A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Signaling

Background:

• RNF43 is a frequently mutated tumor suppressor in cancers, especially colon malignancies.
• RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signaling by targeting the Frizzled receptor for degradation.

Purpose of the Study:

• To investigate the role of RNF43 phosphorylation in its tumor suppressive function.
• To understand how cancer-associated mutations in RNF43 contribute to tumorigenesis.
• To explore therapeutic strategies targeting RNF43 phospho-regulation.

Main Methods:

• Investigated RNF43 phosphorylation using zebrafish development and mouse intestinal organoid models.
• Analyzed the impact of cancer-associated mutations on RNF43 function in Wnt and p53 signaling pathways.
• Utilized phosphomimetic substitutions to assess the restoration of RNF43 tumor suppressive activity.

Main Results:

• RNF43 activity is dependent on phosphorylation at a conserved serine triplet.
• Mutations preventing RNF43 phosphorylation cooperate with Ras to promote tumorigenesis by dysregulating Wnt and p53 signaling.
• Phosphomimetic mutations restored the tumor suppressive function of oncogenic RNF43 mutants.

Conclusions:

• RNF43 phospho-regulation is crucial for normal development and tumor suppression.
• The Wnt-Ras-p53 axis is implicated in multi-step tumorigenesis driven by cooperating RNF43 and KRAS mutations in colon cancer.
• Targeting RNF43 phosphorylation presents a potential therapeutic avenue for RNF43-mutated tumors.