The C-Terminal Kinase Domain–Binding and Suppression Motif Prevents Constitutive Activation of FGFR2
Bibliographic record
Abstract
Genetic alterations in receptor tyrosine kinase genes can generate potent oncogenic drivers. Truncation of the FGFR2 gene by its last exon 18 (E18) is caused by structural alterations, such as focal amplifications and gene fusions/rearrangements, as well as by mutations. All the E18-truncating FGFR2 variants (FGFR2ΔE18) act as strong driver alterations in cancer, and they commonly encode a receptor lacking the carboxy (C) terminal tail. In this study, we analyzed a compendium of Fgfr2-E18 variants to uncover the mechanism by which loss of the C-tail renders FGFR2 oncogenic. Although permutation of previously annotated C-terminal FGFR motifs did not recapitulate the tumorigenicity of FGFR2ΔE18, the functional annotation efforts led to the discovery of a C-terminal phenylalanine-serine motif that mediates binding of the C-tail to the kinase domain and thereby suppresses FGFR2 kinase activity. The permutation of this kinase domain-binding and suppression motif in conjunction with other FGFR2-regulatory C-terminal sites fully phenocopied the oncogenic competence of FGFR2ΔE18. Together, these findings delineate how the C-terminal tail prevents FGFR2 from aberrant oncogenic activation. SIGNIFICANCE: A C-terminal phenylalanine-serine motif suppresses FGFR2 kinase activity by mediating binding of the C-terminal tail to the kinase domain, explaining how C-terminal truncation activates FGFR2 to promote tumorigenesis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".