SCF<sup>β-TRCP</sup> E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation

doi:10.1007/s13238-018-0510-2

Protein Cell

2018, Vol. 9

Issue (10) : 879-889 https://doi.org/10.1007/s13238-018-0510-2

RESEARCH ARTICLE

SCF^β-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation

Yanpeng Ci^1,², Xiaoning Li^2,³, Maorong Chen⁴, Jiateng Zhong^2,⁵, Brian J. North², Hiroyuki Inuzuka^2,⁶, Xi He⁴, Yu Li¹(

), Jianping Guo²(

), Xiangpeng Dai²(

)

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. 5Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, China
⁶. 6Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan

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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

Corresponding Author(s): Yu Li,Jianping Guo,Xiangpeng Dai

Issue Date: 18 October 2018

Cite this article:

Yanpeng Ci,Xiaoning Li,Maorong Chen, et al. SCF^β-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation[J]. Protein Cell, 2018, 9(10): 879-889.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-018-0510-2
https://academic.hep.com.cn/pac/EN/Y2018/V9/I10/879

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