Dissecting the role of MAP3Ks TAK1 and ASK1 in IgE-FcERI mediated mast cell exocytosis
Bibliographic record
Abstract
Mast cells are sentinel immune cells and the main drivers of allergic inflammation. Upon allergen exposure mast cells initiate immediate degranulation in the early-phase of the response, followed by de novo production and secretion of pro-inflammatory mediators in the late-phase. Co-stimulating with allergen and SCF results in the amplification of the pro-inflammatory response launched by allergically-activated mast cells, and a connection between the two signalling pathways is the mitogen activated protein kinase (MAPK) pathway. Therefore, this dissertation includes 3 studies that focussed on MAP3K proteins, TAK1 and ASK1, that are potential nexus points in the signaling mechanisms of the allergic inflammatory response. Our previous work identified TAK1 as a central regulator in co-stimulated mast cells, and study 1 found that TAK1 regulates signaling through both the FcERI and ckit receptor individually as well as supporting that the MAP3K level is an appropriate target for therapeutic development of mast cell stabilizers. Study 2 was carried out to determine if other MAP3Ks, specifically ASK1 also exhibited the regulation observed with TAK1 in allergically-activated mast cells. We found that despite ASK1 sharing the same level in the MAPK cascade, its inhibition did not have as significant an impact in activated mast cells, suggesting that TAK1 is unique in its ability to regulate mast cell function following allergic stimulation. Study 3 was an explorative study to determine how TAK1 is able to exert its regulatory effect on the allergic inflammatory response. We identified a novel interaction between TAK1 and the lipid kinase PIP4K2B. This discovery elucidates the mechanistic placement of TAK1 in mast cells and increases our understanding of the regulation of mast cell inflammatory mechanisms. Taken together, the following research shows that different MAP3Ks exert varying levels of regulatory control in allergically activated mast cells, with TAK1 appearing to be robustly influential, especially compared to ASK1 under the same conditions. Furthermore, we present evidence to support a novel interaction between TAK1 and mechanisms supporting the generation of PIP2, which has the potential to lay the foundation for a new field of study looking into the relationship between the canonical MAPK pathway and lipid metabolism in mast cells.
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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 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".