Disease relevance of STAT6

• Our findings highlight phosphorylated STAT6 as a characteristic distinguishing PMBL from DLBCL, but a common feature to PMBL and cHL, supporting the hypothesis of common pathogenic events in these 2 lymphomas [1].
• STAT6 in dermal endothelial cells appears to be a potent target for controlling cellular infiltrate in allergic and/or neuroinflammatory skin diseases [2].
• The STAT6 pathway may contribute to the hypercontractility of intestinal muscle in Crohn's disease [3].
• Glioblastoma cells were uniformly insensitive to IL-13 and, unlike other glia, failed to phosphorylate STAT6 after IL-13 challenge [4].
• STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells [5].
• As COX-2 over-expression has been clearly linked to apoptosis resistance and other hallmarks of malignancy, these findings suggest a novel role of unphosphorylated STAT6 in the pathogenesis of non-small cell lung cancer [6].
• These data suggest that while active STAT6 is not a transforming factor, expression in T cells predisposes toward the development of lymphoproliferative disorders [7].

Psychiatry related information on STAT6

• Recent studies have demonstrated that STAT6-deficient mice exhibit increased locomotor activity and decreased levels of dopamine transporter expression in the striatum, when compared with the wild-type [8].

High impact information on STAT6

• Before activation, the T(H)2 cytokine locus is already associated with GATA3 and STAT6, showing some looping, but these are insufficient to induce cytokine gene expression [9].
• Here we show that mice lacking signal transducer and activator of transcription 6 (STAT6) were protected from all pulmonary effects of IL-13 [10].
• Other findings suggest a potential regulatory role for STAT5 and STAT6 in transcriptional activation of HSD3B2 promoter [11].
• The lack of Jak3 expression correlated with impaired B cell signaling, as demonstrated by the inability of IL-4 to activate Stat6 in the EBV-transformed cell line from the patient [12].
• An interleukin-4-induced transcription factor: IL-4 Stat [13].

Chemical compound and disease context of STAT6

• High expression of activated STAT6 in tumors was associated with short survival in an independent set of patients with primary CNS lymphoma who were treated with high-dose intravenous methotrexate therapy [14].

Biological context of STAT6

• This inhibition was associated with decreased tyrosine phosphorylation and nuclear translocation of STAT6 and was not evident unless the cells were preincubated with IFN for at least 1 hr before IL-4 stimulation [15].
• IL-4 activates gene expression by inducing tyrosine phosphorylation, homodimerization, and nuclear translocation of the latent transcription factor, STAT6 (signal transducer and activator of transcription-6) [15].
• The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway [16].
• Antibody-mediated neutralization of IL-13 resulted in significant decreases in both cellular proliferation and levels of phosphorylated STAT6 of HL cell lines [17].
• Peptides derived from the STAT6 transactivation domain adjacent to the LXXLL motif as well as antibodies against these peptides showed no inhibitory effect [18].

Anatomical context of STAT6

• Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression [15].
• STAT6 was constitutively phosphorylated in 5 of 5 HL cell lines and in HRS cells from 25 of 32 (78%) classical HL cases [17].
• Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma [1].
• IL-4 suppresses osteoclast development and mature osteoclast function by a STAT6-dependent mechanism: irreversible inhibition of the differentiation program activated by RANKL [19].
• We studied the mechanism of 15-LOX-1 induction in A549 lung epithelial cells and found that genistein, a potent tyrosine kinase inhibitor, prevented phopsphorylation of STAT6, its binding to the 15-LOX-1 promoter, and the expression of catalytically active enzyme [20].

