The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated β-catenin by sequestering TCF4 to the nuclear membrane.
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.
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich 81675, Germany.
Anke
A
Loregger
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich 81675, Germany.
Martina
M
Grandl
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich 81675, Germany.
Raquel
R
Mejías-Luque
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich 81675, Germany. Medical Department II, Technische Universität München, Munich 81675, Germany.
Michael
M
Allgäuer
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich 81675, Germany.
Kathrin
K
Degenhart
Institute for Clinical Chemistry, University Medical Centre Mannheim, Mannheim 68167, Germany.
Verena
V
Haselmann
Division of Molecular Biology and Genetics, Biomedical Sciences Research Center "Alexander Fleming," Vari 16672, Greece.
Christina
C
Oikonomou
Division of Molecular Biology and Genetics, Biomedical Sciences Research Center "Alexander Fleming," Vari 16672, Greece.
Pantelis
P
Hatzis
Department of Surgery, Technische Universität München, Munich 81675, Germany.
Klaus-Peter
KP
Janssen
Department of Surgery, Technische Universität München, Munich 81675, Germany.
Ulrich
U
Nitsche
Zoologisches Institut II, Karlsruhe Institute of Technology, Karlsruhe 76131, Germany.
Dietmar
D
Gradl
Hubrecht Institute, Utrecht 3508, the Netherlands.
Olaf
O
van den Broek
Hubrecht Institute, Utrecht 3508, the Netherlands.
Olivier
O
Destree
Institute of Medical Statistics and Epidemiology, Technische Universität München, Munich 81675, Germany.
Kurt
K
Ulm
Institute for Clinical Chemistry, University Medical Centre Mannheim, Mannheim 68167, Germany.
Michael
M
Neumaier
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich 81675, Germany.
Behnam
B
Kalali
Institute of Pathology, University of Munich, Munich 80337, Germany.
Andreas
A
Jung
Instituto de Biomedicina y Biotecnología de Cantabria, Santander 39011, Spain.
Ignacio
I
Varela
Medical Department II, Technische Universität München, Munich 81675, Germany.
Roland M
RM
Schmid
Medical Department II, Technische Universität München, Munich 81675, Germany.
Roland
R
Rad
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich 81675, Germany.
Dirk H
DH
Busch
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich 81675, Germany. markus.gerhard@tum.de.
Markus
M
Gerhard
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009685:Nuclear Envelope / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases; D060449:Wnt Signaling Pathway / Q000502:physiology*; D014982:Xenopus laevis; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D015513:Oncogene Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases