Research ArticleCancer

The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated β-catenin by sequestering TCF4 to the nuclear membrane

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Sci. Signal.  08 Sep 2015:
Vol. 8, Issue 393, pp. ra90
DOI: 10.1126/scisignal.aac6757

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RNF43 halts Wnt at the nucleus

Wnt signaling is critical to development and is often reactivated in cancer. The E3 ubiquitin ligase RNF43 inhibits Wnt–β-catenin signaling. Rather than promoting the degradation of cell surface Wnt receptors, Loregger et al. found that RNF43 sequestered TCF4, a β-catenin partner and transcription factor, at the nuclear membrane through a mechanism independent of its E3 ligase function. When expressed in frog embryos, RNF43 bearing mutations like those found in human gastrointestinal tumors increased Wnt signaling. Coexpression of wild-type RNF43 suppressed Wnt signaling even in cells with a constitutively active mutant of β-catenin, indicating tumor-suppressive activity of RNF43 functioning downstream of β-catenin.

Abstract

Given its fundamental role in development and cancer, the Wnt–β-catenin signaling pathway is tightly controlled at multiple levels. RING finger protein 43 (RNF43) is an E3 ubiquitin ligase originally found in stem cells and proposed to inhibit Wnt signaling by interacting with the Wnt receptors of the Frizzled family. We detected endogenous RNF43 in the nucleus of human intestinal crypt and colon cancer cells. We found that RNF43 physically interacted with T cell factor 4 (TCF4) in cells and tethered TCF4 to the nuclear membrane, thus silencing TCF4 transcriptional activity even in the presence of constitutively active mutants of β-catenin. This inhibitory mechanism was disrupted by the expression of RNF43 bearing mutations found in human gastrointestinal tumors, and transactivation of the Wnt pathway was observed in various cells and in Xenopus embryos when the RING domain of RNF43 was mutated. Our findings indicate that RNF43 inhibits the Wnt pathway downstream of oncogenic mutations that activate the pathway. Mimicking or enhancing this inhibitory activity of RNF43 may be useful to treat cancers arising from aberrant activation of the Wnt pathway.

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