When the Tail Wags the Dog: Phosphodiesterase 4D7 Regulation of a cAMP‐signalosome Located at the Rear of Migrating Smooth Muscle Cells Regulates Localized RhoA/ROCK Signaling and Tail Retraction During Migration
Bibliographic record
Abstract
Inhibiting the maladaptive migration of human arterial smooth muscle cells (HASMCs) in injured blood vessels may help reduce the development of intimal lesions in vascular diseases, including atherosclerosis or restenosis. Agents that act to increase intracellular levels of cyclic adenosine monophosphate (cAMP) impact numerous individual events involved in coordinating HASMC migration. Signaling via cAMP is ubiquitous and dynamic, and requires control through signaling termination mechanisms. cAMP Phosphodiesterase (PDE) enzymes catalyze the hydrolysis of cAMP and are critical in the control of cAMP signaling, most specifically when they regulate cAMP levels within numerous discrete subcellular domains. Through spatial restriction, these enzymes are thought to allow cAMP‐elevating agents to selectively regulate numerous distinct responses. The PDE4D gene family plays a dominant role in cAMP hydrolysis in HASMCs. Considerable interest exists in the idea that the unique N‐terminal domains of the numerous distinct PDE4D isoform variants promotes their spatial restriction in cells, and that this is coordinated through selective interactions of these PDE4Ds with other proteins. This study examined the targeting of individual PDE4D isoforms in HASMCs through the overexpression of GFP constructs containing the unique N‐terminal domains of the PDE4D isoforms (NT‐PDE4D/GFP) known to be expressed endogenously in these cells (PDE4D8, 9, 5, 7). Although transient over‐expression of NT/PDE4D8‐GFP, NT/PDE4D9‐GFP or NT/PDE4D5‐GFP did not significantly impact HASMC morphology or migration character or speed, over‐expression of NT/PDE4D7‐GFP was observed to alter HASMC morphology of migrating HASMCs as well as their migratory velocity. By combining these observations with the effects of selective siRNA‐mediated knockdown of PDE4D7, we established that PDE4D7 is involved in controlling rear retraction in migrating HASMCs. We show that altering PDE4D7 targeting and expression in these cells affects rear retraction largely through its ability to impact RhoA‐ROCK signaling. We also report that PDE4D7 interacts with AKAP5, PKA and EPAC1 in migrating and immotile HASMCs. Our results suggest a functional role for localized PDE4D7 activity in regulating cAMP‐mediated rear retraction in migrating HASMCs, and identify PDE4D7 as a potential therapeutic target in controlling HASMC migration. Support or Funding Information Canadian Institutes of Health Sciences
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".