Endothelin-1 activates mesangial cell ERK1/2 via EGF-receptor transactivation and caveolin-1 interaction
Bibliographic record
Abstract
Endothelin-1 (ET-1) stimulates glomerular mesangial cell proliferation and extracellular matrix protein transcription through an ERK1/2-dependent pathway. In this study, we determined whether ET-1 activation of glomerular mesangial cell ERK1/2 is mediated through EGF receptor (EGF-R) transactivation and whether intact caveolae are required. We showed that ET-1 stimulated tyrosine phosphorylation of the EGF-R in primary cultured, growth-arrested rat mesangial cells. In response to ET-1, ERK1/2 phosphorylation was increased by 27 +/- 1-fold and attenuated by AG-1478, a specific EGF-R inhibitor, to 9 +/- 1-fold. Moreover, filipin III and beta-cyclodextrin, two cholesterol-depleting drugs known to disrupt caveolae, significantly reduced ET-1-induced phosphorylation of ERK1/2. In addition, preincubation of mesangial cells with a myristoylated peptide that binds to the caveolin-1 scaffolding domain diminished ET-1 activation of ERK1/2. ET-1 caused interaction of caveolin-1 with phosphorylated ERK1/2 identified by coimmunoprecipitation. Activation of ERK1/2 and its interaction with caveolin-1 were reduced by AG-1478, beta-cyclodextrin, or inhibition of PKC. Phosphorylated ERK1/2 localized at focal adhesion complexes along with phospho-caveolin-1, suggesting specific sites of compartmentalization of these signaling molecules. Hence, ET-1 activates mesangial cell ERK1/2 predominantly through a pathway involving EGF-R transactivation, leading to a mechanism involving attachment to caveolin-1, presumably in caveolae.
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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".