Identification and characterization of the signaling mechanisms downstream of Dok-R that mediate cell migration and actin reorganization
Bibliographic record
Abstract
Dok-R was also shown to bind c-Abl in a processive manner that required binding of the c-Abl SH3 and SH2 domains. The binding of c-Abl and Dok-R resulted in increasing c-Abl kinase activity, tyrosine phosphorylation of Dok-R and an increase in c-Abl-mediated membrane protrusions. Together, these results demonstrate a physiological role for Dok-R in modulating cytoskeletal dynamics through complex formation with Nck and Pak and with c-Abl. Angiogenesis requires endothelial cells to undergo several cellular processes such as proliferation, migration and differentiation. Angiopoietin-1 is a growth factor that binds the Tek/Tie-2 receptor tyrosine kinase resulting in Tek autophosphorylation. Various signaling proteins can bind Tek in a phosphotyrosine-dependent manner and activate initiate downstream signaling pathways such as the phosphatidylinositol 3 (PI3)-kinase pathway. Dok-R was originally identified as a Tek-binding partner and can bind in a phosphotyrosine-dependent manner to RasGAP and Nck. The aim of this thesis was to determine the physiological function of Dok-R and to identify the molecular mechanisms that mediate its responses. Since Dok-R was first identified as a Tek-binding protein, angiopoietin-1-dependent cell-based bioassays were developed in order to elucidate the physiological function of Dok-R. Angiopoietin-1 could promote tubule formation, cell migration and survival of endothelial cells with the latter two processes being mediated through the PI3-kinase pathway. These results demonstrate that angiopoietin-1 can mediate multiple endothelial cell processes and may serve as a cell-based system to elucidate the physiological role of Dok-R. Since Dok-R was shown to associate with RasGAP and Nck, two proteins implicated in cell migration, it was hypothesized that Dok-R may also serve a similar role. By using various tyrosine point mutants of Dok-R that abolished binding to either Nck or RasGAP, it was found that angiopoietin-1-mediated migration was enhanced upon overexpression of wildtype Dok-R which required binding to Nck, but not RasGAP. Angiopoietin-1 could activate the serine/threonine kinase Pak, which binds constitutively with Nck, to form a ternary complex resulting in Pak activation and motility. These results demonstrate a role for Dok-R in cell migration through Nck and Pak.
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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) | 0.001 | 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".