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

Linghan Kuang,Yongmei Jiang,Yunhui Jiang,Chenghua Li

doi:10.3389/fcell.2021.757493

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.

Highlights

WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is known as AIP5 (Atropin-1interacting protein 5) or TIUL1 (TG-interacting ubiquitin ligase 1) (Wood et al, 1998; Seo et al, 2004; Zhi and Chen, 2012). It belongs to the Ca2+-dependent lipid-binding (C2)-WW-homologous to the E6-AP carboxyl terminus (HECT) E3 ligase family, which contains 8 extra members, i.e., WWP2 (Zhang et al, 2019), NEDD4
Though it is well known that WWP1 acts as an oncoprotein in breast and prostate cancers, WWP1-mediated ubiquitination and subsequent degradation of KLF5 indicate that WWP1 functions as a tumor suppressor via dampening KLF5’s positive regulation on cell survival and metastasis of these tumors under some circumstances (Chen et al, 2005)
Though functioning as a tumor suppressor under some circumstances, WWP1 is generally accepted as an oncoprotein

Summary

Introduction

WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is known as AIP5 (Atropin-1interacting protein 5) or TIUL1 (TG-interacting ubiquitin ligase 1) (Wood et al, 1998; Seo et al, 2004; Zhi and Chen, 2012). WW domain-containing E3 ubiquitin protein ligase 1 can directly add monoubiquitin or different polyubiquitin chains to a variety of substrate proteins and modulate their stability, trafficking, or functions (Seo et al, 2004; Chen et al, 2005, 2008; Flasza et al, 2006; Zhi and Chen, 2012).

Results

Conclusion