Novel mechanisms of Stat3 activation
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Stat3 (signal transducer and activator of transcription-3) is activated by a number of receptor and non-receptor tyrosine kinases, while a constitutively active form of Stat3 alone is sufficient to induce neoplastic transformation. Results presented in this thesis reveal that Stat3 can also be activated through homophilic interactions by the epithelial (E)-cadherin and cadherin-11, two members of the classical type I and II cadherin family of surface receptors, responsible for the formation of cell to cell junctions. Indeed, by plating cells onto surfaces coated with fragments encompassing the two outermost domains of these cadherins, we definitively demonstrate that cadherin engagement can activate Stat3, even in the absence of direct cell to cell contact. At the same time, levels of the extracellular signal regulated kinase (Erk)1/2, which is often coordinately activated by growth factor receptors and oncogenes, remain unchanged upon cadherin ligation. Most importantly, we report, for the first time, an unexpected surge in total Rac1 and Cdc42 protein levels, triggered by cadherin engagement, and an increase in Rac1 and Cdc42 activity, which is responsible for the Stat3 stimulation observed. Inhibition of cadherin interactions reduced Rac/Cdc42 and Stat3 levels and induced apoptosis, pointing to a significant role of this pathway in cell survival signalling, a finding which could also have important therapeutic implications. To better understand the role of Rac/Cdc42 in the cadherin-mediated Stat3 activation, we compared Stat3 activity in mouse HC11 cells before and after expression of the mutationally activated, RacV12. We demonstrate a dramatic increase in protein levels and activity of both the endogenous Rac and RacV12 with cell density, which was due to inhibition of proteasomal degradation. Moreover, we clearly show that RacV12 expression can activate Stat3 through an increase in expression of members of the IL6 family of cytokines, known potent Stat3 activators. In fact, knockdown experiments indicate that gp130 receptor function, and Stat3 activation, are essential for the migration and proliferation of RacV12-expressing cells, thereby demonstrating that the gp130/Stat3 axis represents an essential target of activated Rac in the regulation of both of these fundamental cellular functions.