Mechanism of activation of an ancestral TEC kinase by PIP <sub>3</sub>
Bibliographic record
Abstract
Abstract The TEC kinases are a family of five paralogous mammalian genes that play crucial roles in cell growth, proliferation and differentiation, particularly in immune cells. The recruitment and activation of the TEC kinases depend on the generation of the lipid second messenger, PIP 3 , in the plasma membrane. However, the mechanisms by which PIP 3 activates the TEC kinases are not well understood. We have elucidated the autoinhibited conformation of an ancestral TEC kinase from the choanoflagellate Monosiga brevicollis. We demonstrate that PIP 3 relieves autoinhibition of MbTEC by displacing its PH domain from an evolutionarily conserved inhibitory interaction with its kinase domain. We also show that a conserved polyproline motif within MbTEC promotes its activation in a kinase-intrinsic mechanism. Finally, we show that the PH domain is sufficient to restore autoinhibition in a constitutively active mutant of MbTEC. Our findings reveal that PIP 3 is necessary and sufficient for both MbTEC activation and inactivation. Significance Statement The Tec family of protein kinases plays an essential role in cell signaling, particularly in the proliferation and differentiation of immune cells. Consequently, their dysregulation is causative of inherited immunodeficiency, while the Tec kinases are also therapeutic targets in the control of hematological malignancies. We have elucidated a conserved mechanism by which the Tec kinases are activated by the lipid second messenger PIP 3 . PIP 3 is necessary and sufficient for Tec activation, while its turnover is sufficient for Tec inactivation. Our work identifies PIP3 as the ultimate gatekeeper of Tec activity in cells, with implications for the rationalization and treatment of human disease.
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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 | 0.000 | 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 | 0.001 | 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 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".