PUBLICATION
The E3 ubiquitin ligase Trip12 semi-selectively attenuates Wnt signaling
- Authors
- Ensing, J., Ide, A.D., Gilliland, C., Tsurho, V., Rudisel, E., Caza, I., Stratman, A.N., Lanning, N.J., Grainger, S.
- ID
- ZDB-PUB-251016-31
- Date
- 2025
- Source
- iScience 28: 113575113575 (Journal)
- Registered Authors
- Grainger, Stephanie, Stratman, Amber
- Keywords
- Biochemistry, Cell biology
- MeSH Terms
- none
- PubMed
- 41098776 Full text @ iScience
Citation
Ensing, J., Ide, A.D., Gilliland, C., Tsurho, V., Rudisel, E., Caza, I., Stratman, A.N., Lanning, N.J., Grainger, S. (2025) The E3 ubiquitin ligase Trip12 semi-selectively attenuates Wnt signaling. iScience. 28:113575113575.
Abstract
Wnt signaling is critical for the development and maintenance of many cell lineages, including hematopoietic stem cells (HSCs). The tight regulation of Wnt signals is essential, as overactivation can drive tumorigenesis. Numerous Wnt ligands and Frizzled (Fzd) receptors exist, and the negative regulation of particular Fzd signals is the focus of this study. We previously identified the requirement of Wnt9a-Fzd9b pairing for early HSC proliferation. However, the mechanisms controlling activation and signal termination are unclear. Here, we show that the E3 ubiquitin ligase Trip12 (thyroid hormone receptor interactor 12) targets the third intracellular loop of Fzd9b at K437, promoting lysosomal degradation by destabilizing Fzd9b membrane expression. Our data further indicates that Trip12 is semi-selective for Fzd9b. The Trip12-mediated reduction of Fzd9b surface expression dampens Wnt9a/Fzd9b signaling, affecting HSC proliferation in zebrafish. Our findings reveal a receptor-specific regulatory mechanism, with implications for targeted Wnt pathway therapies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping