The Stat Proteins

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). 

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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). 

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.

Phosphotyrosine residues as targets of SH2 domains are found in a variety of signaling proteins. As well as the receptor tyrosine kinases and the cytokine receptors, the T-cell receptors and the nonreceptor tyrosine kinases utilize phosphotyrosine-SH2 interactions for signal transmission. Other examples include adaptor or docking proteins like Grb2 and She, phospholipase Cy, and transcription factors like the Stat proteins (see Section 11.2.2). 

Signaling proteins that have been recruited to the activated receptor are often substrates for phosphorylation by the activated tyrosine kinase. Examples are the Stat proteins (see below), the She adaptor protein, and PI3 kinase. I1-2R/ activates PI3 kinase by inducing phosphorylation on tyrosine residues of the p80 regulatory subunit and recruiting PI3 kinase to the cell membrane. 

Membrane Receptors with Associated Tyrosine Kinase Activity 11.2.2.2 The Stat Proteins... 

The Jak/STAT pathway is not the only pathway by which STAT proteins transmit signals to the level of transcription. Over 40 different proteins have been identified that induce phosphorylation and activation of STAT proteins, and several signaling pathways converge at the level of the STAT proteins. Stat proteins can be activated via... 

STAT proteins have several functional domains, including a DNA-binding domain and a Src-homology 2 (SH2) domain. The SH2 domain binds phosphorylated tyrosines on the activated receptor, thus recruiting the STAT protein to the receptor complex. STAT proteins are then substrates for the JAKs and become... 

These data suggest that BCL-6 may be an important regulator of inflammation by repressing the expression of chemokines that recruit leukocytes to sites of injury and infection. Indeed, BCL-6 may be functioning through the identical DNA elements that the STAT proteins bind, to activate transcription. The recipro-... 

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