Abstracts are provided in the language submitted.

Our lab has previously demonstrated that cadherins ,when engaged, trigger a dramatic increase in the levels and activity of the Rac/Cdc42 small GTPases, which subsequently stimulate the secretion of IL6 family cytokines and, thus, the activation of their common receptor, gp130. This results in the phosphorylation of the Signal Transducer and Activator of Transcription-3 (Stat3). When activated, Stat3 upregulates the expression of genes involved in cell division and survival. Src is another potent activator of Stat3. Interestingly, Src is a negative regulator of cadherin function and expression. Since cadherins are a potent activator of Stat3, we revisited the question of Stat3 activation by Src, by exploring the role of cadherin-11 in Balb/c3T3 cells expressing different levels of activated Src527F. We demonstrate that, in Balb/c3T3 fibroblasts, activated Src527F also increases Rac levels, leading to secretion of IL6 family cytokines and gp130 activation, which triggers the Stat3-ptyr705 increase. Our results also demonstrate that cadherin-11 is required to preserve gp130 levels for IL6 family signaling. At the same time, activated Src527F downregulates cadherin-11, in a quantitative manner. As a result, Src527F expression to intermediate levels allows sufficient cadherin-11, hence gp130 levels for Stat3 activation, as expected. However, expressed to high levels, Src527F eliminates cadherin-11, hence gp130 signaling, thus abolishing Stat3-ptyr705 stimulation. Taken together, these data establish for the first time a loop between Src, cadherin-11, gp130, and Stat3 activation that is required for cellular survival which could have significant therapeutic implications.

Hanad Adan