STATs dimers

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... 

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.

Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription. 

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.

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.

These include the receptors for erythropoietin, somatotropin, and interferons. Their receptors are membrane spanning and on activation can activate a distinctive set of cytoplasmic tyrosine kinases (Janus kinases [JAKs]). JAKs phosphory-late signal transducers and activators of transcription (STAT) molecules. STATs dimerize and then dissociate, cross the nuclear membrane, and modulate gene transcription. 

STATs dimerize and then dissociate, cross the nuclear membrane, and modulate gene transcription. 

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. 

If STAT dimers are to act as transcription factors, they must enter the nucleus. How is this achieved ... 

STAT dimers bind to an adaptor protein called importin 5a. This complex is then transferred to the nucleus via the nuclear pore complex. Upon arrival in the nucleus, the STAT dimers are released from importin 5a through the action of Ran that is a GTP-binding protein related to Ras. 

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