E3 ubiquitin ligases: styles, structures and functions

AbstractE3 ubiquitin ligases are a large family of enzymes that join in a three-enzyme ubiquitination cascade together with ubiquitin activating enzyme E1 and ubiquitin conjugating enzyme E2. E3 ubiquitin ligases play an essential role in catalyzing the ubiquitination process and transferring ubiquitin protein to attach the lysine site of targeted substrates. Importantly, ubiquitination modification is involved in almost all life activities of eukaryotes. Thus, E3 ligases might be involved in regulating various biological processes and cellular responses to stress signal associated with cancer development. Thanks to their multi-functions, E3 ligases can be a promising target of cancer therapy. A deeper understanding of the regulatory mechanisms of E3 ligases in tumorigenesis will help to find new prognostic markers and accelerate the growth of anticancer therapeutic approaches. In general, we mainly introduce the classifications of E3 ligases and their important roles in cancer progression and therapeutic functions.

Download Full-text

Functional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics

10.5772/intechopen.100534 ◽

2021 ◽

Author(s):

Julius Tieroyaare Dongdem ◽

Cletus Adiyaga Wezena

Keyword(s):

Therapeutic Potential ◽

Protein Complexes ◽

Ring Finger ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Phd Finger ◽

E3 Ligases ◽

Cellular Processes ◽

Future Drug ◽

Ubiquitin Conjugating Enzyme

E3 ubiquitin ligases of which there are >600 putative in humans, constitute a family of highly heterogeneous proteins and protein complexes that are the ultimate enzymes responsible for the recruitment of an ubiquitin loaded E2 ubiquitin-conjugating enzyme, recognise the appropriate protein substrate and directly or indirectly transfer the ubiquitin load onto the substrate. The aftermath of an E3 ligase activity is usually the formation of an isopeptide bond between the free carboxylate group of ubiquitin’s C-terminal Gly76 and an ε-amino group of the substrate’s Lys, even though non-canonical ubiquitylation on non-amine groups of target proteins have been observed. E3 ligases are grouped into four distinct families: HECT, RING-finger/U-box, RBR and PHD-finger. E3 ubiquitin ligases play critical roles in subcellular signalling cascades in eukaryotes. Dysfunctional E3 ubiquitin ligases therefore tend to inflict dramatic effects on human health and may result in the development of various diseases including Parkinson’s, Amyotrophic Lateral Sclerosis, Alzheimer’s, cancer, etc. Being regulators of numerous cellular processes, some E3 ubiquitin ligases have become potential targets for therapy. This chapter will present a comprehensive review of up-to-date findings in E3 ligases, their role in the pathology of disease and therapeutic potential for future drug development.

Download Full-text

E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms22020476 ◽

2021 ◽

Vol 22 (2) ◽

pp. 476

Author(s):

Abhishek Sinha ◽

Prasanna Vasudevan Iyengar ◽

Peter ten Dijke

Keyword(s):

Signaling Pathway ◽

Cancer Progression ◽

Intracellular Signaling ◽

Transforming Growth Factor ◽

Ubiquitin Ligases ◽

Specific Cell ◽

Type I ◽

E3 Ubiquitin Ligases ◽

Tgfβ Signaling ◽

E3 Ligases

Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. E3 ligases regulate TGFβ signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGFβ’s dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGFβ-induced pro-oncogenic responses.

Download Full-text

Comprehensive database of human E3 ubiquitin ligases: application to aquaporin-2 regulation

Physiological Genomics ◽

10.1152/physiolgenomics.00031.2016 ◽

2016 ◽

Vol 48 (7) ◽

pp. 502-512 ◽

Cited By ~ 31

Author(s):

Barbara Medvar ◽

Viswanathan Raghuram ◽

Trairak Pisitkun ◽

Abhijit Sarkar ◽

Mark A. Knepper

Keyword(s):

