STAT4

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Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT 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 (Jul 1994). "Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation". Molecular and Cellular Biology. 14 (7): 4342–9. doi:10.1128/mcb.14.7.4342. PMC 358805. PMID 8007943.
  2. Kaplan MH (2005). "STAT4: a critical regulator of inflammation in vivo" (PDF). Immunologic Research. 31 (3): 231–42. doi:10.1385/IR:31:3:231. PMID 15888914.
  3. 3.0 3.1 Bacon CM, Petricoin EF, Ortaldo JR, Rees RC, Larner AC, Johnston JA, O'Shea JJ (Aug 1995). "Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes". Proceedings of the National Academy of Sciences of the United States of America. 92 (16): 7307–11. doi:10.1073/pnas.92.16.7307. PMC 41328. PMID 7638186.
  4. Chang HC, Zhang S, Oldham I, Naeger L, Hoey T, Kaplan MH (Aug 2003). "STAT4 requires the N-terminal domain for efficient phosphorylation". The Journal of Biological Chemistry. 278 (34): 32471–7. doi:10.1074/jbc.M302776200. PMID 12805384.
  5. Wurster AL, Tanaka T, Grusby MJ (May 2000). "The biology of Stat4 and Stat6". Oncogene. 19 (21): 2577–84. 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 (Sep 2009). "Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage-specific programming". Journal of Immunology. 183 (6): 3839–47. 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 (May 2010). "A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus". Annals of the Rheumatic Diseases. 69 (5): 834–40. doi:10.1136/ard.2009.115535. PMID 19762360.

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