Protein Phosphatase1 gamma (PP1cγ) Is Required for Thrombin-Induced Integrin αIIbβ3 Activation.
Bibliographic record
Abstract
Abstract Integrin αIIbβ3 activation is critical for platelet physiology and is controlled by agonists- induced signal transduction through kinases and phosphatases. Compared to kinases, a role of phosphatases in platelet integrin αIIbβ3 signaling and activation is less understood. We have previously demonstrated that the catalytic subunit of protein phosphatase 1 (PP1c) associates constitutively with the integrin αIIbβ3 and regulates myosin light chain phosphorylation. Platelets express three isoforms of PP1c namely PP1cα, PP1cβ/δ and PP1cγ1, however their role in platelet physiology is unclear. In this study, we explored a role for the PP1cγ in integrin αIIbβ3 activation using the PP1cγ null mice that lacks both PP1cγ1 and PP1cγ2 splice variants. Deletion of PP1cγ did not alter the expression of PP1cα and PP1cβ/δ in platelets. Compared to the wild type mice, PP1cγ null mice had significantly (P=0.03) more platelets but not other blood cells and increased megakaryocytes in an in vitro bone marrow culture system, suggesting that PP1cγ may regulate platelet production. Compared to the wild type platelets, PP1cγ null platelets exhibited a ∼50% decreased activation (P=0.007) of integrin αIIbβ3 in response to low doses of thrombin as measured by the binding of soluble Alexa-flour 488-conjugated fibrinogen or Jon/A, an antibody to high affinity integrin αIIbβ3. Consistent with this observation, PP1cγ null platelets showed decreased aggregation in response to thrombin or protease activated receptor activating peptide. Soluble fibrinogen binding and aggregation to ADP, collagen and cross linked collagen -related peptide was not different between the PP1cγ null and wild type platelets. Surface expression of integrin αIIbβ3 was comparable in the PP1cγ null platelets indicating that the decreased activation of αIIbβ3 in PP1cγ platelets was not due to decreased integrin expression. These studies suggest that PP1cγ is required for thrombin-induced αIIbβ3 inside-out signaling process. In contrast, αIIbβ3 outside-in signaling process was not altered in PP1cγ null mice as revealed by normal adhesion to immobilized fibrinogen. Intravital microscopy revealed that the thrombus formation induced by a light/dye injury in the cremaster muscle venules was significantly (P=0.03) delayed in PP1cγ null mice compared to wild type mice. These studies illustrates that PP1cγ is an essential component of thrombin signaling that is downstream of protease activated receptors and promotes thrombus formation in part by supporting soluble fibrinogen binding and platelet aggregation.
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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) | 0.001 | 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) | 0.002 | 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".