Human Genome ◽

Large Scale ◽

E3 Ligase ◽

Ubiquitin Ligases ◽

Bayes Rule ◽

E3 Ubiquitin Ligases ◽

E3 Ligases ◽

Aquaporin 2 ◽

Large Scale Data ◽

Level Data

Aquaporin-2 (AQP2) is regulated in part via vasopressin-mediated changes in protein half-life that are in turn dependent on AQP2 ubiquitination. Here we addressed the question, “What E3 ubiquitin ligase is most likely to be responsible for AQP2 ubiquitination?” using large-scale data integration based on Bayes' rule. The first step was to bioinformatically identify all E3 ligase genes coded by the human genome. The 377 E3 ubiquitin ligases identified in the human genome, consisting predominant of HECT, RING, and U-box proteins, have been used to create a publically accessible and downloadable online database ( https://hpcwebapps.cit.nih.gov/ESBL/Database/E3-ligases/ ). We also curated a second database of E3 ligase accessory proteins that included BTB domain proteins, cullins, SOCS-box proteins, and F-box proteins. Using Bayes' theorem to integrate information from multiple large-scale proteomic and transcriptomic datasets, we ranked these 377 E3 ligases with respect to their probability of interaction with AQP2. Application of Bayes' rule identified the E3 ligases most likely to interact with AQP2 as (in order of probability): NEDD4 and NEDD4L (tied for first), AMFR, STUB1, ITCH, ZFPL1. Significantly, the two E3 ligases tied for top rank have also been studied extensively in the reductionist literature as regulatory proteins in renal tubule epithelia. The concordance of conclusions from reductionist and systems-level data provides strong motivation for further studies of the roles of NEDD4 and NEDD4L in the regulation of AQP2 protein turnover.

Download Full-text

Comprehensive Analysis of E3 Ubiquitin Ligases Reveals Ring Finger Protein 223 as a Novel Oncogene Activated by KLF4 in Pancreatic Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.738709 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lei Feng ◽

Jieqing Wang ◽

Jianmin Zhang ◽

Jingfang Diao ◽

Longguang He ◽

...

Keyword(s):

Pancreatic Cancer ◽

Transcriptional Activation ◽

Prognostic Significance ◽

Ring Finger ◽

Ubiquitin Ligases ◽

The Cancer Genome Atlas ◽

Differentially Expressed ◽

E3 Ubiquitin Ligases ◽

E3 Ligases ◽

Elevated Expression

Pancreatic cancer is one of the major malignancies and causes of mortality worldwide. E3 ubiquitin–protein ligases transfer activated ubiquitin from ubiquitin-conjugating enzymes to protein substrates and confer substrate specificity in cancer. In this study, we first downloaded data from The Cancer Genome Atlas pancreatic adenocarcinoma dataset, acquired all 27 differentially expressed genes (DEGs), and identified genomic alterations. Then, the prognostic significance of DEGs was analyzed, and eight DEGs (MECOM, CBLC, MARCHF4, RNF166, TRIM46, LONRF3, RNF39, and RNF223) and two clinical parameters (pathological N stage and T stage) exhibited prognostic significance. RNF223 showed independent significance as an unfavorable prognostic marker and was chosen for subsequent analysis. Next, the function of RNF223 in the pancreatic cancer cell lines ASPC-1 and PANC-1 was investigated, and RNF223 silencing promoted pancreatic cancer growth and migration. To explore the potential targets and pathways of RNF223 in pancreatic cancer, quantitative proteomics was applied to analyze differentially expressed proteins, and metabolism-related pathways were primarily enriched. Finally, the reason for the elevated expression of RNF223 was analyzed, and KLF4 was shown to contribute to the increased expression of RNF233. In conclusion, this study comprehensively analyzed the clinical significance of E3 ligases. Functional assays revealed that RNF223 promotes cancer by regulating cell metabolism. Finally, the elevated expression of RNF223 was attributed to KLF4-mediated transcriptional activation. This study broadens our knowledge regarding E3 ubiquitin ligases and signal transduction and provides novel markers and therapeutic targets in pancreatic cancer.

