Direct regulation of Chk1 protein stability by E3 ubiquitin ligase HUWE1

Fumarylacetoacetate hydrolase (FAH) is the last enzyme in the degradation pathway of the amino acids tyrosine and phenylalanine in mammals that catalyzes the hydrolysis of 4-fumarylacetoacetate into acetoacetate and fumarate. Mutations of the FAH gene are associated with hereditary tyrosinemia type I (HT1), resulting in reduced protein stability, misfolding, accelerated degradation and deficiency in functional proteins. Identifying E3 ligases, which are necessary for FAH protein stability and degradation, is essential. In this study, we demonstrated that the FAH protein level is elevated in liver cancer tissues compared to that in normal tissues. Further, we showed that the FAH protein undergoes 26S proteasomal degradation and its protein turnover is regulated by the anaphase-promoting complex/cyclosome-Cdh1 (APC/C)Cdh1 E3 ubiquitin ligase complex. APC/CCdh1 acts as a negative stabilizer of FAH protein by promoting FAH polyubiquitination and decreases the half-life of FAH protein. Thus, we envision that Cdh1 might be a key factor in the maintenance of FAH protein level to regulate FAH-mediated physiological functions.

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Weak binding to E3 ubiquitin ligase c-Cbl increases EGFRvA protein stability

FEBS Letters ◽

10.1002/1873-3468.12166 ◽

2016 ◽

Vol 590 (9) ◽

pp. 1345-1353 ◽

Cited By ~ 1

Author(s):

Fei Song ◽

Min Zhou ◽

Biao Wang ◽

Bizhi Shi ◽

Hua Jiang ◽

...

Keyword(s):

Protein Stability ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Weak Binding

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pVHL regulates protein stability of TCF/LEF transcription factor family via ubiquitin-independent proteasomal degradation

10.1101/2021.10.14.464355 ◽

2021 ◽

Author(s):

Caixia Wang ◽

Xiaozhi Rong ◽

Haifeng Zhang ◽

Bo Wang ◽

Yan Bai ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Protein Stability ◽

Ubiquitin Ligase ◽

Target Gene ◽

E3 Ubiquitin Ligase ◽

Proteasomal Degradation ◽

26S Proteasome ◽

Cell Fate Decisions ◽

Target Gene Expression

The Wnt/β-catenin signaling pathway plays key roles in development and adult tissue homeostasis by controlling cell proliferation and cell fate decisions. In this pathway, transcription factors TCF/LEFs are the key components to repress target gene expression by recruiting co-repressors or to activate target gene expression by recruiting β-catenin when the Wnt signals are absent or present, respectively. While progress has been made in our understanding of Wnt signaling regulation, the underlying mechanism that regulates the protein stability of the TCF/LEF family is far less clear. Here, we show that von Hippel-Lindau protein (pVHL), which is the substrate recognition component in an E3 ubiquitin ligase complex, controls TCF/LEF protein stability. Unexpectedly, pVHL directly binds to TCF/LEFs and promotes their proteasomal degradation independent of E3 ubiquitin ligase activity. Knockout of vhl in zebrafish embryos leads to a reduction of dorsal habenular neurons and this effect is upstream of dorsal habenular neurons phenotype in tcf7l2-null mutants. Our study uncovers a previously unknown mechanism for the protein stability regulation of the TCF/LEF transcription factors and demonstrates that pVHL contains a 26S proteasome binding domain that drives ubiquitin-independent proteasomal degradation. These findings provide new insights into the ubiquitin-independent actions of pVHL and uncover novel mechanistical regulation of Wnt/β-catenin signaling.

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Protein processing strategies by adeno-associated virus type 5 (AAV5) and the effects of the adenovirus E4orf6/E1b-55k/Cullin 5 E3 ubiquitin ligase complex on AAV protein stability

10.32469/10355/6687 ◽

2008 ◽

Author(s):

Kerry David Farris

Keyword(s):

Protein Stability ◽

Virus Type ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Protein Processing ◽

Adeno Associated Virus ◽

Processing Strategies ◽

Ubiquitin Ligase Complex ◽

Cullin 5

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The E3 ubiquitin ligase Itch controls the protein stability of p63

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0603449103 ◽

2006 ◽

Vol 103 (34) ◽

pp. 12753-12758 ◽

Cited By ~ 157

Author(s):

M. Rossi ◽

R. I. Aqeilan ◽

M. Neale ◽

E. Candi ◽

P. Salomoni ◽

...

Keyword(s):

Protein Stability ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase

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Bifunctional Apoptosis Regulator (BAR), an Endoplasmic Reticulum (ER)-associated E3 Ubiquitin Ligase, Modulates BI-1 Protein Stability and Function in ER Stress

Journal of Biological Chemistry ◽

10.1074/jbc.m110.175232 ◽

2010 ◽

Vol 286 (2) ◽

pp. 1453-1463 ◽

Cited By ~ 30

Author(s):

Juan Rong ◽

Lili Chen ◽

Julia I. Toth ◽

Marianna Tcherpakov ◽

Matthew D. Petroski ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Protein Stability ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

And Function

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Neuregulin-Induced ErbB3 Downregulation Is Mediated by a Protein Stability Cascade Involving the E3 Ubiquitin Ligase Nrdp1

Molecular and Cellular Biology ◽

10.1128/mcb.01245-06 ◽

2007 ◽

Vol 27 (6) ◽

pp. 2180-2188 ◽

Cited By ~ 82

Author(s):

Zhongwei Cao ◽

Xiuli Wu ◽

Lily Yen ◽

Colleen Sweeney ◽

Kermit L. Carraway

Keyword(s):

Growth Factor ◽

Protein Stability ◽

Ubiquitin Ligase ◽

Tyrosine Kinases ◽

Molecular Mechanisms ◽

Egf Receptor ◽

Receptor Tyrosine Kinases ◽

E3 Ubiquitin Ligase ◽

Down Regulation ◽

Neuregulin 1

ABSTRACT The molecular mechanisms underlying epidermal growth factor (EGF) receptor tyrosine kinase down-regulation in response to growth factor binding are coming into focus and involve cbl-mediated receptor ubiquitination followed by lysosomal degradation. However, mechanisms underlying the ligand-stimulated degradation of the related receptor tyrosine kinases of the ErbB family do not involve cbl and remain unexplored. Previous studies have demonstrated that the E3 ubiquitin ligase Nrdp1 contributes to the maintenance of steady-state ErbB3 levels by mediating its growth factor-independent degradation. Here we demonstrate that treatment of cells with the ErbB3 ligand neuregulin-1 (NRG1) stabilizes the deubiquitinating enzyme USP8, which in turn stabilizes Nrdp1. The catalytic activity of USP8 is required for NRG1-induced Nrdp1 stabilization. We provide evidence that Akt-mediated phosphorylation of USP8 threonine residue T907 contributes to USP8 stability. Finally, we demonstrate that Nrdp1 or USP8 knockdown suppresses NRG1-induced ErbB3 ubiquitination and degradation in MCF7 breast cancer cells. We conclude that an NRG1-induced protein stability cascade involving USP8 and Nrdp1 mediates the down-regulation of ErbB3. Our observations raise the possibility that the ligand-induced augmentation of pathways involved in the maintenance of basal levels of receptor tyrosine kinases can contribute to ligand-stimulated down-regulation.

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