Macrophage-Stimulating Protein Stimulates Erythropoietin Receptor Phosphorylation To Promote Enhanced Erk1/2 and Akt Activation in a Gab2-Dependent Pathway.
Bibliographic record
Abstract
Abstract Friend-virus mediated erythroleukemia is a well-established model of murine oncogenesis. Several host factors have been shown to be necessary for Friend-mediated infection including a productive interaction between the Erythropoietin Receptor (EPO-R) and the 55 kDa glycoprotein product of the retroviral envelope gene (gp55). The Fv2 locus has been mapped and shown to be a truncated form of the STK tyrosine kinase (Sf-STK). Sf-STK expression and kinase activity is required for Friend virus infection of sensitive mouse strains. While the EPO-R and Sf-STK are required for Friend disease progression, it is unknown whether Sf-STK modulates EPO-R mediated signaling. EPO-R co-immunoprecipitated Sf-STK and STK specifically in COS-7 and Ba/F3 cells expressing both receptors. While the association between EPO-R and STK was shown to be constitutive, intriguingly, we discovered that co-stimulation with the STK ligand, Macrophage-Stimulating Protein (MSP) and EPO resulted in enhanced tyrosine phosphorylation of the EPO-R, compared to stimulation with EPO alone. Interestingly, STK kinase activity was required for EPO-dependent STK tyrosine phosphorylation, but was not required for MSP dependent EPO-R phosphorylation. Analysis of downstream signaling revealed STK and EPO-R co-operated in ligand induced dose-dependent phosphorylation of Erk1/2 and Akt. Interestingly, MSP and EPO also co-operated to stimulate tyrosine phosphorylation of the adaptor protein Gab2, leading to the recruitment of Shp2 and the p85 subunit of Phosphatidylinositol 3 kinase. These data suggest that Gab2 can couple to enhanced phosphorylation of Erk1/2 and Akt. However, no synergy was observed in MSP co-stimulation of JAK2, STAT1, STAT5, Jnk or p38 phosphorylation, demonstrating that STK activates specific EPO-dependent signaling pathways. EPO-dependent regulation of Socs family members was examined in Ba/F3-EPO-R cell lines expressing various STK constructs. The presence of STK induced Cis and Socs3, but not Socs1, transcript levels by 2.0-fold upon EPO stimulation. STK multi-functional docking sites (Y1330/Y1337) were required to observe optimal induction of Socs3. In contrast, Cis induction required STK tyrosine kinase activity. Our data demonstrate that EPO-R and STK interact at a biochemical level leading to augmentation of downstream signaling. These data suggest that Sf-STK contributes to Friend disease through delivery of mitogenic and/or survival signals to target erythroblast progenitor cells.
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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".