleukin (IL)-12 
      stimulation
    full_text_unavailable: true
  - reference_id: PMID:24058793
    supporting_text: IL-12 induces STAT4 activation, which, in T cells, promoted
      the acquisition of a T helper 1 (Th1) effector phenotype and the 
      subsequent production of IFN-gamma
- description: STAT4 drives Th1 cell differentiation downstream of IL-12 
    signaling. It activates transcription of Th1-associated genes including IFNG
    and cooperates with SWI/SNF-like BAF chromatin remodeling complexes to 
    induce IL12RB2 expression, establishing a positive feedback loop for Th1 
    commitment. STAT4 is essential for Th1-mediated defense against 
    intracellular pathogens.
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0045063
    label: T-helper 1 cell differentiation
  - id: GO:0006952
    label: defense response
  locations:
  - id: GO:0005654
    label: nucleoplasm
  supported_by:
  - reference_id: PMID:24058793
    supporting_text: IL-12 induces STAT4 activation, which, in T cells, promoted
      the acquisition of a T helper 1 (Th1) effector phenotype and the 
      subsequent production of IFN-gamma
- description: STAT4 forms heterodimers with STAT1 (downstream of IL-35 
    signaling) and STAT3 (downstream of IL-23 signaling). The STAT1:STAT4 
    heterodimer mediates IL-35-induced regulatory T cell conversion. The 
    STAT3:STAT4 heterodimer functions downstream of IL-23 in dendritic cells and
    during Th17 stabilization. These heterodimeric complexes bind distinct DNA 
    consensus sequences compared to STAT4 homodimers and recruit different 
    transcriptional co-regulators.
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0019221
    label: cytokine-mediated signaling pathway
  - id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005654
    label: nucleoplasm
  in_complex:
    id: GO:0090575
    label: RNA polymerase II transcription regulator complex
  supported_by:
  - reference_id: PMID:24058793
    supporting_text: IL-23 was shown to activate STAT3 and STAT4 downstream of 
      these receptors... the gp130:IL-12Rbeta2 heterodimeric receptor is 
      essential for induced expression of IL-35, which is initiated by a 
      STAT1:STAT4 heterodimer