GTPase-Dependent Mechanointegration of Shear-Mediated Cell Contractility Through Dynamic Binding of FLNa and FilGAP
Bibliographic record
Abstract
Cellular mechanotransduction is a common mechanism by which cells convert mechanical cues (or stimuli) from their environment into biochemical and cellular responses. In the case of shearing forces, such as when individual cells encounter interstitial shear stress and blood shear stress, mechanotransduction involves mechanical stretching and spatial reconfiguration of Filamin A (FLNa) binding sites and subsequent release of FilGAP molecules normally bound to FLNa. However, the connection and importance of downstream molecular effectors and cellular metrics involved in response to shear stress are not understood. Here we reveal mechano-sensitive GTPase-mediated changes in cell contractility. By varying expression of FilGAP, and expression of FLNa, we show that microfluidic shear stress results in cell contractile changes only when FilGAP and FLNa dynamically bind and dissociate. By using FRET sensors that quantify the Rho or Rac charge state, we demonstrate that only cells with dynamic FLNa and FilGAP convert shear stress into GTPase activity, and the resulting downstream contractile changes. Finally, we show that manipulation of Rho and Rac through pharmacological means rescues the contractile activity, in the absence of intact FLNa-FilGAP mechanosensing. This research clarifies a precise mechanomolecular pathway used for cellular force sensing and may play critical roles in human health challenges from cancer metastasis to cardiovascular 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 | 0.000 | 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".