The Protean Nature of 14-3-3 Proteins in G Protein-Coupled Receptor Signaling: Emphasizing Selectivity and Dynamic Interactions at the Neurokinin Receptor 3 Interface
Bibliographic record
Abstract
Recent models of GPCR signaling extend beyond the canonical paradigm of ligand-induced activation primarily mediated by G-proteins and β-arrestins. Indeed, the various outcomes of GPCR activation are precisely regulated by several factors, including GPCR-interacting proteins, isoform diversity, and GPCR phosphorylation patterns catalyzed by kinases. One underexplored source contributing to the pleiotropic activities of GPCRs is the dynamic recruitment and dissociation of 14-3-3 proteins, a family of ubiquitously expressed adaptor proteins that modulate key cellular processes. Recent studies have shown that GPCR-14-3-3 protein interactions are isoform-specific and can be modulated in a spatiotemporal manner by ligands; however, an investigation of 14-3-3 dynamics across all seven human isoforms and throughout a large panel of GPCRs has yet to be conducted. Thus, this work provides the first characterization of proximal GPCR-14-3-3 protein interactions at a GPCRome scale, achieved by constructing stable reporter cell lines expressing all human 14-3-3 isoforms and performing cell-based high-throughput screening to probe 82 GPCR interactomes. Among the notable findings from this screen, the NK3 receptor emerged as a promising candidate for an in-depth examination of 14-3-3 protein modulation of GPCR activity, especially given the limited literature regarding NK3 signaling, including its relation to G-proteins or β-arrestins. Our findings suggest that different combinations of hetero- and homodimers of 14-3-3 isoforms result in varying functional outcomes at NK3, such as upregulation of NK3 surface expression by 14-3-3γ. Furthermore, 14-3-3γ was found to modulate canonical signaling pathways by attenuating G-protein dissociation and enhancing β-arrestin recruitment signals.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".