WW Domain-Containing E3 Ubiquitin Protein Ligase 1: A Self-Disciplined Oncoprotein

Linghan Kuang; Yunhui Jiang; Chenghua Li; Yongmei Jiang

doi:10.3389/fcell.2021.757493

WW Domain-Containing E3 Ubiquitin Protein Ligase 1: A Self-Disciplined Oncoprotein

Front Cell Dev Biol. 2021 Oct 12:9:757493. doi: 10.3389/fcell.2021.757493. eCollection 2021.

Authors

Linghan Kuang^{1

2}, Yunhui Jiang³, Chenghua Li⁴, Yongmei Jiang^{1

2}

Affiliations

¹ Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.
² Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
³ Pathology Department, The Second People's Hospital of Jingmen, Jingmen, China.
⁴ Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.

Abstract

WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a member of C2-WW-HECT E3 ligase family. Although it may execute carcinostatic actions in some scenarios, WWP1 functions as an oncoprotein under most circumstances. Here, we comprehensively review reports on regulation of WWP1 and its roles in tumorigenesis. We summarize the WWP1-mediated ubiquitinations of diverse proteins and the signaling pathways they involved, as well as the mechanisms how they affect cancer formation and progression. According to our analysis of database, in combination with previous reports, we come to a conclusion that WWP1 expression is augmented in various cancers. Gene amplification, as well as expression regulation mediated by molecules such as non-coding RNAs, may account for the increased mRNA level of WWP1. Regulation of enzymatic activity is another important facet to upregulate WWP1-mediated ubiquitinations. Based on the published data, we conclude that WWP1 employs interactions between multiple domains to autoinhibit its polyubiquitination activity in a steady state. Association of some substrates can partially release certain autoinhibition-related domains and make WWP1 have a moderate activity of polyubiquitination. Some cancer-related mutations can fully disrupt the inhibitory interactions and make WWP1 hyperactive. High expression level or hyperactivation of WWP1 may abnormally enhance polyubiquitinations of some oncoproteins or tumor suppressors, such as ΔNp63α, PTEN and p27, and ultimately promote cell proliferation, survival, migration and invasion in tumorigenesis. Given the dysregulation and oncogenic functions of WWP1 in some cancer types, it is promising to explore some therapeutic inhibitors to tune down its activity.

Keywords: C2-WW-HECT E3 ligase family; WW domain-containing E3 ubiquitin protein ligase 1 (WWP1); Wnt/b-catenin; epidermal growth factor receptor (EGFR); protein degradation; transforming growth factor-beta (TGFβ); tumorigenesis and progression; ubiquitination.

Publication types

Review