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Updated: Mar 12, 2026
Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
Published on: September 13, 2018
The Drosophila F-box protein Slimb controls dSmurf protein turnover to regulate the Hippo pathway
Liangchang Hu1, Ping Wang1, Runan Zhao1
1The State Key Laboratory of Medicinal Chemical Biology and College of Life Science; Nankai University; Tianjin, PR China.
Abstract:
SMAD ubiquitination regulatory factors 1 and 2 (Smurf1/2) are members of the HECT domain E3 ligase family which play crucial roles in the regulation of cell cycle progression, planar cell polarity, cancer metastasis and cell apoptosis. We recently showed that the Drosophila homolog dSmurf controls the stability of Warts kinase to regulate the Hippo pathway. In the current study, we found that the F-box protein Slimb controls dSmurf protein level to regulate the Hippo pathway. Slimb physically associates with dSmurf as revealed by co-immunoprecipitation assay in S2 cells. The C-terminal WD40 repeats of Slimb (188-510 amino acid) and the C-terminal HECT domain of dSmurf (723-1061 amino acid) are necessary for their binding. Interaction with Slimb leads to the ubiquitination and degradation of dSmurf, resulting in negative regulation of dSmurf-mediated Yki phosphorylation and activity in the Hippo pathway. Thus our study revealed a new regulatory mechanism of the Hippo pathway which may provide implications for developing tumor treatment.
Insights
The F-box protein Slimb targets dSmurf for degradation, revealing a new regulatory mechanism for the Hippo pathway. This discovery offers potential insights for developing novel cancer treatments.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- SMAD ubiquitination regulatory factors (Smurf1/2) are E3 ligases regulating critical cellular processes.
- The Drosophila homolog dSmurf stabilizes Warts kinase, impacting the Hippo pathway.
- The Hippo pathway is crucial for cell proliferation, apoptosis, and tissue homeostasis.
Purpose of the Study:
- To investigate the role of F-box protein Slimb in regulating dSmurf stability.
- To elucidate the mechanism by which Slimb controls dSmurf levels.
- To understand the implications of this regulation for the Hippo pathway.
Main Methods:
- Co-immunoprecipitation assays in S2 cells to confirm physical association between Slimb and dSmurf.
- Identification of specific domains (Slimb C-terminal WD40, dSmurf C-terminal HECT) crucial for binding.
- Assessment of dSmurf ubiquitination and degradation upon interaction with Slimb.
Main Results:
- Slimb physically associates with dSmurf.
- The interaction between Slimb and dSmurf leads to dSmurf ubiquitination and subsequent degradation.
- This degradation negatively regulates dSmurf-mediated Yki phosphorylation and activity within the Hippo pathway.
Conclusions:
- Slimb acts as a negative regulator of dSmurf, controlling its protein levels.
- This novel regulatory mechanism involving Slimb-mediated dSmurf degradation impacts the Hippo pathway.
- The findings suggest potential therapeutic targets for cancer treatment by modulating this pathway.
