Regulation of Epidermal Growth Factor Receptor by Clathrin‐Associated Kinases
Bibliographic record
Abstract
The Epidermal Growth Factor (EGF) Receptor (EGFR) is a receptor tyrosine kinase (RTK) that controls many key components of cell physiology, including proliferation, survival, and metabolism. When upregulated, EGFR drives tumor growth and progression in several types of cancer. EGF stimulation elicits EGFR phosphorylation and activation of phosphatidylinositol‐3‐kinase (PI3K), leading to Akt activation by its phosphorylation on T308 and S473. EGF‐stimulated Akt phosphorylation is dependent on clathrin coated pits (CCPs) at the plasma membrane, but not receptor endocytosis 1 . CCPs are 50‐100 nm protein assemblies that are well‐known endocytic portals and lead to eventual receptor downregulation. Importantly, we previously uncovered that CCPs are also required for Akt activation, likely by acting as protein and lipid scaffolds to coordinate signaling intermediates. One of the many proteins that are known to bind to clathrin directly is Activated Cdc42 Kinase 1 (Ack1), a non‐receptor tyrosine kinase implicated in oncogenic RTK signaling and tumor cell survival. Ack1 also interacts with EGFR and directly phosphorylates Akt at Y176, a regulatory site distinct from those required for canonical Akt activation. In addition to clathrin, Ack1 also interacts with a multitude of other proteins. How Ack1 regulates the PI3K/Akt signaling pathway, and how binding of Ack1 to clathrin controls this phenomenon, remains poorly defined. Here, we examine how Ack1 contributes to EGFR signaling. Using siRNA silencing of Ack1 and/or the related isoform Ack2, alone or in combination with inducible expression of fluorescent or mutant Ack constructs, we examined the role of Ack1 in EGFR signaling. Moreover, using various microscopy and image analysis techniques, we examined the mechanism of recruitment of Ack1 to CCPs. Our results indicate a critical role for Ack1 in EGFR signaling, in particular for the activation of PI3K‐Akt signaling. The improved understanding of the regulation and outcome of EGFR signals by proteins such as Ack1 and scaffolds such as clathrin‐coated pits, can lead to the development of novel cancer treatments.
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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 | 0.001 |
| 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".