The role of LC3C and autophagy in degradation of the Met receptor tyrosine kinase and transferrin receptor
Bibliographic record
Abstract
Autophagy is a cellular degradation pathway inducible by different stressors, crucial to regulating homeostasis and cell invasion.In cancer, autophagy can promote tumour progression or suppress it, depending on the tumour grade.In selective autophagy, specific cargo are targeted for degradation using autophagy-related genes (ATGs), such as ATG8 proteins that engage with proteins to be degraded, often with cargo receptor proteins.Our lab previously established that an understudied ATG8 ortholog, LC3C, selectively targets the Met receptor tyrosine kinase for autophagic degradation.When activated by its ligand, hepatocyte growth factor (HGF), Met triggers cell migration and invasion and is associated with poor prognoses in various cancers.Studies also show LC3C expression is decreased in several cancers, including breast cancer.Together, this suggests an anti-tumorigenic role for LC3C, but how this role is mediated and how it targets Met for degradation are unknown.We used Bio-ID to identify LC3C-specific interactors mediating selective Met and transferrin receptor (TfR) targeting.Through immunofluorescence and co-immunoprecipitation experiments, we determined LC3C selectively targets Met and TfR for autophagic degradation from endosomes to the forming autophagosome.We confirmed LC3C can engage with plasma membrane cargo independently of mature autophagosome formation and conjugation machinery.We found LC3C selectively engages with cargo differently from the well-studied ATG8 ortholog LC3B, which is at least partially due to the extended C-terminal tail of LC3C and more peripheral localization.We established that LC3C engages with cargo receptors such as OPTN, which was identified as an interaction candidate in the Bio-ID screen.Using knockdown cell lines lacking cargo receptors, we found that LC3C engagement with TfR is decreased without the presence of cargo receptors, but this mechanism may not be limited to one cargo receptor.From a second BioID screen that studied LC3C under HGF stimulation, we established LC3C has a specific interactome under conditions of migration and may exert a role in cell migration in cancer cells.This work defined a new role for LC3C in targeting signaling proteins for degradation.These results are significant as LC3C expression is decreased in some cancers, which could contribute to higher Met activity and invasiveness.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 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".