Cyclin-Dependent Protein Kinase 5 Primes Microtubule-Associated Protein Tau Site-Specifically for Glycogen Synthase Kinase 3β
Why this work is in the frame
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Bibliographic record
Abstract
In the preceding paper, we showed that GSK3beta phosphorylates tau at S(202), T(231), S(396), and S(400) in vivo. Phosphorylation of S(202) occurs without priming. Phosphorylation of T(231), on the other hand, requires priming phosphorylation of S(235). Similarly, priming phosphorylation of S(404) is essential for the sequential phosphorylation of S(400) and S(396) by GSK3beta. The priming kinase that phosphorylates tau at S(235) and S(404) in the brain is not known. In this study, we find that in HEK-293 cells cotransfected with tau, GSK3beta, and Cdk5, Cdk5 phosphorylates tau at S(202), S(235), and S(404). S(235) phosphorylation enhances GSK3beta-catalyzed T(231) phosphorylation. Similarly, Cdk5 by phosphorylating S(404) stimulates phosphorylation of S(400) and S(396) by GSK3beta. These data indicate that Cdk5 primes tau for GSK3beta in intact cells. To evaluate if Cdk5 primes tau for GSK3beta in mammalian brain, we examined localizations of Cdk5, tau, and GSK3beta in rat brain. We also analyzed the interaction of Cdk5 with tau and GSK3beta in brain microtubules. We found that Cdk5, GSK3beta, and tau are virtually colocalized in rat brain cortex. When bovine brain microtubules are analyzed by FPLC gel filtration, Cdk5, GSK3beta, and tau coelute within an approximately 450 kDa complex. From the fractions containing the approximately 450 kDa complex, tau, Cdk5, and GSK3beta co-immunoprecipitate with each other. In HEK-293 cells transfected with tau, Cdk5, and GSK3beta in different combinations, tau binds to Cdk5 in a manner independent of GSK3beta and to GSK3beta in a manner independent of Cdk5. However, Cdk5 and GSK3beta bind to each other only in the presence of tau, suggesting that tau connects Cdk5 and GSK3beta. Our results suggest that in the brain, tau, Cdk5, and GSK3beta are components of an approximately 450 kDa complex. Within the complex, Cdk5 phosphorylates tau at S(235) and primes it for phosphorylation of T(231) by GSK3beta. Similarly, Cdk5 by phosphorylating tau at S(404) primes tau for a sequential phosphorylation of S(400) and S(396) by GSK3beta.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| 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 | 0.001 | 0.000 |
| Research integrity | 0.001 | 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 it