<scp>HERC3</scp> promotes <scp>YAP</scp>/<scp>TAZ</scp> stability and tumorigenesis independently of its ubiquitin ligase activity

Yuan, Bo; Liu, Jinquan; Shi, Aiping; Cao, Jin; Yu, Yi; Zhu, Yezhang; Zhang, Chengbin; Qiu, Yifei; Luo, Hongjie; Cao, Xiaolei; Xu, Pinglong; Shen, Li; Liang, Tingbo; Zhao, Bin; Feng, Xin‐Hua

doi:10.15252/embj.2022111549

Cited by 15 publications

(5 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, UBE3C may be involved in efficiently transporting misfolded CFTR and ABCB1 to the proteasome for degradation, even without relying on its E3 ligase activity. This mechanism aligns with a model in which certain Ub ligases directly present the substrate protein to the 20S proteasome, facilitating their degradation and essentially acting as 'recruiters' [51][52][53].…”

Section: Discussionsupporting

confidence: 74%

UBE3C Facilitates the ER-Associated and Peripheral Degradation of Misfolded CFTR

Kamada,

Tateishi,

Nakayamada

et al. 2023

Cells

View full text Add to dashboard Cite

The ubiquitin E3 ligase UBE3C promotes the proteasomal degradation of cytosolic proteins and endoplasmic reticulum (ER) membrane proteins. UBE3C is proposed to function downstream of the RNF185/MBRL ER-associated degradation (ERAD) branch, contributing to the ERAD of select membrane proteins. Here, we report that UBE3C facilitates the ERAD of misfolded CFTR, even in the absence of both RNF185 and its functional ortholog RNF5 (RNF5/185). Unlike RNF5/185, UBE3C had a limited impact on the ubiquitination of misfolded CFTR. UBE3C knockdown (KD) resulted in an additional increase in the functional ∆F508-CFTR channels on the plasma membrane when combined with the RNF5/185 ablation, particularly in the presence of clinically used CFTR modulators. Interestingly, although UBE3C KD failed to attenuate the ERAD of insig-1, it reduced the ERAD of misfolded ∆Y490-ABCB1 and increased cell surface expression. UBE3C KD also stabilized the mature form of ∆F508-CFTR and increased the cell surface level of T70-CFTR, a class VI CFTR mutant. These results suggest that UBE3C plays a vital role in the ERAD of misfolded CFTR and ABCB1, even within the RNF5/185-independent ERAD pathway, and it may also be involved in maintaining the peripheral quality control of CFTR.

show abstract

Section: Discussionsupporting

confidence: 74%

UBE3C Facilitates the ER-Associated and Peripheral Degradation of Misfolded CFTR

Kamada,

Tateishi,

Nakayamada

et al. 2023

Cells

View full text Add to dashboard Cite

show abstract

“…7D). We further assessed the impact of GRK3 on TAZ, active-TAZ, YAP phosphorylation at Ser-381 (which recruits the SCFb-TrCP E3 ligase for ubiquitination dependent YAP degradation), and YAP phosphorylation at Ser-127 and TAZ at Ser-89 (which leads to their 14-3-3-dependent cytoplasmic sequestration) (27) . Western blot analysis demonstrated that GRK3 knockdown had no noticeable effect on these proteins and phosphorylation events (Fig.…”

Section: Trim58 Activates Grk3/hippo-yap Pathway Via Myh9mentioning

confidence: 99%

TRIM58 downregulation maintains stemness via MYH9-GRK3-YAP axis activation in triple-negative breast cancer stem cells

