Pituitary Tumor-Derived Fibroblast Growth Factor Receptor 4 Isoform Disrupts Neural Cell-Adhesion Molecule/N-Cadherin Signaling to Diminish Cell Adhesiveness: A Mechanism Underlying Pituitary Neoplasia
Bibliographic record
Abstract
We previously identified pituitary tumor-derived fibroblast growth factor receptor 4 (ptd-FGFR4), an alternatively transcribed N-terminally truncated cytoplasmic receptor isoform. Unlike wild-type FGFR4, ptd-FGFR4 facilitates cell transformation and results in pituitary tumor formation in transgenic mice. To investigate differences in the tumorigenic properties of FGFR4 and ptd-FGFR4, we examined their abilities to modulate cell adhesiveness. Introduction of ptd-FGFR4 into GH4 pituitary cells or NIH 3T3 fibroblasts resulted in significant reduction in cell adhesion to a collagen IV matrix compared with FGFR4- or empty vector-transfected cells. This adhesive difference was evident in the absence or presence of FGF stimulation. Furthermore, treatment with beta1-integrin neutralizing antibody markedly reduced adhesiveness in FGFR4-transfected cells but had little effect on the depressed adhesiveness of ptd-FGFR4-transfected cells. Unlike wild-type FGFR4, ptd-FGFR4 does not associate with neural cell-adhesion molecule (NCAM). Cells expressing FGFR4 demonstrate membranous N-cadherin with a noninvasive growth pattern identical to control GH4 cells when injected into immunodeficient mice. In contrast, ptd-FGFR4-expressing cells develop invasive tumors in vivo with marked loss of N-cadherin that localizes to the cytoplasm. Consistent with these changes, beta-catenin expression was diminished and its interaction with N-cadherin was disrupted in the presence of ptd-FGFR4, but both were intact in the presence of wild-type FGFR4. These data highlight the importance of membrane-anchored FGFR4 in assembling a multiprotein FGFR4 complex with NCAM and N-cadherin playing pivotal functions in maintaining normal cell adhesion. Disruption of distinct NCAM/N-cadherin proadhesive complexes by a tumor-derived FGFR4 isoform provides a novel mechanism beyond ligand independence that explains the pathobiology of proliferative and infiltrative but nonmetastatic neoplasms.
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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 | 0.000 |
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".