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Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model
Published on: April 17, 2026
The unfolded protein response selectively targets active smoothened mutants
Suresh Marada1, Daniel P Stewart, William J Bodeen
1Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
Molecular and Cellular Biology
|April 11, 2013
Summary
Targeting cancer-driving Smoothened mutants with unfolded protein response (UPR) inducers offers a novel therapeutic strategy. This approach leverages endoplasmic reticulum stress to degrade mutant Smoothened, attenuating oncogenic Hedgehog signaling without affecting normal development.
Area of Science:
- Oncology
- Molecular Biology
- Developmental Biology
Background:
- The Hedgehog signaling pathway is crucial for development and implicated in various cancers.
- Smoothened is a key therapeutic target, but resistance and active mutants pose challenges.
- Active Smoothened mutants are retained in the endoplasmic reticulum (ER) due to quality control mechanisms.
Purpose of the Study:
- To investigate if endoplasmic reticulum stressors inducing the unfolded protein response (UPR) can target and degrade active Smoothened mutants.
- To determine if UPR modulation can specifically attenuate oncogenic Hedgehog signaling driven by resistant Smoothened mutants.
Main Methods:
- Induction of the unfolded protein response (UPR) using ER stressors.
- Assessment of Smoothened protein levels and degradation pathways.
- Evaluation of Hedgehog pathway activity in cellular and in vivo models (Drosophila melanogaster).
Main Results:
- UPR induction led to ER-associated degradation of active Smoothened mutants.
- This degradation effectively attenuated deregulated Hedgehog signaling driven by mutant Smoothened.
- The UPR agonist thapsigargin reduced mutant Smoothened-induced phenotypes in vivo.
- Wild-type Smoothened and normal Hedgehog patterning remained unaffected.
Conclusions:
- Modulating the unfolded protein response (UPR) is a potential therapeutic strategy to target resistant Smoothened mutants in cancer.
- This approach offers a specific window to inhibit oncogenic signaling driven by active Smoothened mutants.
- UPR induction selectively degrades mutant Smoothened, sparing physiological signaling pathways.
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