Xiaoning Li
Maorong Chen
Jiateng Zhong
Brian J. North
Hiroyuki Inuzuka
Xi He
Yu Li
Jianping Guo
Xiangpeng Dai
1 School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China;
2 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
3 Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China;
4 The FM Kirby Neurobiology Center, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA;
5 Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, China;
6 Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan
Funds: This work was partly supported by the National Natural Science Foundation of China No. 31571323 to Y. Li. X. He acknowledges support by NIH (RO1-GM057603) and by Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (P30 HD-18655).
Received Date: 2017-10-24
Rev Recd Date:2018-01-09
Abstract
Abstract
Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin 1-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiquitinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phosphorylation-and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regulation of Wnt signaling by β-TRCP in a contextdependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3.Keywords: ZNRF3,
β-TRCP,
Wnt,
ubiquitination,
CKI
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