Abstract 510: Altered c-Src Activity by Aldosterone in Vascular Smooth Muscle Cells From SHR Involves PDGFR, C-terminal Src Kinase (Csk) and Csk-binding Protein (CBP).
Bibliographic record
Abstract
We previously demonstrated that non-genomic signaling by aldosterone through c-Src-dependent pathways is up-regulated in SHR vascular smooth muscle cells (VSMCs). In the present study we examined molecular mechanisms underlying aldosterone-mediated aberrant regulation of c-Src, by focusing on processes that control c-Src catalytic activation as well as recruitment of enzyme regulators in SHR VSMCs. Through intramolecular interactions, c-Src undergoes conformational changes that determine its activation state. The inactive conformation occurs when the phosphorylated Tyr527 binds to the SH2 domain of the kinase. In cultured VSMCs from WKY aldosterone (100 nM) induced c-Src Tyr527 phosphorylation (153.5 ± 13.6 %), whereas this response was blunted in SHR cells indicating the lack of the regulatory loop of the kinase. C-terminal Src kinase (Csk) is a cytosolic kinase that catalyzes c-Src Tyr527 phosphorylation. This kinase is recruited to the membrane by the phosphorylated form of its transmembrane adaptor protein Csk-binding protein (CBP), in order to regulate c-Src activity. Aldosterone-stimulated VSMCs from SHR displayed reduced Csk content in the membrane fractions and lower levels of CBP phosphorylation compared with cells from WKY. Phospho-caveolin-1 (Cav 1 Tyr14) serves as a docking protein for recruiting Csk to membrane microdomains for the negative regulation of c-Src. Aldosterone induced Cav-1 phosphorylation increase in cells from WKY with a reduced response in those from SHR (176.4 ± 18.0 vs 116.3 ± 8.2 %). PDGFR is a potent activator of c-Src catalytic activity through the phosphorylation of the Tyr216 in the SH2 domain of the kinase, which overrides the inhibitory action of the Tyr 527. Aldosterone induced an increase in phosphorylation of both PDGFR (186.6 ± 26.2 vs 281.9 ± 26.7 %) and c-Src Tyr216 (145 ± 10.1 vs 200 ± 22.2 %) in VSMCs from SHR versus WKY. These events were inhibited by the MR antagonist, eplerenone and the PDGFR inhibitor, AG1296. Our findings demonstrate that key regulators of c-Src activity, specifically PDGFR, Csk and CBP, are altered in SHR VSMCs. These data identify new targets of interest in cellular processes associated with aldosterone-mediated vascular hypertrophy in hypertension.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".