Abstract 5097: ITCH E3 ubiquitin ligase regulates LATS1 tumor suppressor stability
Bibliographic record
Abstract
Abstract The Large Tumour Suppressor 1 (LATS1) is a serine/threonine kinase and tumour suppressor found downregulated in many human tumour types. Our lab and others previously revealed that LATS1 plays critical regulatory roles in various cancer development events, including cell proliferation, cell migration and apoptosis. However, despite such biological importance, relatively little is known regarding to how LATS1 is regulated at the molecular level. Through a recent binidng screen, we identified a HECT class E3 ubiqitin ligase ITCH (or API4) as a novel binding partner of LATS1. Further mapping showed that this interaction is particularly mediated through the PPxY (P, proline; x, any amino acids; Y, tyrosine) motifs of LATS1 and the WW domains of ITCH. Significantly, we found that ectopic expression of ITCH readily promotes downregulation of LATS1 proteins in a dose dependent manner and that this effect requries an intact ligase activity of ITCH. Further experiments also revealed that ITCH can promote in vivo polyubiquitination and subsequent degradation of LATS1 through the 26S proteasome pathway. Consistent with these results, stable shRNA knockdown of endogenous ITCH also causes upregulation of endogenous LATS1 in the MDA-MB-231 breast cancer cells, suggesting ITCH is a direct regulator of LATS1's protein stability. Together, our study provided convincing evidences demonstrating ITCH as the first negative regulator of the LATS1 tumour suppressor. Further elucidation of the effect of ITCH on LATS1's tumour suppressive activity may therefore shed light on our understanding of their roles in cancer development and therapy. 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 5097.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".