Bibliographic record
Abstract
Endocytic trafficking is an important regulator of signalling down stream of multiple cell surface receptors. Receptors are internalized from the plasma membrane on endocytic vesicles and shuttled to multiple cellular locations through distinct endocytic compartments. These sorting events are regulated by multiple endocytic adaptor proteins that recognize and bind distinct signals within the intracellular domains of membrane receptors and promote the assembly of machinery necessary for endocytosis. Numb is an endocytic adaptor protein that was identified in Drosophila as a regulator of cell fate decisions. Vertebrate homologues of Drosophila Numb have been identified and suggest an evolutionarily conserved role for the Numb protein. Numb is thought to influence cell fate selection by antagonizing Notch receptor signalling; however no mechanism of inhibition has been reported. Notch is a cell surface receptor that controls cell fate specification and developmental processes in many different contexts throughout development and adulthood. Deregulation of Notch signalling disrupts embryonic development and is implicated in neurogenerative disorders and cancers. The work herein examines the biochemical mechanism of Numb function in the down regulation of Notch signalling. Identification and observed function of Numb binding partners suggests that Numb may play a role within both the endocytic and ubiquitination pathways. We show that Numb associates with the E3 ubiquitin ligase Itch to cooperatively promote ubiquitination of the membrane-bound Notch receptor; however does not target Notch for proteasomal degradation. Further work demonstrates that overexpression of Numb also results in accumulation of Notch within enlarged cytoplasmic vesicles associated with ARF6 and Rab7. Changes in the levels of Numb protein disrupts the dynamics of Notch trafficking, and this trafficking requires the interaction of Numb with Itch. Furthermore disruption of Numb function in mice results in skin abnormalities that are not the sole consequence of deregulated Notch signalling but reveal a role for Numb in cell adhesion. Together these studies into Numb function suggest Numb regulates the activities of cell surface receptors such as Notch by directing intracellular trafficking events and highlights the role of endocytic adaptors, in general, in regulating developmental signalling pathways.
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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) | 0.002 | 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".