Enzymatic analysis of WWP2 E3 ubiquitin ligase using protein microarrays identifies autophagy-related substrates

Jiang, Hanjie; Chiang, Claire Y; Chen, Zan; Nathan, Sara; D’Agostino, Gabriel D.; Paulo, João A.; Song, Guang; Zhu, Heng; Gabelli, S.B.; Cole, Philip A.

doi:10.1016/j.jbc.2022.101854

Cited by 9 publications

(4 citation statements)

References 86 publications

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“…Furthermore, a-SMA down-regulation during the early stages of AS has been associated with OPN, a secreted matricellular cytokine involved in cell adhesion, proliferation and migration. VSMC with synthetic phenotype typically express OPN, which acts as a critical regulator of proliferative cardiovascular diseases [ 26 – 29 ]. In the current study, the expression levels of OPN, α-SMA and SM22α in Hcy-treated VSMC or in ApoE -/- mice fed with HMD were the same as those observed in previous studies and verified the transition of VSMC into a synthetic phenotype during the onset of AS.…”

Section: Discussionmentioning

confidence: 99%

“…WWP2, encoded by the WWP2 gene, is expressed in several tissues/organs throughout the human body and regulates several cellular, physiological and pathological processes [ 29 , 30 ]. WWP2 was associated with oxidative stress-mediated VSMC injury in different cardiovascular diseases, such as AS, ischemia-reperfusion injury, cardiomyopathy and heart failure [ 31 , 32 ], suggested that WWP2 could be a significant target for treating several cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

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Proliferation, migration and phenotypic transformation of VSMC induced via Hcy related to up-expression of WWP2 and p-STAT3

Wang,

Gui,

et al. 2024

PLoS ONE

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To provide a theoretical basis for the prevention and treatment of atherosclerosis (AS), the current study aimed to investigate the mechanism underlying the effect of homocysteine (Hcy) on regulating the proliferation, migration and phenotypic transformation of vascular smooth muscle cells (VSMC) via sirtuin-1 (SIRT1)/signal transducer and activator of transcription 3 (STAT3) through Nedd4-like E3 ubiquitin-protein ligase WWP2 (WWP2). Here, Based on the establishment of ApoE-/- mouse models of high Hcy As and the model of Hcy stimulation of VSMC in vitro to observe the interaction between WWP2 and STAT3 and its effect on the proliferation, migration, and phenotypic transformation of Hcy-induced VSMC, which has not been previously reported. This study revealed that WWP2 could promote the proliferation, migration, and phenotype switch of Hcy-induced VSMC by up-regulating the phosphorylation of SIRT1/STAT3 signaling. Furthermore, Hcy might up-regulate WWP2 expression by inhibiting histone H3K27me3 expression through up-regulated UTX. These data suggest that WWP2 is a novel and important regulator of Hcy-induced VSMC proliferation, migration, and phenotypic transformation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proliferation, migration and phenotypic transformation of VSMC induced via Hcy related to up-expression of WWP2 and p-STAT3

Wang,

Gui,

et al. 2024

PLoS ONE

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“…PINK1 and PRKN , which are highly studied autophagy-related genes, are also involved in this process. The PHB2 gene stabilizes PINK1 in mitochondria, facilitating the recruitment of Parkin (the product of PRKN ), ubiquitin, and optineurin (the product of OPTN ) to promote mitophagy [ 83 , 84 , 85 , 86 ]. However, a recent study challenges the necessity of PINK1 and PRKN for initiating mitophagy [ 87 ].…”

Section: Clustering Solid Tumors Based On Autophagy-related Genesmentioning

confidence: 99%

Insights from a Computational-Based Approach for Analyzing Autophagy Genes across Human Cancers

Carrasco

Giovanini

Ramos

et al. 2023

Genes

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In the last decade, there has been a boost in autophagy reports due to its role in cancer progression and its association with tumor resistance to treatment. Despite this, many questions remain to be elucidated and explored among the different tumors. Here, we used omics-based cancer datasets to identify autophagy genes as prognostic markers in cancer. We then combined these findings with independent studies to further characterize the clinical significance of these genes in cancer. Our observations highlight the importance of innovative approaches to analyze tumor heterogeneity, potentially affecting the expression of autophagy-related genes with either pro-tumoral or anti-tumoral functions. In silico analysis allowed for identifying three genes (TBC1D12, KERA, and TUBA3D) not previously described as associated with autophagy pathways in cancer. While autophagy-related genes were rarely mutated across human cancers, the expression profiles of these genes allowed the clustering of different cancers into three independent groups. We have also analyzed datasets highlighting the effects of drugs or regulatory RNAs on autophagy. Altogether, these data provide a comprehensive list of targets to further the understanding of autophagy mechanisms in cancer and investigate possible therapeutic targets.

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“…Several high-throughput approaches have been developed to discover E3-substrate pairs. [5][6][7][8][9][10][11] However, each has technical limitations, which can result in a low yield of true positives from initial hits, requiring additional low-throughput validation. Luciferase reporting assays such as Yeast Two-Hybrid or in vitro ubiquitylation phage display offers high throughput options to find substrates through gene libraries.…”

Section: Introductionmentioning

confidence: 99%

Identifying E3 Ligase Substrates With Quantitative Degradation Proteomics

Jordan

Ordureau

2023

ChemBioChem

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Controlled protein degradation by the ubiquitin‐proteasome pathway is critical for almost all cellular processes. E3 ubiquitin ligases are responsible for targeting proteins for ubiquitylation and subsequent proteasomal degradation with spatial and temporal precision. While studies have revealed various E3‐substrate pairs involved in distinct biological processes, the complete substrate profiles of individual E3 ligases are largely unknown. Here we report a new approach to identify substrates of an E3 ligase for proteasomal degradation using unnatural amino acid incorporation pulse‐chase proteomics (degradomics). Applying this approach, we determine the steady‐state substrates of the C‐terminal to LisH (CTLH) E3 ligase, a multi‐component complex with poorly defined substrates. By comparing the proteome degradation profiles of active and inactive CTLH‐expressing cells, we successfully identify previously known and new potential substrates of CTLH ligase. Altogether, degradomics can comprehensively identify degradation substrates of an E3 ligase, which can be adapted for other E3 ligases in various cellular contexts.

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Enzymatic analysis of WWP2 E3 ubiquitin ligase using protein microarrays identifies autophagy-related substrates

Cited by 9 publications

References 86 publications

Proliferation, migration and phenotypic transformation of VSMC induced via Hcy related to up-expression of WWP2 and p-STAT3

Proliferation, migration and phenotypic transformation of VSMC induced via Hcy related to up-expression of WWP2 and p-STAT3

Insights from a Computational-Based Approach for Analyzing Autophagy Genes across Human Cancers

Identifying E3 Ligase Substrates With Quantitative Degradation Proteomics

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