Transglutaminase 2 Binds to the CD44v6 Cytoplasmic Domain to Stimulate CD44v6/ERK1/2 Signaling and Maintain an Aggressive Cancer Phenotype
Bibliographic record
Abstract
Transglutaminase 2 (TG2) is a key cancer cell survival protein in many cancer types. As such, efforts are underway to characterize the mechanism of TG2 action. In this study, we report that TG2 stimulates CD44v6 activity to enhance cancer cell survival via a mechanism that involves formation of a TG2/CD44v6/ERK1/2 complex that activates ERK1/2 signaling to drive an aggressive cancer phenotype. TG2 and ERK1/2 bind to the CD44v6 C-terminal intracellular cytoplasmic domain to activate ERK1/2 and stimulate cell proliferation and invasion. This is the same region that binds to ERM proteins and ankyrin to activate CD44v6-dependent cell proliferation, invasion, and migration. We further show that treatment with hyaluronan (HA), the physiologic CD44v6 ligand, stimulates CD44v6 activity, as measured by ERK1/2 activation, but that this response is severely attenuated in TG2 or CD44v6 knockdown or knockout cells. Moreover, treatment with TG2 inhibitor reduces tumor growth and that is associated with reduced CD44v6 level and ERK1/2 activity, and reduced stemness and epithelial-mesenchymal transition (EMT). These changes are replicated in CD44v6 knockout cells. These findings suggest that a unique TG2/CD44v6/ERK1/2 complex leads to increased ERK1/2 activity to stimulate an aggressive cancer phenotype and stimulate tumor growth. These findings have important implications for cancer stem cell maintenance and suggest that cotargeting of TG2 and CD44v6 with specific inhibitors may be an effective anticancer treatment strategy. IMPLICATIONS: TG2 and CD44v6 are important procancer proteins. TG2 and ERK1/2 bind to the CD44v6 C-terminal domain to form a TG2/CD44v6/ERK1/2 complex that activates ERK1/2 to stimulate the cancer phenotype.
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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 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".