The role of Cbl-mediated ubiquitination in the regulation of the Met receptor tyrosine kinase /
Bibliographic record
Abstract
The Met receptor tyrosine kinase (RTK) and its ligand, the hepatocyte growth factor/scatter factor (HGF/SF), which regulate epithelial cell remodelling, dispersal and invasion, are deregulated in many human cancers. In the last twenty years, mechanisms of RTK activation and signalling have been studied extensively. In contrast, very little is known about the mechanisms of down-regulation of RTKs. At the time I began my thesis work, the family of Cbl ubiquitin-protein ligases emerged as negative regulators for RTKs. In this thesis, I demonstrate that c-Cbl is an important negative regulator of the Met receptor. Upon HGF stimulation, c-Cbl promotes ubiquitination of the Met RTK. This requires the association of the c-Cbl tyrosine kinase binding (TKB) domain with a DpYR binding motif, including Y1003, present in the juxtamembrane of the Met receptor. A Met Y1003F receptor, which lacks the c-Cbl TKB binding site, is not ubiquitinated, transforms fibroblast and epithelial cells in vitro and is tumorigenic in vivo. I demonstrate that ubiquitination of the Met receptor is not required for its internalization from the plasma membrane, but is essential for its lysosomal degradation. In the presence of HGF, the Met Y1003F receptor is poorly degraded and remains phosphorylated, leading to sustained activation of the Ras-MAPK pathway. Moreover, fusion of a ubiquitin moiety to the carboxy-terminus of Met Y1003F is sufficient to decrease Met receptor stability, prevent sustained MEK1/2 activation and reduce cell transformation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".