Characterization of Protein Tyrosine Phosphatase 1B activator peptides in cells
Bibliographic record
Abstract
The Protein Tyrosine Phosphatase (PTP) family of phosphatases regulates cell signaling through dephosphorylation of serine, threonine and tyrosine residues of downstream effector proteins. The role of PTPs is very well known in normal cell functions, as well as in disease states such as diabetes and cardiovascular diseases. We previously reported on the role of the phosphotyrosine recognition loop (PTBL) of PTP1B in protein‐protein interactions (Londhe et al. 2020, Nat. Chem. Biol., 16(2):122‐125) and showed that interfering with protein‐protein interactions between PTP1B and 14‐3‐3zusing R18, a pan‐14‐3‐3 inhibitor, destabilizes the reversibly oxidized form of PTP1B (PTP1B‐OX) and activates the phosphatase. We rationally designed peptides using phosphotyrosine recognition loop of PTP1B to determine whether selective and effective activation of PTPs was possible. We first performed a structural analysis to compare the changes occurring in PTP1B‐OX compared to its reduced form. Using this approach, we observed profound conformational changes in the phosphotyrosine recognition loop (PTBL) of PTP1B and rationally designed peptides comprised of the sequence of amino acids of the newly exposed loop, with a TAT (transactivator of transcription) peptide sequence in amino or carboxy‐terminal to facilitate cell permeability. Targeting the PTP1B‐OX‐14‐3‐3z interaction using R18 and TAT‐PTBL peptide led to disruption in protein‐protein interaction and maintained PTP1B in its active form. Interestingly, destabilizing the PTP1B‐OX form by treating cells with rationally designed PTP1B activator peptides also decreased EGFR phosphorylation at PTP1B sites. In cells stimulated with exogenousH 2 O 2 to bypass the NOX‐mediated PTP1B oxidation, the pretreatment with R18 and TAT‐PTBL prevented the interaction between PTP1B‐OX and 14‐3‐3z. Then we observed that our TAT‐PTBL peptide was not interfering with NOX‐mediated reactive oxygen species (ROS) generation, whereas R18, a pan‐14‐3‐3 inhibitor, decreased ROS production significantly. Finally, exposing A431 epidermoid carcinoma cells to PTP1B activator peptides prevented EGFR phosphorylation and impaired colony formation. Collectively our data suggest that the biological activity of PTP1B activator peptides is likely to be therapeutically useful, and could translate into drug leads.
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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 | 0.001 |
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".