Epidermal growth factor-induced DNA synthesis : key roles for phosphatidylinositol 3-kinase and the adaptor protein Gab2
Bibliographic record
Abstract
In primary rat hepatocytes, we found that activation of the Pl3-kinase pathway is both necessary and sufficient to account for EGF-induced DNA synthesis. To identify the mechanism of EGF-induced Pl3-kinase activation, we demonstrated that three distinct p85-associated complexes were formed following EGF: ErbB3-p85, Shc-p85 and a large complex Gab2-Grb2-SHP2-p85. The latter accounted for >80% of total Pl3-kinase activity. Further experiments showed that these complexes are differentially localized in rat liver following EGF treatment. ErbB3-p85 and Shc-p85 complexes were localized to PM and Endosomes; whereas the multimeric Gab2-Grb2-SHP2-p85 complex was formed rapidly and exclusively in cytosol. A central role for Gab2 in EGF-induced Pl3-kinase activation and DNA synthesis was established when we observed that over-expression of wild-type Gab2 augmented these EGF actions, whereas a Gab2 mutant lacking p85 binding sites did not effect such augmentation. Over-expression of the PH-domain of Gab2 did not affect EGF-induced Gab2 phosphorylation, Pl3-kinase activation and DNA synthesis, whereas over-expressed Gab2 lacking the PH-domain was comparable to wild-type Gab2 in respect to these EGF-induced signals. These data demonstrated that Gab2 is phosphorylated and mediates EGF signaling in a PH-domain independent manner. We then explored the mechanism of Gab2 phosphorylation by EGF; our results demonstrated that PP1, a selective inhibitor of Src family kinases, blocked EGF-induced Gab2 tyrosine phosphorylation and downstream events. Moreover, Gab2 phosphorylation was increased in Csk knock-out cells in which Src family kinases are constitutively activated. A constitutive association between Gab2 and Src via proline rich sequences on Gab2 was demonstrated since deletion of proline rich sequences in Gab2 prevented EGF-induced association of Src with Gab2, Gab2 phosphorylation, Pl3-kinase/Akt activation, and DNA synthesis. The role of SHP2 was defin
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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) | 0.010 | 0.003 |
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".