STAT4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:9284918 STAT4 is phosphorylated following interleukin (IL)-12 stimulation and is essential for IL-12 signal transduction
GO:0006952 defense response	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:24058793 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
GO:0042127 regulation of cell population proliferation	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:24058793 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
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:9284918 STAT4 is phosphorylated following interleukin (IL)-12 stimulation and is essential for IL-12 signal transduction
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:24058793 STAT dimers could then bind their target sequence, recruit coactivators and effect transcription
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:24058793 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
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:24058793 Most cytokines predominantly transmit signals via Janus kinase (just another kinase, or JAK)-signal transducer and activator of transcription (STAT) pathways
GO:0019221 cytokine-mediated signaling pathway	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:24058793 Most cytokines predominantly transmit signals via Janus kinase (just another kinase, or JAK)-signal transducer and activator of transcription (STAT) pathways
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:9284918 STAT4 is phosphorylated following interleukin (IL)-12 stimulation and is essential for IL-12 signal transduction
GO:0090575 RNA polymerase II transcription regulator complex	IBA GO_REF:0000033	ACCEPT	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). 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. Supporting Evidence: PMID:24058793 IL-12 works mainly through inducing mostly STAT4 homodimers... IL-23 was shown to activate STAT3 and STAT4 downstream of these receptors
GO:0043434 response to peptide hormone	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:24058793 Most cytokines predominantly transmit signals via Janus kinase (just another kinase, or JAK)-signal transducer and activator of transcription (STAT) pathways
GO:0003677 DNA binding	IEA GO_REF:0000120	ACCEPT	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. 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.
GO:0003700 DNA-binding transcription factor activity	IEA GO_REF:0000120	ACCEPT	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. Reason: Correct annotation consistent with experimental evidence. The IEA is broader than GO:0000981 but captures the essential molecular function of STAT4.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Nuclear localization of STAT4 inferred from UniProt subcellular location. Consistent with experimental data showing nuclear translocation upon activation. 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.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasmic localization of STAT4 inferred from UniProt subcellular location. Consistent with experimental data showing STAT4 is cytoplasmic before activation. 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.
GO:0005829 cytosol	IEA GO_REF:0000117	ACCEPT	Summary: Cytosolic localization from ARBA machine learning. Consistent with Reactome TAS annotations and the established biology of STAT proteins being cytosolic before activation. 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.
GO:0006355 regulation of DNA-templated transcription	IEA GO_REF:0000002	ACCEPT	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). 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.
GO:0006955 immune response	IEA GO_REF:0000117	ACCEPT	Summary: STAT4 participates in immune responses, particularly Th1-mediated immunity. This broad annotation from ARBA is correct but very general. 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.
GO:0007165 signal transduction	IEA GO_REF:0000002	ACCEPT	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. 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.
GO:0019221 cytokine-mediated signaling pathway	IEA GO_REF:0000117	ACCEPT	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. 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.
GO:0090575 RNA polymerase II transcription regulator complex	IEA GO_REF:0000117	ACCEPT	Summary: STAT4 forms transcription regulator complexes. This IEA from ARBA is consistent with the IBA annotation for the same term and ComplexPortal data. Reason: Correct. Duplicates the IBA annotation. STAT4 forms homodimers and heterodimers that function as Pol II transcription regulator complexes.
GO:0005515 protein binding	IPI PMID:22740693 The oncoprotein HBXIP uses two pathways to up-regulate S100A...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:22740693 HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:32814053 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
GO:0042802 identical protein binding	IPI PMID:18591661 Tyrosine phosphorylation regulates the partitioning of STAT1...	ACCEPT	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. 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. Supporting Evidence: PMID:18591661 the N-domain dissociation constants of STAT1, STAT3, and STAT4 differed by more than three orders of magnitude PMID:24058793 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
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Nucleoplasm localization from HPA immunofluorescence curation. STAT4 enters the nucleoplasm upon activation, which is consistent with its function as a nuclear transcription factor. Reason: Correct. STAT4 translocates to the nucleus (specifically the nucleoplasm) upon phosphorylation. HPA immunofluorescence data supports this localization.
