Regulation of T cell activation by thousand-and-one amino acid kinase 3
Bibliographic record
Abstract
Canonical signaling from the T cell receptor triggers the physiological response of a T cell.The canonical TCR signaling pathway relies on activation of the Src kinase LCK, which is negatively regulated by the inhibitory phosphatase SHP-1 in a mechanism that turns off TCR signaling.Here we demonstrate that TAOK3, a serine/threonine kinase expressed in many different cell types including T cells, acts as an important regulator of the SHP-1/LCK crosstalk.TAOK3-deficient human T cells demonstrated impaired LCK-dependent signal transduction in response to canonical TCR signaling, resulting in a defect in IL-2 response.This impairment was a result of enhanced interaction of LCK with SHP-1 after TCR engagement, which led to rapid termination of TCR signals.This evidence demonstrates that TAOK3 is a positive regulator of TCR signaling by preventing premature SHP-1-mediated inactivation of LCK.Signal transduction downstream of the TCR requires a tightly regulated balance between the activity of LCK and SHP-1.Here, we show that TAOK3 directly binds and regulates SHP-1 function in vitro by phosphorylating the inhibitory C-terminal serine residue S591 in SHP-1.Mutagenesis analysis exemplified that specific sites on the TAOK3 molecule are important for its functional effects in cell proliferation and IL-2 production in response to canonical TCR signaling, as observed by effects of enhanced rate of cell growth and increased IL-2 response of T cell lines.Moreover, these effects were correlated with independent point mutations, demonstrating that two of the most prominent functional T cell activation readouts can be uncoupled by differential TAOK3 mutagenesis.To investigate the functional effect of TAOK3 deficiency in primary mouse T cells, we developed a novel CRISPR/Cas9-mediated gene editing model in which Taok3 targeting was induced in a tissue-specific manner.Knockdown of TAOK3 impaired the response to canonical TCR signaling as observed by diminished phosphorylation of ERK1/2 and defective IL-2 response.However, TAOK3-deficient mouse T cells displayed enhanced cell proliferation in response to TCR signaling, suggesting an increased consumption of IL-2.This was further demonstrated by downregulation of IL-2 receptor chains, which are known to internalize in response to ligand binding.This effect highlights the existence of compensatory mechanisms operating in response to TAOK3 deficiency in primary mouse T cells.In summary, the work presented here demonstrates that TAOK3 is a critical novel modulator of T cell activation, acting as a positive regulator of canonical TCR signaling by preventing early SHP-1-mediated inactivation of LCK.Our findings highlight TAOK3 as a relevant novel target for therapies aimed at T cell-dependent autoimmunity, immunity to infectious diseases, graft rejection and immunity to cancer.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".