Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3
Bibliographic record
Abstract
Intracellular pH (pHi) influences diverse cellular processes, including cell proliferation, metabolism, and migration, and is linked to metabolic diseases and cancer. Protonation alters protein charge and conformation, modulating different aspects of protein function. How pHi fluctuations are sensed by signaling proteins and translated into cellular responses remains incompletely understood. Here, we reveal that pHi plays a key role in regulating the stability of the mitogen-activated protein kinase Extracellular signal-regulated kinase 3 (ERK3). Intracellular acidification markedly increases the half-life of ERK3, whereas alkalinization accelerates its degradation. The pH-dependent regulation of ERK3 is rapid, reversible, and consistent across cell types. Mechanistically, we identified a region in the C-terminus of ERK3 that contains pH-sensing motifs. We further show by quantitative proteomics that short-term acidification or alkalinization globally affects the cellular proteome. Our findings underscore the critical role of pHi in ERK3 turnover and suggest a broader role for pH in regulating protein stability and cell signaling.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".