STAT4

Signal transducer and activator of transcription 4
Identifiers
SymbolsSTAT4 ; SLEB11
External IDsOMIM: 600558 HomoloGene: 20679 GeneCards: STAT4 Gene
Orthologs
SpeciesHumanMouse
Entrez677520849
EnsemblENSG00000138378ENSMUSG00000062939
UniProtQ14765P42228
RefSeq (mRNA)NM_001243835NM_011487
RefSeq (protein)NP_001230764NP_035617
Location (UCSC)Chr 2:
191.89 – 192.02 Mb		Chr 1:
51.99 – 52.11 Mb
PubMed search

STAT4 is a transcription factor belonging to the Signal Transducer and Activator of Transcription protein family.[1] It is required for the development of Th1 cells from naive CD4+ T cells[2] and IFN-γ production in response to IL-12.[3]

Structure

Human as well murine STAT4 genes lie next to STAT1 gene locus suggesting that the genes arose by gene duplication.[1] STAT proteins have several functional domains, including an N-terminal interaction domain, a central DNA-binding domain, an SH2 domain, and the C-terminal transactivation domain.[4]

Expression

Distribution of STAT4 is restricted to myeloid cells, thymus and testis.[1] In resting human T cells it is expressed at very low levels, but its production is amplified by PHA stimulation.[3]

Activation

Two chains of IL-12 receptor form heterodimer after IL-12 binding and activate the receptor associated JAK kinases, termed JAK2 and TYK2. Stat4 is phosphorylated by these tyrosine kinases, homodimerizes via its SH2 domain and translocates into nucleus to activate gene transcription.[5]

Target genes

STAT4 binds to hundreds of sites in the genome,[6] among others to the promoters of genes for cytokines (IFN-γ, TNF), receptors (IL18R1, IL12rβ2, IL18RAP), and signaling factors (MYD88).[6]

References

  1. ↑ 1.0 1.1 1.2 Yamamoto K, Quelle FW, Thierfelder WE, Kreider BL, Gilbert DJ, Jenkins NA, Copeland NG, Silvennoinen O, Ihle JN (1994). "Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation". Molecular and cellular biology 14 (7): 4342–4349. PMC 358805. PMID 8007943.
  2. ↑ Kaplan MH (2005). "STAT4: A Critical Regulator of Inflammation in Vivo". Immunologic Research 31 (3): 231–242. doi:10.1385/IR:31:3:231. PMID 15888914.
  3. ↑ 3.0 3.1 Bacon CM; Petricoin, E. F.; Ortaldo, J. R.; Rees, R. C.; Larner, A. C.; Johnston, J. A.; O'Shea, J. J. (1995). "Interleukin 12 Induces Tyrosine Phosphorylation and Activation of STAT4 in Human Lymphocytes". Proceedings of the National Academy of Sciences 92 (16): 7307–7311. doi:10.1073/pnas.92.16.7307.
  4. ↑ Chang HC, Zhang S, Oldham I, Naeger L, Hoey T, Kaplan MH (2003). "STAT4 Requires the N-terminal Domain for Efficient Phosphorylation". Journal of Biological Chemistry 278 (34): 32471–32477. doi:10.1074/jbc.M302776200. PMID 12805384.
  5. ↑ Wurster AL, Tanaka T, Grusby MJ (2000). "The biology of Stat4 and Stat6". Oncogene 19 (21): 2577–2584. doi:10.1038/sj.onc.1203485. PMID 10851056.
  6. ↑ 6.0 6.1 Good SR, Thieu VT, Mathur AN, Yu Q, Stritesky GL, Yeh N, O'Malley JT, Perumal NB, Kaplan MH (2009). "Temporal Induction Pattern of STAT4 Target Genes Defines Potential for Th1 Lineage-Specific Programming". The Journal of Immunology 183 (6): 3839–3847. doi:10.4049/jimmunol.0901411. PMC 2748807. PMID 19710469.

Further reading

  • Svenungsson E, Gustafsson J, Leonard D, Sandling J, Gunnarsson I, Nordmark G, Jönsen A, Bengtsson AA, Sturfelt G, Rantapää-Dahlqvist S, Elvin K, Sundin U, Garnier S, Simard JF, Sigurdsson S, Padyukov L, Syvänen AC, Rönnblom L. (2010). "A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus.". Ann Rheum Dis. 69 (5): 834–40. doi:10.1136/ard.2009.115535. PMID 19762360.

External links