STAT (Signal Transducer and Activator of Transcription) proteins are important signal transducers and activators of transcription; this family comprises seven members (STATs1, 2, 3, 4, 5A, 5B and 6).
This transcription factors are latent in the cytoplasm until they are activated by extracellular signalling proteins (mainly cytokines and grow factors but also some peptides) that bind to specific cell-surface receptors.
At least several dozen receptors with intrinsic tyrosine kinase activity such as those for epidermal growth factor (EGF) and platelet/derived growth factor (PDGF), seem to be able to mediate the activation of STAT proteins. STAT proteins could be also down regulated by a negative crosstalk. Seven different genes have been identified in mammals, the encoded proteins vary in length between 750 and 850 amino acid residues and share 20 to 50 % pairwise sequence identity. STAT proteins bind as dimers to DNA target sites with a 9-base-pair consensus sequence, TTCCGGGAA.
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STAT3 is involved in a wide spectrum of biological functions that include embryo implantation, development, acute phase induction in hepatocytes and immune responses. STAT3 plays a key role in inflammatory, autoimmune and certain neoplastic diseases.
The STAT3 gene is located on the long (q) arm of chromosome 17 at position 21.31, more precisely, is located from base pair 37,718,868 to base pair 37,794,038.
The N-terminal domain is a bundle of four antiparallel helices (α1, α2, α3 and α4) connected by a short loops. The 4-helix bundle is immediately followed by the eight-stranded β-barrel. The β-barrel domain is linked to the SH2 domain by a small helical domain, formed by two helix-loop-helix modules called “connector domain” (it shows structural similarity to calcium binding domain in troponin C). The SH2 domain is composed by a central three-stranded β-pleated sheet flanked by helix α and strand β. Residues 689 to 701 connect the SH2 domain with the phosphotyrosine peptide and they are hydrophilic and disordered.
The binding of IL-6 family cytokines (including IL-6, oncostatin M and leukemia inhibitory factor) to the gp130 receptor triggers STAT3 phosphorylation by JAK2.
For activation, Stat proteins are recruited to the receptor through the binding of phosphotyrosine peptides by the SH2 domain.
After activation and dimerization STAT3 migrates into the nucleus. Importin α5/NPI-1 mediates the nuclear transport of STAT3 and has a STAT3 binding domain in C terminus. In nucleus STAT3 dimer bind DNA, in particular four loops per monomer contact the sugar-phosphate backbones of both DNA strands and recognize bases in the major groove, and activate specific target genes like the cis element ISRE (IFN-stimulated Response Element) thereby initiating transcription of several IFN-inducible genes.
This transcriptional activation by STAT3 proteins requires the recruitment of coactivators such as CBP (CREB-binding Protein)/p300.
STAT3 proteins recognize a conserved element in the promoter of p21/WAF1 (Wildtype p53-Activated Fragment-1) and increase the mRNA expression of this cell cycle regulatory gene. STAT3 activates several other genes involved in cell cycle progression such as Fos, Cyclin-D, CDC25A, c-Myc or Pim1 and up-regulates antiapoptotic genes such as BCL2 (B-Cell CLL/Lymphoma-2), BCLXL and Beta2-Macroglobulin. Thus, many STAT3 target genes are key components of the regulation of cell cycle progression from G1 to S phase.
Accordingly, STAT3 activation is often associated with cell growth or transformation, and disruption of the STAT3 gene causes embryonic lethality. Following IL-6 stimulation, transcriptional cofactor NCOA/SRC1a interacts with STAT3 and potentiates its transcriptional activity through its CBP/p300-interacting domain AD1. Pathways other than JAK kinases involving mTOR (mammalian Target of Rapamycin) or p70S6 kinase, MAPK (Mitogen Activated Protein Kinase), p38, and MEK (MAPK/ERK Kinase) signaling cascades also lead to phosphorylation and activation of STAT3.
RhoA efficiently modulate STAT3 transcriptional activity by inducing its simultaneous tyrosine and serine phosphorylation via Src Family of Kinases and JAK2. The JNK (c-Jun N-terminal Kinase)/ERK (Extracellular-Signal Regulated Kinase) Pathway mediates serine phosphorylation (Ser727) and cooperation of both tyrosine as well as serine phosphorylation is necessary for full activation of STAT3. The Type-I Interferon (IFN-Alpha/Beta) promotes the DNA-binding activity of the transcription factors including STAT3, which is involved in the induction of NF-KappaB (Nuclear Factor-KappaB) DNA-binding activity and in the induction of antiviral and antiproliferative activity. STAT3 is also activated in response to the small guanine nucleotide-binding protein Rac1. The Rac functions in growth factor-induced activation of STAT3 in two ways. It apparently helps localize STAT3 to kinase complexes at the cell surface through Ras and also promotes activation of kinases, like MLKs (Mixed-Lineage Kinases), JAK2, TYK2 that phosphorylate STAT3 at Tyr705. The SOCS (Suppressor of Cytokine Signaling) family of proteins negatively regulates the receptor-associated JAK-STAT3 pathway of transcriptional activation.