GO:0016604 nuclear body	IDA GO_REF:0000052	KEEP AS NON CORE	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. 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.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	NAS PMID:15864272 Mechanisms of type-I- and type-II-interferon-mediated signal...	ACCEPT	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. 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. Supporting Evidence: PMID:15864272 the classical JAK (Janus activated kinase)-STAT (signal transducer and activator of transcription) pathway of signalling
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	NAS PMID:24058793 STAT heterodimers in immunity: A mixed message or a unique s...	ACCEPT	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. 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. Supporting Evidence: PMID:24058793 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
GO:0045944 positive regulation of transcription by RNA polymerase II	NAS PMID:15864272 Mechanisms of type-I- and type-II-interferon-mediated signal...	ACCEPT	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. 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. Supporting Evidence: PMID:15864272 the classical JAK (Janus activated kinase)-STAT (signal transducer and activator of transcription) pathway of signalling
GO:0045944 positive regulation of transcription by RNA polymerase II	NAS PMID:24058793 STAT heterodimers in immunity: A mixed message or a unique s...	ACCEPT	Summary: Positive regulation of transcription from ComplexPortal, citing the STAT heterodimer review. Consistent with STAT4's role as a transcriptional activator in immune cells. Reason: Correct. Duplicates the annotation from PMID:15864272. STAT4 activates transcription of target genes including IFNG. Supporting Evidence: PMID:24058793 STAT dimers could then bind their target sequence, recruit coactivators and effect transcription
GO:0003700 DNA-binding transcription factor activity	IMP PMID:37256972 Variant STAT4 and Response to Ruxolitinib in an Autoinflamma...	ACCEPT	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. 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. Supporting Evidence: PMID:37256972 Genome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4
GO:0005634 nucleus	IMP PMID:37256972 Variant STAT4 and Response to Ruxolitinib in an Autoinflamma...	ACCEPT	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. 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. Supporting Evidence: PMID:37256972 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
GO:0070741 response to interleukin-6	IMP PMID:37256972 Variant STAT4 and Response to Ruxolitinib in an Autoinflamma...	UNDECIDED	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. 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. Supporting Evidence: PMID:37256972 primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion
GO:0005634 nucleus	IDA PMID:7638186 Interleukin 12 induces tyrosine phosphorylation and activati...	ACCEPT	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. 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. Supporting Evidence: PMID:7638186 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 PMID:9284918 STAT4 is phosphorylated following interleukin (IL)-12 stimulation and is essential for IL-12 signal transduction
GO:0035722 interleukin-12-mediated signaling pathway	IDA PMID:7638186 Interleukin 12 induces tyrosine phosphorylation and activati...	ACCEPT	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. 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. Supporting Evidence: PMID:7638186 IL-12 induces tyrosine phosphorylation of a recently identified STAT family member, STAT4 PMID:9284918 STAT4 is phosphorylated following interleukin (IL)-12 stimulation and is essential for IL-12 signal transduction
GO:0045063 T-helper 1 cell differentiation	IDA PMID:14688310 Sustained IL-12 signaling is required for Th1 development.	ACCEPT	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. 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. Supporting Evidence: PMID:24058793 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
GO:0003700 DNA-binding transcription factor activity	IDA PMID:31562212 STAT4 Directs a Protective Innate Lymphoid Cell Response to ...	ACCEPT	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. 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. Supporting Evidence: PMID:31562212 the transcription factor STAT4 is required for the proliferative and IFN-γ effector response by ILC1s and ILC3s
GO:0000785 chromatin	ISA GO_REF:0000113	ACCEPT	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. 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.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	ISA GO_REF:0000113	ACCEPT	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. 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.
