RNF4-Dependent Oncogene Activation by Protein Stabilization
Jane J. Thomas,
Mona Abed,
Julian Heuberger,
Rostislav Novak,
Yaniv Zohar,
Angela P. Beltran Lopez,
Julie S. Trausch-Azar,
Ma. Xenia G. Ilagan,
David Benhamou,
Gunnar Dittmar,
Raphael Kopan,
Walter Birchmeier,
Alan L. Schwartz,
Amir Orian
Affiliations
Jane J. Thomas
Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Mona Abed
Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Julian Heuberger
Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany
Rostislav Novak
Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Yaniv Zohar
Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Angela P. Beltran Lopez
Instituto de Biotecnologia, Universidad Nacional de Colombia, Bogota D.C. 11132, Colombia
Julie S. Trausch-Azar
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Ma. Xenia G. Ilagan
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA
David Benhamou
Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Gunnar Dittmar
Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany
Raphael Kopan
Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
Walter Birchmeier
Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany
Alan L. Schwartz
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
Amir Orian
Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Ubiquitylation regulates signaling pathways critical for cancer development and, in many cases, targets proteins for degradation. Here, we report that ubiquitylation by RNF4 stabilizes otherwise short-lived oncogenic transcription factors, including β-catenin, Myc, c-Jun, and the Notch intracellular-domain (N-ICD) protein. RNF4 enhances the transcriptional activity of these factors, as well as Wnt- and Notch-dependent gene expression. While RNF4 is a SUMO-targeted ubiquitin ligase, protein stabilization requires the substrate’s phosphorylation, rather than SUMOylation, and binding to RNF4’s arginine-rich motif domain. Stabilization also involves generation of unusual polyubiquitin chains and docking of RNF4 to chromatin. Biologically, RNF4 enhances the tumor phenotype and is essential for cancer cell survival. High levels of RNF4 mRNA correlate with poor survival of a subgroup of breast cancer patients, and RNF4 protein levels are elevated in 30% of human colon adenocarcinomas. Thus, RNF4-dependent ubiquitylation translates transient phosphorylation signal(s) into long-term protein stabilization, resulting in enhanced oncoprotein activation.