Novel interactions mediated by the adaptor protein Dok-4 regulate growth factor signaling and could influence the response to acute kidney injury
Bibliographic record
Abstract
Ischemia-reperfusion injury (IRI) causes acute kidney injury, particularly inducing cell death in proximal tubule epithelial cells (TECs).Following injury, surviving TECs regenerate to repair injured tubules, a process which in animal models, is enhanced by endogenous and exogenous growth factors (GFs), such as epidermal growth factor.Unfortunately, GF-based intervention has been disappointing in human trials, suggesting that negative regulatory mechanisms must be overcome to maximize the benefit of these interventions.We hypothesize that Dok-4, a conserved member of the Dok family of inhibitory adapter proteins, which is highly expressed in epithelial tissues yet remains virtually uncharacterized, mediates anti-mitogenic signaling in renal tubules following IRI by recruiting β2-chimaerin, a negative regulator of the Rho GTPase Rac1.We have found that Dok-4 and β2-chimaerin both to be upregulated in the injured kidney following ischemia-reperfusion.We have found that Dok-4 interacts with β2-chimaerin and that structurally, the Dok-4/β2-chimaerin interaction occurs directly through the Dok-4 phosphotyrosine-binding (PTB) domain and a phosphorylated tyrosine residue at position 153 (Y153) of β2-chimaerin, and that the interaction is potentiated by tyrosine kinases.We have identified the homologous α2-chimaerin, as containing the same PTB binding motif (NPIY143), and confirmed that, as with β2-chimaerin, it interacts with the Dok-4 PTB domain upon phosphorylation.We also found that the interaction with Dok-4 is greatly enhanced by the active (open) conformation of β2-chimaerin.Functionally, we have found that Dok-4 and β2-chimaerin cooperate to inhibit Rac1 activity at the cell membrane and that this inhibitory effect requires membrane localization mediated by the Dok-4 pleckstrin homology domain.From these results, we propose a model whereby Dok-4 acts to recruit β2-chimaerin to the membrane, where it is stabilized in its active form and is able to attenuate Rac1 signaling and presumably, downstream proliferative signaling events.IRI is associated with the progression to end-stage renal disease and negative patient
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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) | 0.004 | 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".