TGF-β induced activation of ERK regulates Smad degradation
Bibliographic record
Abstract
2697 The Transforming Growth Factor-Beta (TGF-β) family is a collection of structurally related peptides that include Activins, Bone Morphogenic Proteins (BMP), as well as the TGF-β’s. These growth factors are involved in a variety of cellular processes such as apoptosis, differentiation, and proliferation. TGF-β binding to its Serine/Threonine kinase receptor causes the recruitment and subsequent activation of transcription factors known as Smad2 and Smad3. These normally cytoplasmic proteins translocate into the nucleus and either negatively or positively regulate gene expression. TGF-β effects on proliferation depend on the cell type involved, as growth is stimulated in mesenchymal cells but inhibited in epithelial cells. Here we report that in addition to activating the Smad signaling pathway, TGF-β directly induces the phosphorylation of Extracellular Signal Regulated Kinase (Erk) in fibroblasts, but not in epithelial cells. The activation occurs through phosphotidylinositol 3-Kinase (PI3-K). TGF-β triggered Erk activation is dependant on Mek1/2 activity, as Mek inhibition abolishes Erk phosphorylation. However, TGF-β stimulated Erk activation appears to differ from the classical Ras/Raf/Mek/MAPK (mitogen activated protein kinase) signaling pathway in that the inhibition of Ras farnesylation does not inhibit Erk phosphorylation. Furthermore, TGF-β stimulation results in Raf-1 phosphorylation at S338, a site associated with Raf-1 activation. It has been shown that Smad2 and Smad3 contain MAPK/CDK phosphorylation sites. Phosphorylation of these sites is thought to regulate Smad nuclear translocation and/or transcriptional activity. TGF-β stimulated phosphorylation of the MAPK sites within the Smad2 linker region appears to be Erk dependant and occurs predominantly in the nucleus. This phosphorylation event is necessary for nuclear Smad proteasomal degradation as treatment with the proteasome inhibitor MG132 results in elevated phosphorylated Smad protein levels. Together, this data shows a new TGF-β dependant pathway leading to the activation of Erk which interacts with and regulates the classical Smad signaling pathway.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.003 |
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".