Abstract IA10: Inhibition of the Hippo pathway by AMPK-family kinases
Bibliographic record
Abstract
Abstract Inactivation of the Hippo pathway is a common feature in numerous cancers, yet mutations in pathway components are relatively rare. To uncover novel Hippo pathway regulators, we conducted multidimensional high-throughput screens. These efforts uncovered two AMPK family kinases, MARK4 and NUAK2, as negative regulators of the Hippo pathway. MARK kinases, including MARK3 and MARK4, phosphorylate both SAV1 and MST1/2 and inhibit MST1/2-dependent activation of LATS. Moreover, we showed that DLG5 acts as a scaffold to promote MARK-mediated phosphorylation of MST. In contrast to MARKs, NUAK2 interacts with and phosphorylates LATS. Interestingly, NUAK2 is induced by YAP/TAZ in cooperation with AP-1 and this is required for robust YAP/TAZ signaling. Inhibition or loss of NUAK2 reduces the growth of cultured cancer cells and mammary tumors in mice. In human patient samples, NUAK2 expression is elevated in aggressive, high-grade bladder cancer and strongly correlates with a YAP/TAZ gene signature. Thus, we identified a positive feed-forward loop in the Hippo pathway that establishes a key role for NUAK2 in enforcing the tumor-promoting activities of YAP/TAZ. Citation Format: Liliana Attisano. Inhibition of the Hippo pathway by AMPK-family kinases [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA10.
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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 | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".