Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Sep 8;8(393):ra90.
doi: 10.1126/scisignal.aac6757.

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

Anke Loregger  1 , Martina Grandl  1 , Raquel Mejías-Luque  1 , Michael Allgäuer  2 , Kathrin Degenhart  1 , Verena Haselmann  3 , Christina Oikonomou  4 , Pantelis Hatzis  4 , Klaus-Peter Janssen  5 , Ulrich Nitsche  5 , Dietmar Gradl  6 , Olaf van den Broek  7 , Olivier Destree  7 , Kurt Ulm  8 , Michael Neumaier  3 , Behnam Kalali  1 , Andreas Jung  9 , Ignacio Varela  10 , Roland M Schmid  11 , Roland Rad  11 , Dirk H Busch  1 , Markus Gerhard  12
Affiliations

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

Anke Loregger et al. Sci Signal. .

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.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

MeSH terms

LinkOut - more resources