Download Full-text

The Janus Face of p53-Targeting Ubiquitin Ligases

Cells ◽

10.3390/cells9071656 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1656 ◽

Cited By ~ 3

Author(s):

Qian Hao ◽

Yajie Chen ◽

Xiang Zhou

Keyword(s):

Cancer Progression ◽

Ubiquitin Ligases ◽

Tp53 Gene ◽

Mutant P53 ◽

E3 Ubiquitin Ligases ◽

Tumor Suppressor P53 ◽

Wild Type ◽

Cell Growth Arrest ◽

Cancer Cell Survival ◽

P53 Status

The tumor suppressor p53 prevents tumorigenesis and cancer progression by maintaining genomic stability and inducing cell growth arrest and apoptosis. Because of the extremely detrimental nature of wild-type p53, cancer cells usually mutate the TP53 gene in favor of their survival and propagation. Some of the mutant p53 proteins not only lose the wild-type activity, but also acquire oncogenic function, namely “gain-of-function”, to promote cancer development. Growing evidence has revealed that various E3 ubiquitin ligases are able to target both wild-type and mutant p53 for degradation or inactivation, and thus play divergent roles leading to cancer cell survival or death in the context of different p53 status. In this essay, we reviewed the recent progress in our understanding of the p53-targeting E3 ubiquitin ligases, and discussed the potential clinical implications of these E3 ubiquitin ligases in cancer therapy.

Download Full-text

E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis

Cells ◽

10.3390/cells8050510 ◽

2019 ◽

Vol 8 (5) ◽

pp. 510 ◽

Cited By ~ 21

Author(s):

Santina Venuto ◽

Giuseppe Merla

Keyword(s):

Cell Cycle ◽

Cancer Progression ◽

Current Knowledge ◽

Ubiquitin Ligases ◽

Cell Protein ◽

E3 Ubiquitin Ligases ◽

Daughter Cells ◽

Protein Ubiquitination ◽

Functional Units ◽

Trim Proteins

The cell cycle is a series of events by which cellular components are accurately segregated into daughter cells, principally controlled by the oscillating activities of cyclin-dependent kinases (CDKs) and their co-activators. In eukaryotes, DNA replication is confined to a discrete synthesis phase while chromosome segregation occurs during mitosis. During mitosis, the chromosomes are pulled into each of the two daughter cells by the coordination of spindle microtubules, kinetochores, centromeres, and chromatin. These four functional units tie chromosomes to the microtubules, send signals to the cells when the attachment is completed and the division can proceed, and withstand the force generated by pulling the chromosomes to either daughter cell. Protein ubiquitination is a post-translational modification that plays a central role in cellular homeostasis. E3 ubiquitin ligases mediate the transfer of ubiquitin to substrate proteins determining their fate. One of the largest subfamilies of E3 ubiquitin ligases is the family of the tripartite motif (TRIM) proteins, whose dysregulation is associated with a variety of cellular processes and directly involved in human diseases and cancer. In this review we summarize the current knowledge and emerging concepts about TRIMs and their contribution to the correct regulation of cell cycle, describing how TRIMs control the cell cycle transition phases and their involvement in the different functional units of the mitotic process, along with implications in cancer progression.

Download Full-text

Establishment of a Wheat Cell-Free Synthesized Protein Array Containing 250 Human and Mouse E3 Ubiquitin Ligases to Identify Novel Interaction between E3 Ligases and Substrate Proteins

PLoS ONE ◽

10.1371/journal.pone.0156718 ◽

2016 ◽

Vol 11 (6) ◽

pp. e0156718 ◽

Cited By ~ 21

Author(s):

Hirotaka Takahashi ◽

Atsushi Uematsu ◽

Satoshi Yamanaka ◽

Mei Imamura ◽

Tatsuro Nakajima ◽

...

