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Review
. 2023 Feb 7:29:1610931.
doi: 10.3389/pore.2023.1610931. eCollection 2023.

Emerging roles of the HECT E3 ubiquitin ligases in gastric cancer

Aiqin Sun  1   2 , Xianyan Tian  1 , Yifei Chen  1 , Wannian Yang  1 , Qiong Lin  1
Affiliations
Review

Emerging roles of the HECT E3 ubiquitin ligases in gastric cancer

Aiqin Sun et al. Pathol Oncol Res. .

Abstract

Gastric cancer (GC) is one of the most pernicious gastrointestinal tumors with extraordinarily high incidence and mortality. Ubiquitination modification of cellular signaling proteins has been shown to play important roles in GC tumorigenesis, progression, and prognosis. The E3 ubiquitin ligase is the crucial enzyme in the ubiquitination reaction and determines the specificity of ubiquitination substrates, and thus, the cellular effects. The HECT E3 ligases are the second largest E3 ubiquitin ligase family characterized by containing a HECT domain that has E3 ubiquitin ligase activity. The HECT E3 ubiquitin ligases have been found to engage in GC progression. However, whether HECT E3 ligases function as tumor promoters or tumor suppressors in GC remains controversial. In this review, we will focus on recent discoveries about the role of the HECT E3 ubiquitin ligases, especially members of the NEDD4 and other HECT E3 ligase subfamilies, in GC.

Keywords: HECT E3 ubiquitin ligases; gastric cancer; oncoprotein; tumor suppressor; ubiquitination.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Overview of structural domain organization of HECT E3 family members. HECT E3 ubiquitin ligases are grouped into three subfamilies: NEDD4, HERC, and “Other” HECT E3 subfamily on the basis of their N-terminal structural properties to the HECT domain. The NEDD4 subfamily is characterized by C2 and WW domains, and “Other” HECT E3 subfamily carries a myriad of structural domains in their N-terminal region. The domain abbreviations used are as follows: C2, Calcium-dependent lipid binding domain; WW, WW domain; HECT, homologous to E6AP C-terminus; ARM, armadillo repeat-containing domain; UBA, ubiquitin-associated domain; WWE, WWE domain; BH3, Bcl-2 homology 3 domain; UBM, ubiquitin-binding motif; ANK, Ankyrin repeat-containing domain; NLS, nuclear localization sequence; UBR, ubiquitin-recognin box; PABC//MLLE, polyadenylate-binding protein C-terminal domain; IQ, IQ motif/EF-hand binding site; DOC, APC10/DOC domain.
FIGURE 2
FIGURE 2
Regulation of important signaling pathways by HECT E3 ligases in GC. SMURF1 mediated pluripotency degradation of MEKK2, which resulted in inactivation of MEK1/2–ERK1/2 signaling. SMURF1, WWP1, and WWP2 have similar functions by regulating PIAK/AKT signaling pathway. Limiting ITCH activity causes accumulation of SMAD7 and blocks TGF- β1 signal transduction to inhibit GC progression. ITCH also exerts tumor-suppressive functions by down-regulating the protein level of β-catenin and p-Dvl2. HACE1 executes its regulation of the Wnt/β-catenin signaling pathway through its E3 ligase activity. UBE3C promotes ubiquitination and degradation ANX1 to activate the WNT/β-catenin signaling in GC development. UBE3C directly binds to p53, and it mediates p53 degradation to inhibit the p53 pathway in GC.
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Grants and funding

This work was supported by the National Natural Science Foundation of China (Nos. 82002581, 81871888, and 82172942), China Postdoctoral Science Foundation (No. 2020M671375), Jiangsu Province Postdoctoral Research Funding Scheme (No. 2020Z261).