Control of B cell activation and migration by PI 3-kinase: role of inositol polyphosphate 4-phosphatases
Bibliographic record
Abstract
Abstract Balanced activation of the PI3K pathway by antigen and other stimuli is required for effective humoral immunity while avoiding autoimmunity and lymphoproliferative disease. The critical regulatory phosphatase SHIP dephosphorylates the PIP3 generated by PI3K to produce a distinct molecule PI(3,4)P2. A number of key signaling molecules bind to PIP3, including the protein kinase Btk; however much less is known about the function of PI(3,4)P2. The inositol phosphatase INPP4A can specifically hydrolyze PI(3,4)P2; however the functions of this phosphatase in B cell activation are unknown. We hypothesized that INPP4A can provide a tool to deplete PI(3,4)P2 and determine its range of functions. Human B lymphocytes over-expressing active or phosphatase-dead INPP4A were generated, and the cells expressing active enzyme were found to generate lower levels of PI(3,4)P2 upon chemokine or BCR stimulation. Chemokine-induced migration responses were inhibited by active, but not inactive INPP4A. An assessment of BCR signaling was carried out that compared BCR-stimulated cells expressing active versus inactive INPP4A in a screen encompassing over 800 protein phosphorylation sites. The results indicate that active INPP4A can suppress phosphorylation of Akt and known Akt targets. We are currently assessing whether PDK1, a major kinase upstream of Akt which also directly binds PI(3,4)P2, is regulated by INPP4A. Interestingly, other kinases known to interact with PDK1 (PKCdelta, RSK) or to be directly phosphorylated by PDK1 (PKCgamma) showed decreased phosphorylation in cells expressing active INPP4A. We are currently testing the hypothesis that PDK1/Akt and Btk/PLCγ2 signal osomes are differentially regulated by INPP4A.
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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) | 0.001 | 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".