Abstract 4411: Cadherin engagement induces a dramatic increase in tyr-705 phosphorylation of the signal transducer and activator of transcription-3 (Stat3α) but not the dominant-negative isoform Stat3β
Bibliographic record
Abstract
Abstract The purpose of this study was to examine the role of Stat3α and Stat3β in survival and apoptosis of normal and tumor cells. The Stat3 transcription factor is activated by cytokine receptors of the IL6 family, and receptor and non-receptor tyrosine kinases, plays an etiological role in neoplasia. Stat3 activation entails phosphorylation at tyr-705, Stat3 dimerization through a reciprocal, SH2 domain-phosphotyrosine interaction, and nuclear translocation. This triggers transcription of genes involved primarily in cellular survival such as survivin, MCl1 and Bcl-xL, as well as cell division such as myc. We previously demonstrated that engagement of E- or N-cadherin or cadherin-11 induces a dramatic increase in total protein levels and activity of the small GTPases, Rac and Cdc42, through inhibition of proteasomal degradation. Activated Rac leads to a surge in secretion of cytokines of the IL6 family through the transcription factor NFκB and Jak kinases, and this in turn, activates Stat3 in an autocrine manner. Stat3 inhibition in confluent, non-transformed cells induces apoptosis, pointing to a key survival role for Stat3. Full-length Stat3 (termed Stat3α) is composed of an SH2 domain, tyr-705 and a COOH terminus encoding the transcription activation domain (TAD). Stat3β is a naturally-occurring splice variant which is lacking TAD. Therefore, Stat3β dimerizes with Stat3α but is defective in transcriptional activation, resulting in inhibition of Stat3α function. Since tyr-705 is present in both isoforms, we examined the phosphorylation pattern of Stat3α vs Stat3β. Our results demonstrate that cadherin engagement brought about through confluence of non-transformed mouse fibroblasts results in phosphorylation of Stat3α-tyr705, despite the fact that the sequence around tyr-705 is the same in both isoforms. The Large Tumor antigen of Simian virus 40 oncogene (TAg) interacts with the p53 and pRb tumor-suppressors, and this leads to activation of the E2F family of transcription factors, targeting cell division genes. At the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for antiapoptotic signals, such as Stat3. Interestingly, our data demonstrated that SVLT expression results in phosphorylation of Stat3β. Therefore, this feedback loop that reduces the activity of Stat3α, triggers apoptosis of transformed cells selectively, because of their high E2F levels. As a result, certain tumor cells which may naturally express high Stat3β levels would be very sensitive to pharmacological Stat3 inhibition, a finding which could have significant therapeutic implications. Citation Format: Zaid Taha, Stephanie Guy, Maximillian Niit, Leda Raptis, Adina Vultur, Rozanne Arulanandam. Cadherin engagement induces a dramatic increase in tyr-705 phosphorylation of the signal transducer and activator of transcription-3 (Stat3α) but not the dominant-negative isoform Stat3β. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4411.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".