There, Stat3 dimers bind DNA sequences to activate the transcription of specific genes involved in cell division and survival, such as myc, bcl-xL, mcl-1, and survivin while they downregulate the tumor suppressor p53, thus protecting tumor cells from apoptosis. Following phosphorylation of the critical tyrosine-705 residue (ptyr705), Stat3 monomers associate with each other through reciprocal SH2-ptyr705 interactions to form dimers that translocate to the nucleus. Thus, Stat3 is recruited to the activated receptors and, in turn, becomes phosphorylated by the receptor itself, or by associated Janus kinase (JAK) or Src family kinases. Ligand engagement leads to phosphorylation of specific tyrosine residues on the receptors, which provide docking sites for the Src homology 2 (SH2) domain of Stat3. Stat3 is activated by receptor tyrosine kinases such as EGFR, cytokine receptors such as the Interleukin-6 receptor (IL6R), and non-receptor tyrosine kinases such as Src.
COREL PHOTO PAINT 8 ACTIVATOR
The signal transducer and activator of transcription-3 (Stat3) is a latent cytoplasmic transcription factor. This fine balance between Src 527F and cadherin-11 levels which is required for Stat3 activation and cellular survival could have significant therapeutic implications. Taken together, these data establish for the first time a loop between Src, cadherin-11, gp130, and Stat3 activation. However, expressed to high levels, Src 527F eliminates cadherin-11, hence gp130 signaling, thus abolishing Stat3-ptyr705 stimulation. As a result, Src 527F expression to intermediate levels allows sufficient cadherin-11, hence gp130 levels for Stat3 activation, as expected. At the same time, however, activated Src 527F downregulates cadherin-11, in a quantitative manner.
Interestingly, our results also demonstrate that cadherin-11 is required to preserve gp130 levels for IL6 family signaling. In the present report we demonstrate that, in mouse Balb/c3T3 fibroblasts, mutationally activated Src 527F also increases Rac levels, leading to secretion of IL6 family cytokines and gp130 activation, which triggers the Stat3-ptyr705 increase. This results in phosphorylation of the Signal Transducer and Activator of Transcription-3 (Stat3) on tyrosine-705, which then dimerizes, migrates to the nucleus, and activates transcription of genes involved in cell division and survival. We previously demonstrated that engagement of cadherins, cell to cell adhesion molecules, triggers a dramatic increase in levels and activity of the Rac/Cdc42 small GTPases, which is followed by secretion of IL6 family cytokines and activation of their common receptor, gp130, in an autocrine manner.