STAT3 INHIBITORS
STAT3 in embryogenesis:
Biological effects of Stat3 have also been evaluated by targeted gene ablation in transgenic mice. Unlike the results with ablation of other Stat family genes, all of which have produced viable mice with relatively limited phenotypes, ablation of Stat3 led to early embryonic lethality. In fact, loss of Stat3 is lethal even in embryonic stem cells. Homozygous Stat3-null embryos degenerate rapidly between 6.5 and 7.5 days of embryogenesis, just after blastocyst implantation. Stat3 mRNA is present in both maternal and extraembryonic tissues during early postimplantation stages of murine development. Furthermore, activated Stat3 protein is present from embryonic days 4.5 to 9.5 in decidual swellings of the visceral endoderm. Because the visceral endoderm plays an important supportive role during early embryogenesis, fostering metabolic exchange between embryo and placenta, it has been hypothesized that Stat3 may be involved in a nutritional process that supportsthe implanted blastocyst.
STAT3 in the acute-phase response:
In the liver, STAT3, mainly activated by IL-6 and its related cytokine, and IL-22, has been shown to play key roles in acute phase response, protection against liver injury, promotion of liver regeneration, glucose homeostasis, and hepatic lipid metabolism. In addition, several other factors were also reported to activate STAT3 in the liver. These include IL-10, EGF, hepatitis viral proteins.
In the liver, IL-6 stimulates hepatocytes to produce a variety of acute-phase proteins, including serum amyloid A, C-reactive protein, complement C3, fibrinogen, and macroglobulin. Recent evidence from knockout mice suggests that IL-6 also plays an important role in liver regeneration and protection against liver injury. Mice with targeted disruption of the IL-6 gene have impaired liver regeneration, whereas increasing evidence suggests that IL-6 may play more important roles in protection against liver injury during liver regeneration.
IL-6 is a hepatoprotective factor and may have therapeutic potentials in preventing fatty liver transplant failure and treating fatty liver disease.
The role of IL-6 in the liver is believed to be linked through the IL-6R1 and gp130 protein, which are expressed on hepatocytes at high levels. The interaction of IL-6 with the IL-6Rα induces homodimerization of gp130, which is followed by activation of the receptor-associated Janus kinases, known as JAK1, JAK2 and Tyk2. This receptorkinase complex interacts with and activates the SH2- containing cytoplasmic STAT3 transcription factor, which then translocates to the nucleus to activate the transcription of many target genes, such as: c-jun, c-myc, Jun B, cycline D1, C/EBP, p21WAF1/Cip1, and acute-phase genes. Treatment with IL-6 induces activation of STAT3 in primary human hepatocytes, human hepatoma cells, and primary rat hepatocytes.
Conditional deletion of the gp130 gene in hepatocytes promotes liver injury. Disruption of the STAT3 gene impairs liver regeneration and causes insulin resistance associated with increased hepatic expression of gluconeogenic genes, whereas overexpression of constitutively activated STAT3 reduces blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice and protects against Fas induced fulminant hepatitis via a redox-dependent and -independent mechanisms.
Several STAT3 downstream genes have been identified as important factors contributing to the hepatoprotective and hepatomitogenic effect of IL-6/STAT3. These genes include Bcl-2, Bcl-xL, Mcl-1, FLIP, Ref-1, cyclin D1, c-myc, etc. Inhibition of natural killer T cells may be another mechanism contributing to the hepatoprotective effect of IL-6.
These findings suggest that STAT3, activated by IL-6, plays an important role in hepatoprotection, liver regeneration, and glucose homeostasis via induction of a variety of antiapoptotic and mitogenic proteins, glucose homeostasis, and fat metabolism.
STAT3 in cancer:
STATs are activated by cytokines and many growth factor receptors with intrinsic tyrosine-kinase activity. The growth factor receptors that are known to activate STAT3 include the epidermal growth factor receptors EGFR and HER2 (also known as NEU), FGFR (fibroblast growth factor receptor), IGFR (insulin-like growth factor receptor), HGFR (hepatocyte growth factor receptor; also known as MET), PDGFR (platelet-derived growth factor receptor) and VEGFR (VEGF receptor).
The onco proteins SRC and ABL are also activators of STAT3.
Furthermore, many tumour-produced factors, such as IL-10, IL-6 and VEGF, which are crucial for both tumour growth and immunosuppression, activate STAT3 to create an efficient ‘feedforward’ mechanism to ensure increased STAT3 activity both in tumour cells and in tumour-associated immune cells.
STAT3 regulates important gene products involved in:
GENES REGULATED BY STAT3
GENES REGULATED BY STAT3
GENES REGULATED BY STAT3
IL-10 and IL-12 have not tryptophan in aminoacidic sequence.
IL-10 interaction with STAT3
STAT3-mediated anti-inflammatory signalling 2006
Pathophysiology of Interleukin-23 in Experimental Autoimmune Encephalomyelitis 2006
" Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice 2003"http://www.jci.org/articles/view/17085/files/JCI0317085.f3/medium
Interleukin-12 and the regulation of innate resistance and adaptive immunity
