Stat protein

Roles of STAT Proteins in Cytokine-lndncible and Constitutive Gene Induction... 

In mammalia, seven different members encoded by distinct genes have been identified, all of which are activated by a distinct set of cytokines. Diversity in signaling is provided by variants of STAT proteins derived from either alternative splicing of RNA transcripts or proteolytic processing (e.g., STATs 1,3,4, and 5) and the ability of certain STATs to form both homodimers and heterodimers with each other. In response to inteiferon-y monomeric STAT1 dimerizes, while upon interferon-a stimulation a heterotrimeric complex consisting of STAT 1 and STAT2 with associated... 

Besides the cytokine receptors that lack intrinsic kinase activity but have associated JAK kinases, STAT proteins can be activated by a variety of G-protein coupled receptors and growth factor receptors with intrinsic tyrosine kinase activity (for example EGF, PDGF, CSF-1, and angiotensin receptor). Increasing evidence suggests a critical role for STAT family members in oncogenesis and aberrant cell proliferation. Constitutively activated STATs have been found in many transformed cell lines and a wide variety of human tumor entities. Numerous non-receptor tyrosine kinases and viral oncoproteins, such as v-Src, v-Abl, v-Sis, and v-Eyk, have been identified to induce DNA-binding activity of STAT proteins. 

Horvath CM (2000) STAT proteins and transcriptional responses to extracellular signals. Trends Biochem Sci 25 496-502... 

Catlett-Falcone R, Dalton WS, Jove R (1999) STAT proteins as novel targets for cancer therapy. Curr Opin Oncol 11 490-496... 

Beside other functions in signal transduction, protein inhibitors of activated STAT suppress the DNA-binding activity of STAT proteins. 

PIAS (protein inhibitors of activated STATs) proteins were first discovered in yeast-two-hybrid screens as interacting molecules with STAT transcription factors. The mammalian family consists ofthe founding member PIAS3, which was described as a repressor of STAT3, and three additional members, PIAS1, PIASy (also known as PIAS4), and PIASx (also known as... 

Figure 8.3 Schematic representation of the general domain structure of a STAT protein. A conserved ( C or con ) domain is located at the N-terminus, followed by the DNA-binding domain (D). Y represents a short se-guence that contains the tyrosine residue phosphorylated by the Janus kinase. The carboxy terminus domain (Tr) represents a transcriptional activation domain...

The phosphorylation state of the transcription factor NF-AT has a different effect on translocation. The phosphorylated form of this protein is localized in the cytosol and requires dephosphorylation by the protein phosphatase calcineiuln in order to be translocated to the nucleus (see also 7.5.2). Other examples for phosphorylation-dependent nuclear translocation include the STAT-proteins (see 11.1.3.2) and the SMAD-proteins (see 12.1.2). 

Starting from the activated Jak kinases, a signaling pathway leads directly to transcription factors that are phosphorylated by the Jak kinases on tyrosine residues and activated for stimulation of transcription (review Horvath and Darnell, 1997). These transcription factors belong to a class of proteins known as Stat proteins (Stat = signal transducer and activator of transcription). At least seven different Stat proteins are known (Statl-4, StatSa, StatSb, Stat6). The first Stat proteins, Statl and Stat2, were foimd in association with signal transduction via interferon y. 

The Stat proteins are found in a latent form in the cytosol and are activated by cytokine receptors and their associated kinases. On binding of the cytokine to the receptor and activation of the Jak kinase, the Stat proteins are recruited, via their SH2 domains, to the receptor-kinase complex and are then phosphorylated by the Jak kinase on a conserved Tyr residue at the C-terminus. 

The phosphorylated Stat proteins form homodimeric or heterodimeric complexes and are transported as such into the nucleus (Fig. 11.7). In the nucleus, they bind to corresponding DNA elements in the promoter region of cytokine responsive genes. Stimulation of transcription takes place in cooperation with other proteins such as p300, CBP (see 1.4.6), glucocorticoid receptors and c-jim. 

The Stat proteins have SH2 and SH3 domains, a DNA binding domain and a C-ter-minal domain required for transcription activation. The activating phosphorylation takes place for Statl on Tyr701 in the vicinity of the C-terminus. In the imphosphoryla-ted form, the Stat proteins exist as monomers, whereas in the phosphorylated form, they are dimers. 

Dimerization is mediated by the phosphotyrosine residue and the SH2 domain. Highly resolved structural investigation show that the phosphotyrosine residue of one Stat protein binds to the SH2 domain of the partner and vice versa, so that the phosphoty-rosine-SH2 bonds fimction as a double clasp (structure in complex with DNA Becker et al., 1998 Chen et al., 1998). The binding to DNA is in the form of a dimer, with the Stat-DNA complex showing a large similarity to the structure of the NFxB-DNA complex (see Fig. 1.10). 

Fig. 11.7. Model of activation of Stat proteins. The Stat proteins are phosphorylated (at Tyr701 for Statl) as a consequence of binding to the receptor-Jak complex, and Stat dimers are formed. The dimerization is mediated by phosphotyrosine-SH2 interactions. In the dimeric form, the Stat proteins are transported into the nucleus, bind to corresponding DNA elements, and activate the transcription of neighboring gene sections. In the figure, activation of Stat proteins is shown using the IL-6 receptor as an example (according to Taniguchi, 1995). Other Jak kinases and Stat proteins may also take part in signal conduction via IL-6, in addition to the Jak kinases and Statl shown.

There are at least six different Stat proteins, from which it can be assumed that these are phosphorylated with differing efficacy by the various receptor tyrosine kinases. In addition, expression of Stat proteins is cell and tissue specific. 

At the DNA level, variability of the DNA elements specific for Stat proteins and accessibility of the promoter sites are further determining factors for specificity of signal transduction. 

David, M., E. Petricoin, 3rd, C. Benjamin, R. Pine, M.J. Weber, and A.C. Lamer, Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science, 1995. 269(5231) 1721-3. 

Bartoli, M., Gu, X., Tsai, N. T., Venema, R. C., Brooks, S. E., et al. 2000. Vascular endothelial growth factor activates STAT proteins in aortic endothelial cehs.. /. Biol. Chem. 275 33189-33192. 

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