Processing by Convertases Is Required for Glypican-3-induced Inhibition of Hedgehog Signaling
Bibliographic record
Abstract
Glypican-3 (GPC3) is one of the six members of the mammalian glypican family. We have previously reported that GPC3 inhibits Hedgehog (Hh) signaling by competing with Patched (Ptc) for Hh binding. We also showed that GPC3 binds with high affinity to Hh through its core protein, but that it does not interact with Ptc. Several members of the glypican family, including GPC3, are subjected to an endoproteolytic cleavage by the furin-like convertase family of endoproteases. Surprisingly, however, we have found that a mutant GPC3 that cannot be processed by convertases is as potent as wild-type GPC3 in stimulating Wnt activity in hepatocellular carcinoma cell lines and 293T cells and in promoting hepatocellular carcinoma growth. In this study, we show that processing by convertases is essential for GPC3-induced inhibition of Hh signaling. Moreover, we show that a convertase-resistant GPC3 stimulates Hh signaling by increasing the binding of this growth factor to Ptc. Consistent with this, we show that the convertase-resistant mutant binds to both Hh and Ptc through its heparan sulfate (HS) chains. Unexpectedly, we found that the mutant core protein does not bind to Hh. We also report that the convertase-resistant mutant GPC3 carries HS chains with a significantly higher degree of sulfation than those of wild-type GPC3. We propose that the structural changes generated by the lack of cleavage determine a change in the sulfation of the HS chains and that these hypersulfated chains mediate the interaction of the mutant GPC3 with Ptc.
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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 | 0.000 | 0.001 |
| 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 | 0.000 |
| 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".