GO:0005829 cytosol	TAS Reactome:R-HSA-8950269	ACCEPT	Summary: Cytosol localization from Reactome IL-23 signaling pathway (STAT4 phosphorylation by JAK2/TYK2 in IL23 receptor complex). Reason: Correct. STAT4 is cytosolic before being recruited to the IL-23 receptor complex for phosphorylation. Reactome pathway annotation is well curated.
GO:0005829 cytosol	TAS Reactome:R-HSA-8950448	ACCEPT	Summary: Cytosol localization from Reactome (STAT4 binds IL12RB2 in IL-12 receptor complex). Reason: Correct. STAT4 is recruited from the cytosol to the IL-12 receptor complex by binding IL12RB2.
GO:0005829 cytosol	TAS Reactome:R-HSA-8950453	ACCEPT	Summary: Cytosol localization from Reactome (JAK1/JAK2 phosphorylates STAT1 and STAT4 at IL12RB2:IL6ST receptor). Reason: Correct. STAT4 is phosphorylated at the receptor complex in the cytosol before translocating to the nucleus.
GO:0005829 cytosol	TAS Reactome:R-HSA-8950522	ACCEPT	Summary: Cytosol localization from Reactome (p-STAT1:p-STAT4 translocates to the nucleus). This Reactome event represents the starting point (cytosol) of the translocation. Reason: Correct. The STAT1:STAT4 heterodimer starts in the cytosol before nuclear translocation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8952749	ACCEPT	Summary: Cytosol localization from Reactome (STAT4 binds p-Y-IL23R in IL23 receptor complex). Reason: Correct. STAT4 is recruited from cytosol to the IL-23 receptor.
GO:0005829 cytosol	TAS Reactome:R-HSA-8983872	ACCEPT	Summary: Cytosol localization from Reactome (JAK2 phosphorylates STAT4 at IL12RB2 homodimer). Reason: Correct. STAT4 is phosphorylated by JAK2 at the IL12RB2 homodimeric receptor in the cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-8983876	ACCEPT	Summary: Cytosol localization from Reactome (STAT4 binds IL12RB2 homodimer). Reason: Correct. STAT4 is recruited from cytosol to bind the IL12RB2 homodimer receptor (IL-35 signaling context).
GO:0005829 cytosol	TAS Reactome:R-HSA-8983878	ACCEPT	Summary: Cytosol localization from Reactome (p-STAT4 dissociates from IL12RB2 homodimer). Reason: Correct. After phosphorylation, STAT4 dissociates from the receptor in the cytosol before dimerization and nuclear translocation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8983983	ACCEPT	Summary: Cytosol localization from Reactome (p-STAT1 and p-STAT4 dissociate from IL12RB2:IL6ST receptor). Reason: Correct. Phosphorylated STATs dissociate from the receptor complex in the cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-8983996	ACCEPT	Summary: Cytosol localization from Reactome (STAT1 and STAT4 associate with IL12RB2:IL6ST receptor). Reason: Correct. STAT4 is recruited from the cytosol to the receptor complex.
GO:0005829 cytosol	TAS Reactome:R-HSA-8986985	ACCEPT	Summary: Cytosol localization from Reactome (IFN-lambda signaling: STAT4 among STATs phosphorylated by the IFNLR complex). Reason: Correct. STAT4 can be phosphorylated in the context of IFN-lambda signaling, consistent with its cytosolic pre-activation localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-8987033	ACCEPT	Summary: Cytosol localization from Reactome (p-STAT4 dissociates from IFN-lambda receptor complex). Reason: Correct. Phosphorylated STAT4 dissociates in the cytosol after IFN-lambda receptor signaling.
GO:0005829 cytosol	TAS Reactome:R-HSA-8987266	ACCEPT	Summary: Cytosol localization from Reactome (STAT4 among STATs binding to IFN-lambda receptor complex). Reason: Correct. STAT4 is recruited from cytosol to the IFN-lambda receptor.
