Clathrin and TOM1L1 regulate epidermal growth factor receptor signaling at the plasma membrane
Bibliographic record
Abstract
Epidermal growth factor (EGF) receptor (EGFR) controls many aspects of cell physiology via the activation of intracellular signaling pathways. Aberrant EGFR signaling and overexpression of EGFR is a characteristic of various cancer types. Ligandbound EGFR elicits phosphorylation of Gab1, which activates phosphatidylinositol-3-kinase (PI3K), which in turn leads to Akt phosphorylation and activation. Akt is a central regulator of cell survival and metabolism. Rapidly upon binding EGF, the receptor is recruited to clathrin-coated pits (CCPs), eventually leading to EGFR endocytosis. As such, receptor-proximal EGFR signaling occurs while the receptor is enriched with CCPs at the plasma membrane. We have recently found that clathrin, but not receptor endocytosis, is required for EGF-stimulated phosphorylation of Akt, yet how clathrin controls EGFR signaling at the plasma membrane remains poorly understood. Clathrin interacts with and recruits numerous proteins to the plasma membrane. To examine how specific clathrin-interacting proteins may underlie the requirement for clathrin in EGFR signaling, I have examined the role of TOM1L1, which interacts with clathrin, EGFR and Src-family kinases (SFKs) through distinct domains. SiRNA gene silencing of TOM1L1 impairs EGF-stimulated Akt phosphorylation, as did expression of a dominant-interfering mutant of TOM1L1 deficient in clathrin binding. Using fluorescent labeling of clathrin, TOM1L1 and other signaling intermediates coupled to total internal reflection fluorescence microscopy; I found that CCPs are enriched in TOM1L1 and phosphorylated Gab1 upon EGF stimulation. These findings indicate that the clathrin-binding adaptor TOM1L1 regulates EGF-stimulated Akt phosphorylation, thus revealing a novel molecular mechanism of regulation of EGFR signaling at the plasma membrane.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".