Associations of STAT6 with chemical compounds

• Also, simvastatin was unable to augment Ym1 expression in DCs developed from STAT6-/- or IL-4R alpha-/- mice [21].
• Activation of STAT6 appears to be a key factor in P-selectin expression induced by substance P and IL-4 because treatment with STAT6 decoy oligodeoxynucleotides significantly inhibited P-selectin expression [2].
• Both IL-4 and IL-13 increased specific STAT6-DNA binding in control cells, and this was inhibited by anti-STAT6 Ab (P < 0.05) or leflunomide (P < 0.05) [3].
• Preincubation of human cultured smooth muscle cells with IL-4 (P < 0.001) or IL-13 (P < 0.05) significantly enhanced carbachol-induced contraction, and this was significantly inhibited by the STAT6 inhibitor leflunomide (P < 0.0001) [3].
• The coculture of allergen-treated DC and CD4+ T cells also led to a dose-dependent expression of active signal transducer and activator of transcription-6 (STAT6), which was visible already after 1 hr [22].

Physical interactions of STAT6

• However, cotransfection of all three chains did not further increase IL-4 binding or alter the extent of STAT6 activation suggesting that all three chains together do not seem to participate in IL-4 function [23].
• Although only one consensus STAT6 binding site is contained in the TFF3 gene, located in the intron 1, it did not operate as an enhancer in the context of an SV40 promoter/luciferase construct [24].
• To define the mechanism of coactivator recognition, we determined the crystal structure of the NCoA-1 PAS-B domain in complex with the STAT6 LXXLL motif [25].
• Activation of STAT6 is not dependent on phosphotyrosine-mediated docking to the interleukin-4 receptor and can be blocked by dominant-negative mutants of both receptor subunits [26].
• However, reconstitution of these X-SCID B cells with gammac enhanced IL-4-mediated responses including STAT6 phosphorylation and DNA binding activity and resulted in increased CD23 expression [27].

Enzymatic interactions of STAT6

• By contrast, production of IL-4 and expression of phosphorylated STAT6 were not associated with the intensity of mononuclear cell infiltration [28].

Regulatory relationships of STAT6

• Interleukin 4 regulates phosphorylation of serine 756 in the transactivation domain of Stat6. Roles for multiple phosphorylation sites and Stat6 function [29].
• Exogenous expression of Ets-1 in conjunction with STAT6 activation strongly inhibited expression of a Socs-1 promoter-luciferase reporter [30].
• Here we show that anti-CD28/IL-2-primed Th2 cells expressed high levels of activated STAT6, but no cytokine mRNA [31].
• Cotransfection with a dominant negative STAT6 mutant expression vector inhibited activation of the eotaxin promoter by IL-13 [32].
• Th2 cells remained responsive to IL-12, which repressed STAT6 DNA binding and activated STAT4, and switched the cells to Th1 [31].

Other interactions of STAT6

• IL-13 efficiently caused activation of STAT6 protein in cells transfected with the IL-13Ralpha1 and IL-4Ralpha chains, and IL-13Ralpha2 inhibited this activation [16].
• Only 4 of 24 NHL cases demonstrated constitutive STAT6 activation, whereas STAT3 activation was observed in 6 of 13 (46%) cases of B-cell NHL and 8 of 11 (73%) cases of T-cell NHL [17].
• One sequence set was selected from random oligonucleotides by recombinant STAT1, STAT5A, or STAT6 [33].
• Detailed analysis indicated that STAT5A specificity is more similar to that of STAT6 than that of STAT1, as expected from the evolutionary relationships [33].
• Thus, STAT6 activation mediates a transcriptional enhancement of TFF3 by induction of de novo synthesized protein in goblet cells [24].

Analytical, diagnostic and therapeutic context of STAT6

• Western blotting demonstrated phosphorylation of STAT6 in cultured GVEC upon incubation with IL-4 or IL-13 [34].
• IL-13-induced STAT6 activation was also inhibited as determined by dual luciferase assay and electrophoretic mobility shift assay (EMSA) [35].
• Phosphorylation of signal transducer and activator of transcription factor 6 (STAT6) was examined by immunoblotting [36].
• Crystallization and preliminary crystallographic studies of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain [37].
• Real time RT-PCR analysis revealed a dampened expression of the Th1-associated gene, T-bet, and a time-dependent increase in the mRNA for the Th2-associated genes, GATA-3, c-MAF and STAT6, upon treatment with ATRA [38].

References