GO:0005829 cytosol	TAS Reactome:R-HSA-9006870	ACCEPT	Summary: Cytosol localization from Reactome (IL-21 receptor STAT phosphorylation). Reason: Correct. STAT4 can be phosphorylated in the context of IL-21 signaling, consistent with cytosolic localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-9006873	ACCEPT	Summary: Cytosol localization from Reactome (IL-21 receptor STAT binding). Reason: Correct. STAT4 binds the IL-21 receptor complex in the cytosol.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8950181	ACCEPT	Summary: Nucleoplasm localization from Reactome (p-Y693-STAT4 dimer translocates to the nucleus). Reason: Correct. The phosphorylated STAT4 dimer translocates from cytosol to nucleoplasm to regulate transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8950522	ACCEPT	Summary: Nucleoplasm localization from Reactome (p-STAT1:p-STAT4 translocates to the nucleus). The STAT1:STAT4 heterodimer enters the nucleoplasm. Reason: Correct. The STAT1:STAT4 heterodimer translocates to the nucleoplasm to regulate transcription.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8950724	ACCEPT	Summary: Nucleoplasm localization from Reactome (p-Y705-STAT3:p-Y693-STAT4 translocates to the nucleus). The STAT3:STAT4 heterodimer enters the nucleoplasm. Reason: Correct. The STAT3:STAT4 heterodimer (formed downstream of IL-23 signaling) translocates to the nucleoplasm.
GO:0005829 cytosol	TAS Reactome:R-HSA-8950181	ACCEPT	Summary: Cytosol localization from Reactome (p-Y693-STAT4 dimer translocates to the nucleus - starting compartment is cytosol). Reason: Correct. The STAT4 dimer originates in the cytosol before nuclear translocation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8950724	ACCEPT	Summary: Cytosol localization from Reactome (STAT3:STAT4 heterodimer translocation - starting compartment). Reason: Correct. The STAT3:STAT4 heterodimer originates in the cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-8950778	ACCEPT	Summary: Cytosol localization from Reactome (p-Y693-STAT4 dimerizes in the cytosol). Reason: Correct. STAT4 homodimerization occurs in the cytosol before nuclear translocation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8950780	ACCEPT	Summary: Cytosol localization from Reactome (p-STAT3 binds p-STAT4 in the cytosol to form the STAT3:STAT4 heterodimer). Reason: Correct. STAT3:STAT4 heterodimerization occurs in the cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-8952807	ACCEPT	Summary: Cytosol localization from Reactome (p-STAT4 dissociates after IL12:IL12R interaction). Reason: Correct. Phosphorylated STAT4 dissociates from the IL-12 receptor complex in the cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-8952823	ACCEPT	Summary: Cytosol localization from Reactome (p-STAT4, p-STAT3 dissociate from IL23 receptor). Reason: Correct. Phosphorylated STAT4 and STAT3 dissociate from the IL-23 receptor in the cytosol before dimerization.
GO:0003700 DNA-binding transcription factor activity	TAS PMID:9284918 cDNA cloning, expression and chromosome mapping of the human...	ACCEPT	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. 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. Supporting Evidence: PMID:9284918 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
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	TAS PMID:9284918 cDNA cloning, expression and chromosome mapping of the human...	ACCEPT	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. 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. Supporting Evidence: PMID:9284918 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)
GO:0034097 response to cytokine	IDA PMID:7638186 Interleukin 12 induces tyrosine phosphorylation and activati...	NEW	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. 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. Supporting Evidence: PMID:24058793 IL-12 works mainly through inducing mostly STAT4 homodimers... IL-23 was shown to activate STAT3 and STAT4 downstream of these receptors
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:26990433 STAT4-mediated transcriptional repression of the IL5 gene in...	NEW	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. 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. Supporting Evidence: PMID:26990433 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

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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