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• W2315938045 abstract "Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCStat3 (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. We recently demonstrated a dramatic increase in the activity of Stat3 in breast carcinoma as well as normal epithelial cells and fibroblasts, as a consequence of cell to cell adhesion (Oncogene 23:2600). Given the generally accepted, positive role of Stat3 in proliferation, the Stat3 activity increase observed in confluent cells, that is when cells do not divide, was an unexpected observation. Interestingly, by plating cells onto surfaces coated with fragments encompassing the two outermost domains of 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, we demonstrated that cadherin engagement per se can directly activate Stat3, in the absence of cell to cell contact. Examination of the mechanism of the cadherin-mediated, Stat3 activation unexpectedly revealed for the first time a dramatic surge in total Rac1 and Cdc42 protein levels by cadherin engagement, and a proportional increase in Rac1 and Cdc42 activity. Therefore, to examine the potential role of Rac/Cdc42 in the density-dependent, Stat3 activation, the ability of mutationally activated RacV12 to activate Stat3 at high cell densities was examined. The results revealed 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 in both cases. In addition, RacV12-expressing cells had higher Stat3, tyrosine-705 phosphorylation and activity levels at all densities, indicating that RacV12 is, in fact, able to activate Stat3. Further examination of the mechanism of Stat3 activation showed that both cadherin engagement and RacV12 expression caused a surge in mRNA of Interleukin-6 (IL6) family cytokines, known potent Stat3 activators. Knockdown of gp130, the common subunit of this family reduced Stat3 activity in densely growing normal, as well as in RacV12-transformed cells, indicating that the IL6 family may be responsible for the Stat3 activation both by cadherin engagement and Rac mutational activation. Indeed, Rac knockdown reduced the density-mediated, Stat3 activation, indicating that Rac is responsible for the Stat3 stimulation observed upon cadherin ligation. Inhibition of cadherin interactions using a peptide, a soluble cadherin fragment or genetic ablation induced apoptosis, pointing to a significant role of this pathway in cell survival signalling, a finding which could also have important therapeutic implications. (supported by CIHR, CBCF-Ontario chapter, US Army breast cancer program, NSERC and Breast Cancer Action Kingston).Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 991." @default.
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• W2315938045 date "2010-04-15" @default.
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• W2315938045 title "Abstract 991: Cadherin-cadherin engagement promotes cell survival via Rac/Cdc42 and Stat3" @default.
• W2315938045 doi "https://doi.org/10.1158/1538-7445.am10-991" @default.
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