Authors
Laura de-la-Puente-Ovejero, Ana Domostegui, Inés María García-Pérez, Gonzalo Aizpurua, Lucía Lomba-Riego, Pilar Ximenez-Embún, Cristina Mayor-Ruiz, Mariano Barbacid, Sara García-Alonso
Published in
Life science alliance. Volume 9. Issue 12. Epub Sep 22, 2026.
Abstract
Scaffold integrity is essential for the activity of proteins that function through protein-protein interactions rather than catalytic output. RAF1 exemplifies this duality: although it is a bona fide kinase and a core component of the MAPK cascade, its tumor-promoting role is largely kinase-independent, relying instead on scaffold-mediated suppression of apoptosis. Genetic Raf1 ablation in KRAS-driven lung adenocarcinoma mouse models induces tumor regression without systemic toxicity, making it an attractive candidate for targeted protein degradation. Chemogenetic systems like the dTAG platform are widely used for preclinical target validation. Here, we generated a dTAG-RAF1 mouse model and showed that pharmacological degradation is efficient and systemically well tolerated but fails to reproduce the tumor regression observed upon genetic Raf1 ablation. Mechanistically, the N-terminal FKBP12F36V tag (dTAG) perturbs the RAF1 interactome, including scaffold associations with apoptotic regulators, thereby blunting the phenotypic consequences of its degradation. These results establish scaffold integrity as a determinant of chemogenetic system fidelity and argue that degradation tools must be validated at the functional level, not only for target elimination, before assessing their therapeutic relevance.
PMID:
42772903
Bibliographic data and abstract were imported from PubMed on 23 Sep 2026.
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