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

• Verfasst von: Loregger, Anke [VerfasserIn]
• Verfasst von: Haselmann, Verena [VerfasserIn]
• Verfasst von: Neumaier, Michael [VerfasserIn]
• Titel: The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated β-catenin by sequestering TCF4 to the nuclear membrane
• Verf.angabe: Anke Loregger, Martina Grandl, Raquel Mejías-Luque, Michael Allgäuer, Kathrin Degenhart, Verena Haselmann, Christina Oikonomou, Pantelis Hatzis, Klaus-Peter Janssen, Ulrich Nitsche, Dietmar Gradl, Olaf van den Broek, Olivier Destree, Kurt Ulm, Michael Neumaier, Behnam Kalali, Andreas Jung, Ignacio Varela, Roland M. Schmid, Roland Rad, Dirk H. Busch, and Markus Gerhard
• Fussnoten: Gesehen am 06.03.2018
• Titel Quelle: Enthalten in: Science signaling
• Jahr Quelle: 2015
• Band/Heft Quelle: 8(2015,393) Artikel-Nummer ra90
• ISSN Quelle: 1937-9145
• DOI: doi:10.1126/scisignal.aac6757
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1570569606

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.