Phosphoinositide 3‐kinase (PI3K) activation and actin dynamics within force sensing anchors are required to stabilize VLA‐4 integrin‐mediated leukocyte adhesion
Bibliographic record
Abstract
During inflammation, leukocytes modulate α4β1 (VLA‐4) integrin avidity in order to rapidly form stable nascent adhesive contacts to VCAM‐1‐expressing endothelial cells and resist detachment forces imparted by the flowing blood. Linkage to the actin cytoskeleton is critical for integrin function, yet the exact role of the actin cytoskeleton in leukocyte adhesion stabilization under conditions of fluid forces remains poorly understood. We report that mechanical forces imparted by flow induce formation of upstream tension‐bearing anchors attached to the VCAM‐1‐coated surface and Rac, but not Cdc42, small GTPase‐dependent polymerization of F‐actin within these structures. These structures are critical for adhesion stabilization, since disruption of actin polymerization dramatically inhibits VLA‐4‐dependent resistance to detachment, but does not affect VLA‐4 expression, affinity modulation, clustering or constitutive linkage to F‐actin. A key mediator of force‐induced Rac activation and actin polymerization is PI3K. Live cell imaging revealed accumulation of PIP3 within tension‐bearing anchors and blockade of PI3K or deficiency of PI3Kgamma isoform reproduced the adhesion defect produced by inhibition of actin polymerization. Our results implicate a novel mechanism in the leukocyte adhesion cascade necessary for stabilization of nascent adhesive contacts. Research supported by a CGS CIHR Doctoral Award.
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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 | 0.000 |
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 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".