{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q14765","secondaryAccessions":["Q96NZ6"],"uniProtkbId":"STAT4_HUMAN","entryAudit":{"firstPublicDate":"2000-05-30","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"1996-11-01","entryVersion":223,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"Signal transducer and activator of transcription 4"}}},"genes":[{"geneName":{"value":"STAT4"}}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P42228"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10415122"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10961885"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11114383"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12213961"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26990433"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34508746"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35614130"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37256972"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7638186"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8943379"}],"value":"Transcriptional regulator mainly expressed in hematopoietic cells that plays a critical role in cellular growth, differentiation and immune response (PubMed:10961885, PubMed:37256972, PubMed:8943379). Plays a key role in the differentiation of T-helper 1 cells and the production of interferon-gamma (PubMed:12213961, PubMed:35614130). Also participates in multiple neutrophil functions including chemotaxis and production of the neutrophil extracellular traps (By similarity). After IL12 binding to its receptor IL12RB2, STAT4 interacts with the intracellular domain of IL12RB2 and becomes tyrosine phosphorylated (PubMed:10415122, PubMed:7638186). Phosphorylated STAT4 then homodimerizes and migrates to the nucleus where it can recognize STAT target sequences present in IL12 responsive genes. Although IL12 appears to be the predominant activating signal, STAT4 can also be phosphorylated and activated in response to IFN-gamma stimulation via JAK1 and TYK2 and in response to different interleukins including IL23, IL2 and IL35 (PubMed:11114383, PubMed:34508746). Transcription activation of IFN-gamma gene is mediated by interaction with JUN that forms a complex that efficiently interacts with the AP-1-related sequence of the IFN-gamma promoter (By similarity). In response to IFN-alpha/beta signaling, acts as a transcriptional repressor and suppresses IL5 and IL13 mRNA expression during response to T-cell receptor (TCR) activation (PubMed:26990433)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P42228"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10415122"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34508746"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9890938"}],"value":"Forms a homodimer or a heterodimer with a related family member. Interacts with ARL2BP (By similarity). The SH2 domain interacts, in vitro, with IL12RB2 via a short cytoplasmic domain. Interacts with STAT1 (PubMed:34508746). Interacts with JUN; this complex efficiently interacts with the AP-1-related sequence of the IFN-gamma (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q14765","intActId":"EBI-1186538"},"interactantTwo":{"uniProtKBAccession":"O14901","geneName":"KLF11","intActId":"EBI-948266"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q14765","intActId":"EBI-1186538"},"interactantTwo":{"uniProtKBAccession":"O43504","geneName":"LAMTOR5","intActId":"EBI-713382"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q14765","intActId":"EBI-1186538"},"interactantTwo":{"uniProtKBAccession":"Q9BVL2","geneName":"NUP58","intActId":"EBI-2811583"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q14765","intActId":"EBI-1186538"},"interactantTwo":{"uniProtKBAccession":"Q14765","geneName":"STAT4","intActId":"EBI-1186538"},"numberOfExperiments":2,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35614130"}],"value":"Translocated into the nucleus in response to phosphorylation"}]},"subcellularLocations":[{"location":{"value":"Cytoplasm","id":"SL-0086"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35614130"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37256972"}],"value":"Nucleus","id":"SL-0191"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35614130"}],"value":"Acetylation at Lys-667 is required for JAK2-mediated phosphorylation and activation of STAT4"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10961885"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12213961"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8943379"}],"value":"Tyrosine phosphorylated upon IL12 and IFN-alpha activation, but not by IFN-gamma in T-lymphocytes and NK cells (PubMed:8943379). Serine phosphorylation is required for maximal transcriptional activity but not for DNA binding (PubMed:8943379). Phosphorylation by MAP2K6 at Ser-721 is required for full transcriptional activity induced by IL12 (PubMed:10961885). However this serine phosphorylation is not required for cell proliferation although critical for IFN-gamma production (PubMed:12213961)"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Systemic lupus erythematosus 11","diseaseAccession":"DI-02653","acronym":"SLEB11","description":"A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. 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The disorder is associated with high morbidity and mortality due to squamous-cell carcinoma, restrictive pulmonary disease, sepsis, and gangrene.","diseaseCrossReference":{"database":"MIM","id":"620443"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37256972"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the transcription factor STAT family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":748,"modifier":"EXACT"}},"description":"Signal transducer and activator of transcription 4","featureId":"PRO_0000182420"},{"type":"Domain","location":{"start":{"value":569,"modifier":"EXACT"},"end":{"value":664,"modifier":"EXACT"}},"description":"SH2","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00191"}]},{"type":"Modified residue","location":{"start":{"value":667,"modifier":"EXACT"},"end":{"value":667,"modifier":"EXACT"}},"description":"N6-acetyllysine","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35614130"}]},{"type":"Modified residue","location":{"start":{"value":693,"modifier":"EXACT"},"end":{"value":693,"modifier":"EXACT"}},"description":"Phosphotyrosine; 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