TGFβ (transforming growth factor β) receptor type III directs clathrin-mediated endocytosis of TGFβ receptor types I and II
Bibliographic record
Abstract
The TGFbeta (transforming growth factor beta) pathway is an essential cell signalling pathway that is implicated in both normal developmental processes, such as organogenesis, and pathological disorders, such as cancer and fibrosis. There are three prototypical TbetaRs (TGFbeta receptors): TbetaRI (TbetaR type I), TGbetaRII (TbetaR type II) and TGFbetaRIII (TbetaR type III, also known as betaglycan). Whereas the role of TbetaRII and TbetaRI in TGFbeta signal propagation has been established, the contribution of TbetaRIII to TGFbeta signalling is less well understood. At the cell surface, TbetaRI and TbetaRII receptors can be internalized by clathrin-mediated endocytosis and clathrin-independent membrane-raft-dependent endocytosis. Interestingly, the endocytic route of the receptors plays a direct role in TGFbeta-dependent Smad signal transduction; receptors endocytosed via clathrin-mediated endocytosis activate Smad signalling, whereas receptors endocytosed via membrane rafts are targeted for degradation. The objective of the present study was to evaluate the contribution of TbetaRIII to TbetaRII and TbetaRI membrane partitioning, receptor half-life and signalling. Using sucrose-density ultracentrifugation to isolate membrane-raft fractions, we show that TbetaRIII recruits both TbetaRII and TbetaRI to non-raft membrane fractions. Immunofluorescence microscopy analysis demonstrated that overexpression of TbetaRIII affects intracellular trafficking of TbetaRII by recruiting TbetaRII to EEA1 (early endosome antigen 1)- and Rab5-positive early endosomes. Using 125I-labelled TGFbeta1 to follow cell-surface receptor degradation we show that overexpression of TbetaRIII also extends the receptor half-life of the TbetaRII-TbetaRI complex. Interestingly, we also show, using a luciferase reporter assay, that TbetaRIII increases basal TGFbeta signalling. As numerous pathologies show aberrant activation of TGFbeta signalling, the present study illustrates that TbetaRIII may represent a novel therapeutic target.
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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 | 0.000 | 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 | 0.001 |
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".