Li,

Jiang,

et al. 2024

Cancer Gene Ther

View full text Add to dashboard Cite

BackgroundTRIM58 is, a member of the TRIM protein family, which possess with E3 ubiquitin ligase activities. Studies have revealed that weak expression of TRIM58 plays key roles, has been implicated in the tumor progression of tumor formation due to its reduced expression. However, its role in regulating the stemness of breast cancer stem cells (CSCs) remains unexplored. MethodsThe expression of TRIM58 was examined in breast cancer cells and triple-negative breast cancer (TNBC) patient specimens. Human TNBC CSCs were enriched from TNBC patient cancer tissues using serumfree medium. Stemness functions of TRIM58 in CSCs were assessed using western blot, cell viability analysis, tumorsphere formation assay, and subcutaneous tumorigenesis assays. Mechanistic investigations of TRIM58 on stemness and differentiation were conducted using coimmunoprecipitation, mass spectrometry, q-PCR, ubiquitination detection, label-free quantitative proteomics, and dual luciferase reporter assays. ResultsTRIM58 was underexpressed in TNBC tissues and cells compared to adjacent mucosa tissue, and its downregulation was signi cantly associated with shorter survival. Overexpression of TRIM58 reduced the proportion of CD44+/CD24-cells, upregulated differentiation genes, and inhibited stemness-related gene expression in TNBC CSCs. In vitro and in vivo experiments revealed that TRIM58 overexpression in CSCs suppressed tumor sphere formation and tumorigenic capacity. Co-IP results indicated direct interaction between TRIM58 and MYH9, with TRIM58 inducing MYH9 degradation via ubiquitination in differentiated cells. Label-free quantitative proteomics identi ed GRK3 and Hippo-YAP as downstream targets and signaling pathways of MYH9. TIMER database analysis, immunohistochemistry, western blotting, DNA-protein pulldown experiments, and dual luciferase reporter assays demonstrated that MYH9 regulated GRK3 transcriptional activation in CSCs. ConclusionsThis study highlights the negative impact of TRIM58 on the stemness of triple-negative breast CSCs. Elevated TRIM58 expression in CSCs downregulates MYH9 protein levels by promoting ubiquitinmediated degradation, thereby inhibiting downstream GRK3 transcription, inactivating the Hippo-YAP stemness pathway, and ultimately promoting CSC differentiation.

show abstract

“…We found that CPNE3 modulates the YAP1 pathway without significantly affecting the expression of LATS1/2, an upstream regulator of YAP1, indicating that LATS kinase is not necessary for CPNE3 to regulate YAP1 [ 35 ]. Moreover, CPNE3 overexpression or deletion did not significantly change the expression of YAP1 mRNA, indicating that CPNE3 controls YAP1 function in GC cells by influencing post-transcriptional or protein degradation levels [ 36 , 37 ]. Here, we demonstrated that CPNE3 inhibits E3 ubiquitin ligase recruitment by competitively binding YAP1 to β-TRCP, prolonging the protein half-life of YAP1, and promoting YAP1 entry into the nucleus to activate the transcription of target genes downstream of the Hippo pathway, so forming a positive feedback loop [ 27 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

YAP1-CPNE3 positive feedback pathway promotes gastric cancer cell progression

Li,

Zhong,

Shi

et al. 2024

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Hippo-Yes-associated protein 1 (YAP1) plays an important role in gastric cancer (GC) progression; however, its regulatory network remains unclear. In this study, we identified Copine III (CPNE3) was identified as a novel direct target gene regulated by the YAP1/TEADs transcription factor complex. The downregulation of CPNE3 inhibited proliferation and invasion, and increased the chemosensitivity of GC cells, whereas the overexpression of CPNE3 had the opposite biological effects. Mechanistically, CPNE3 binds to the YAP1 protein in the cytoplasm, inhibiting YAP1 ubiquitination and degradation mediated by the E3 ubiquitination ligase β-transducin repeat-containing protein (β-TRCP). Thereby activating the transcription of YAP1 downstream target genes, which creates a positive feedback cycle to facilitate GC progression. Immunohistochemical analysis demonstrated significant upregulation of CPNE3 in GC tissues. Survival and Cox regression analyses indicated that high CPNE3 expression was an independent prognostic marker for GC. This study elucidated the pivotal involvement of an aberrantly activated CPNE3/YAP1 positive feedback loop in the malignant progression of GC, thereby uncovering novel prognostic factors and therapeutic targets in GC.

show abstract

HERC3 promotes YAP/TAZ stability and tumorigenesis independently of its ubiquitin ligase activity

Cited by 15 publications

References 47 publications

UBE3C Facilitates the ER-Associated and Peripheral Degradation of Misfolded CFTR

UBE3C Facilitates the ER-Associated and Peripheral Degradation of Misfolded CFTR

TRIM58 downregulation maintains stemness via MYH9-GRK3-YAP axis activation in triple-negative breast cancer stem cells

YAP1-CPNE3 positive feedback pathway promotes gastric cancer cell progression

Contact Info

Product

Resources

About