Dimerization, of STATs

Figure 15.30. Phosphorylation-Induced Dimerization of STAT Proteins. The phosphorylation of a key tyrosine residue on each STAT protein leads to an interaction between the phosphotyrosine and an SH2 domain on another STAT monomer. The STAT dimer produced by these reciprocal interactions has a high affinity for specific DNA sequences and is able to alter gene expression after binding to DNA.

Stimulation of the g and a interferon receptors leads to the activation of Jak kinase family members which phosphorylate a variety of STAT transcription factors. Regulation of interferon-responsive genes is the result of phosphorylation-dependent nuclear translocation and dimerization of STAT transcription factors, which is required to activate their DNA binding and transcriptional regulatory functions. 

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... 

STAT phosphorylation ensures its binding to the receptor, with subsequent disengagement from the receptor in dimeric form. STAT dimerization is believed to involve intermolecular associations between the SH2 domain of one STAT and phosphotyrosine of its partner. Dimerization appears to be an essential prerequisite for DNA binding. Dimers may consist of two identical STATs, but STAT1-STAT2 and STAT1-STAT3 heterodimers are also frequently formed in response to certain cytokines. The STAT dimers then translocate to the nucleus where they bind to specific... 

Disassociation (and dimerization) of activated STATs, and translocation to nucleus... 

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.

Fig. 11.8 A) Domain structure of STATs. STATs bind to receptors and dimerize via bivalent SH2-phosphotyrosine interactions. Phosphorylation ofthe conserved tyrosine is required for STATs dimerization. The N-terminal region mediates oligomerization of STAT dimers. B) Dimer of Stat2 bound to DNA. Dimerization is mediated by reciprocal SH2-Tyr-phosphate interactions ofthe monomers. The view is along the DNA helix. The DNA binding domain is in red, the linker domain in orange and the SH2 domain in light green. The C-termini ofthe two Stat2 molecules are shown in yellow and magenta.

By quantitative immunoblotting, the time courses of the phosphorylated (monomeric, x2, and dimeric, xf) STAT-5 in the cytoplasm yt(t), the total amount of STAT-5 in the cytoplasm y2(t) and the activation of the Epo receptor were determined. The measured values represent relative units. For a detailed description of the biochemical techniques to measure the different components, see Ref. 21. 

STATs are also inactivated. The protein inhibitors of activated STAT (PIAS) family of proteins bind to phosphorylated STATs and prevent their dimerization or promote the dissociation of STAT dimers. STATs also may be inactivated by dephosphorylation, although the specific phosphatases have not yet been identified, or by targeting activated STATs for proteolytic degradation. 

Fig. 44.16. C54okine signaling through the JAK/STAT pathway. 1. Cytokine binding to receptors initiates dimerization and activation of the JAK kinase, which phosphorylates the receptor on tyrosine residues. 2. STAT proteins bind to the activated receptors and are themselves phosphorylated. 3. Phosphorylated STAT proteins dimerize, travel to the nucleus, and initiate gene transcription. 4. One of the proteins whose s5mthesis is stimulated by STATs is SOCS (suppressor of cytokine signaling), which inhibits further activation of STAT proteins (circle 5) by a variety of mechanisms.

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