Complement-mediated Activation of Calcium-independent Phospholipase A2γ
Bibliographic record
Abstract
In experimental membranous nephropathy, complement C5b-9-induces glomerular epithelial cell (GEC) injury and proteinuria. The effects of C5b-9 are mediated via signaling pathways, including calcium-independent phospholipase A 2 γ (iPLA 2 γ), and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. The iPLA 2 γ pathway is cytoprotective. This study addresses the mechanisms of iPLA 2 γ activation. iPLA 2 γ activity was monitored by quantifying prostaglandin E 2 (PGE 2 ) production. In GECs, iPLA 2 γ localized at the endoplasmic reticulum and mitochondria. Complement-mediated production of PGE 2 was amplified in GECs that overexpress iPLA 2 γ, compared with control cells, and was blocked by the iPLA 2 γ inhibitor bromoenol lactone in both iPLA 2 γ-overexpressing and control GECs. In GECs that overexpress iPLA 2 γ, complement-mediated PGE 2 production was reduced by inhibitors of MAP/ERK kinase 1 (MEK1) and p38 but not JNK. In COS-1 cells that overexpress iPLA 2 γ and cyclooxygenase-1, PGE 2 production was induced by co-expression of constitutively active MEK1 or MAPK-interacting kinase 1 (MNK1) as well as by stimulation with epidermal growth factor (EGF) + ionomycin. Complement- and EGF + ionomycin-stimulated iPLA 2 γ activity was attenuated by the S511A/S515A double mutation. Moreover, complement and EGF + ionomycin enhanced phosphorylation of Ser-511. Thus, complement-mediated activation of iPLA 2 γ is mediated via ERK and p38 pathways, and phosphorylation of Ser-511 and/or Ser-515 plays a key role in the catalytic activity and signaling of iPLA 2 γ. Defining the mechanisms by which complement activates iPLA 2 γ provides opportunities for development of novel therapeutic approaches to GEC injury and proteinuria. Background: Calcium-independent phospholipase A 2 γ (iPLA 2 γ) is a mediator of complement-induced glomerular injury. Results: Complement stimulated iPLA 2 γ through activation of mitogen-activated protein kinases. Conclusion: Phosphorylation of iPLA 2 γ plays a role in activation and signaling. Significance: Understanding the regulation of iPLA 2 γ activity is essential for developing novel therapeutic approaches to glomerular injury and proteinuria.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".