Abstract 5868: Role of STAT3 vs AKT in cellular survival
Bibliographic record
Abstract
Abstract Cell to cell adhesion is mediated by the cadherin family of proteins. We previously demonstrated that cadherin engagement (which is favored under conditions of confluence) triggers a dramatic increase in Rac protein levels, followed by an increase in IL6 secretion and Stat3 (Signal Transducer and Activator of Transcription-3) activation. This is critical for survival of both normal and neoplastic cells. On the other hand, cell adhesion to the substratum, ie the extracellular matrix at the focal adhesion sites, is mediated by the integrin receptors. The focal adhesion kinase (FAK) binds β1-integrins and this forces FAK in an open configuration and autophosphorylation at tyr397 which constitutes a binding site for Src-SH2. This results in phosphorylation of FAK at tyr 576, 577, 861 and 925. The FAK/Src complex then activates downstream effectors such as Ras/Erk and phosphatidylinositol-3 kinase (PI3k)/Akt. Our results demonstrate that mouse fibroblasts or epithelial cells placed in suspension (ie in the absence of anchorage to a substratum or cell to cell adhesion) have very low levels of activated Akt-pser473, but levels are increased dramatically upon subsequent aggregation, ie cadherin engagement. Interestingly, cells growing attached in monolayers had high Akt-pser473 levels at low densities, which increased only slightly with confluence. This pointed to the possibility that a kinase may be phosphorylating Akt upon attachment to the substratum. The results showed that FAK knockout cells have very low Akt-pser473 at low cell densities, while reintroduction of wt-FAK reinstated the high Akt-pser473 levels. Furthermore, expression of a mutant form of FAK where the 5 sites that are phosphorylated by Src are converted to phenylalanine, did not result in an increase in Akt-pser473 levels, demonstrating a Src requirement for Akt, pser473 phosphorylation. Conclusions: Cell survival signals are a prerequisite for tissue function, as well as drug resistance. In cultured, non-neoplastic cells grown to low densities the integrin/FAK/cSrc signal activates PI3k/Akt and promotes survival, in the absence of cadherin engagement. Interestingly, the integrin/FAK signal does not activate Stat3, despite the fact that mutationally activated Src is a potent Stat3 activator. Additional mechanisms, perhaps involving Jak and/or activated receptors may also be required for Stat3 activation in cells grown attached but at low densities. On the other hand, upon cadherin engagement at high cell densities, activation of both the cadherin/Stat3 and integrin/FAK/Akt pathways can promote survival. Therefore, co-ordinate activation of these complementary pathways could greatly enhance survival and growth of disseminated tumor cells at distant metastastic sites, and might promote resistance to chemotherapeutic agents. In this scenario, pharmacological inhibition of both FAK/Src and Stat3 would enhance patient survival. Note: This abstract was not presented at the meeting. Citation Format: Maximilian Niit, Joshua Rosen, Rozanne Arulanandam, Victoria Hoskin, Bruce Elliott, Leda Raptis. Role of STAT3 vs AKT in cellular survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5868. doi:10.1158/1538-7445.AM2017-5868
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
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 source (direct Gemma or distilled Codex), 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".