STAT activation

Originally discovered as DNA-binding proteins that mediate interferon signaling, recent data demonstrated that STAT1 can also exert constitutive functions in the nucleus, which do not require STAT activation with tyrosine phosphorylation. Cells lacking STAT1 are... 

Table 8.6 Ligands which, upon binding to their cell surface receptors, are known to promote activation of one or more STATs. (The STATs activated are also shown.) This list, though representative, is not exhaustive...

Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA IL-2 receptor 3-dependent STATS activation is required for the development of Foxp3 + regulatory T cells. J Immunol 2007 178 280-290. 

EMSA assays can also be exploited to measure STAT nuclear localization, which is, similar to NFkB localization, a measure of STAT activity. Determination of JAK phosphorylation is carried out by immunoprecipitation of the JAK proteins from cell lysates, followed by SDS-PAGE electrophoresis, immunoblotting with antiphosphotyrosine antibody and JAK-specific antibody re-probing [99]. 

Kinase inhibitors such as H7, which inhibits serine threonine kinases, resulted in sustained JAK2/STAT activation, suggesting that besides protein dephosphorylation, protein phosphorylation is also required. Furthermore, both inhibition of protein synthesis with cycloheximide and inhibition of... 

Alas S, Bonavida B. Rituximab inactivates signal transducer and activation of transcription 3 (STATS) activity in B-non-Hodgkin s lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res 2001 61 5137-5144. 

Alas S, Bonavida B. Inhibition of constitutive STATS activity sensitizes resistant non-Hodgkin s lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis.C/tw Cancer Res 2003 9 316-326. 

STAT1 is activated by various ligands including cytokines, IFN-a, IFN-y, IL-4, IL-5, IL-13, growth factors and hormones. It has four conserved domains N-terminal, C-terminal, SH2 domain and DNA-binding domain, which is typical of all STAT family members. The SH2 domain is distinct for each STAT and a stable SH2-phosphotyrosine bond is formed after the SH2 domain binds to its specific phosphotyrosine domain. This SH2-pTyr bond is responsible for STAT activation... 

In the slime mould, Dictyostelium discoideum, a STAT-like DNA-binding protein, DIF (the differentiation-inducing factor), is expressed. DIF is about 700 amino-acid residues long, and has substantial homology with mammalian STATs. DIF is, like STAT, activated by phosphorylation of tyrosines. It is essential for differentiation of the stalk cells of D. discoideum A The long evolutionary path that the STATs have travelled from Dictyostelium to mammals underlines their conserved and essential role as signal transmitters and transcriptional activators in early development. 

Demoulin JB, Uyttenliove C, Van Roost E, et al. A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9, Mol CeU Biol 1996 16 4710-6. 

It is known that STAT activation, BMP-signaUng-dependent Idl expression, and canonical Wnt signaling are involved in the self-renewal of mES cells. However, SCI did not affect these pathways, suggesting that pluripotin may function by a previously uncharacterized mechanism. 

Beyond these (essentially technical) considerations, further studies are needed to extend our imderstanding of STAT activation in neutrophils. First, the activation of STAT family members other than STAT1/STAT3/STAT5 needs to be further investigated, especially since all STAT proteins are expressed in these... 

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