Keyword(s):

Ubiquitin Ligases ◽

Protein Array ◽

E3 Ubiquitin Ligases ◽

E3 Ligases ◽

Substrate Proteins ◽

Human And Mouse

Download Full-text

Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges

Cells ◽

10.3390/cells10123309 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3309

Author(s):

Peng Ye ◽

Xiaoxia Chi ◽

Jong-Ho Cha ◽

Shahang Luo ◽

Guanghui Yang ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Ubiquitin Ligases ◽

Immune Checkpoints ◽

E3 Ubiquitin Ligases ◽

E3 Ligases ◽

Beneficial Effects ◽

Clinical Strategies ◽

Immune Pathway ◽

Future Direction ◽

Cancer Immunotherapies

Cancer immunotherapies, including immune checkpoint inhibitors and immune pathway–targeted therapies, are promising clinical strategies for treating cancer. However, drug resistance and adverse reactions remain the main challenges for immunotherapy management. The future direction of immunotherapy is mainly to reduce side effects and improve the treatment response rate by finding new targets and new methods of combination therapy. Ubiquitination plays a crucial role in regulating the degradation of immune checkpoints and the activation of immune-related pathways. Some drugs that target E3 ubiquitin ligases have exhibited beneficial effects in preclinical and clinical antitumor treatments. In this review, we discuss mechanisms through which E3 ligases regulate tumor immune checkpoints and immune-related pathways as well as the opportunities and challenges for integrating E3 ligases targeting drugs into cancer immunotherapy.

Download Full-text

Genome-wide analysis of HECT E3 ubiquitin ligase gene family in Solanum lycopersicum

Scientific Reports ◽

10.1038/s41598-021-95436-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bhaskar Sharma ◽

Harshita Saxena ◽

Harshita Negi

Keyword(s):

Gene Family ◽

Ubiquitin Ligase ◽

Plant Development ◽

Stress Responses ◽

E3 Ubiquitin Ligase ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

E3 Ligases ◽

Genome Wide Analysis ◽

Genome Wide

AbstractThe E3 ubiquitin ligases have been known to intrigue many researchers to date, due to their heterogenicity and substrate mediation for ubiquitin transfer to the protein. HECT (Homologous to the E6-AP Carboxyl Terminus) E3 ligases are spatially and temporally regulated for substrate specificity, E2 ubiquitin-conjugating enzyme interaction, and chain specificity during ubiquitylation. However, the role of the HECT E3 ubiquitin ligase in plant development and stress responses was rarely explored. We have conducted an in-silico genome-wide analysis to identify and predict the structural and functional aspects of HECT E3 ligase members in tomato. Fourteen members of HECT E3 ligases were identified and analyzed for the physicochemical parameters, phylogenetic relations, structural organizations, tissue-specific gene expression patterns, and protein interaction networks. Our comprehensive analysis revealed the HECT domain conservation throughout the gene family, close evolutionary relationship with different plant species, and active involvement of HECT E3 ubiquitin ligases in tomato plant development and stress responses. We speculate an indispensable biological significance of the HECT gene family through extensive participation in several plant cellular and molecular pathways.

Download Full-text

Regulation of E3 ubiquitin ligases by homotypic and heterotypic assembly

F1000Research ◽

10.12688/f1000research.21253.1 ◽

2020 ◽

Vol 9 ◽

pp. 88 ◽

Cited By ~ 1

Author(s):

Vishnu Balaji ◽

Thorsten Hoppe

Keyword(s):

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Substrate Selection ◽

Post Translational Modifications ◽

E3 Ligases ◽

Physiological Conditions ◽

P Protein ◽

Heterotypic Interactions ◽

Enzymatic Machinery ◽

Substrate Proteins

Protein ubiquitylation is essential for the maintenance of cellular homeostasis. E3 ubiquitin ligases are key components of the enzymatic machinery catalyzing the attachment of ubiquitin to substrate proteins. Consequently, enzymatic dysfunction has been associated with medical conditions including cancer, diabetes, and cardiovascular and neurodegenerative disorders. To safeguard substrate selection and ubiquitylation, the activity of E3 ligases is tightly regulated by post-translational modifications including phosphorylation, sumoylation, and ubiquitylation, as well as binding of alternative adaptor molecules and cofactors. Recent structural studies identified homotypic and heterotypic interactions between E3 ligases, adding another layer of control for rapid adaptation to changing environmental and physiological conditions. Here, we discuss the regulation of E3 ligase activity by combinatorial oligomerization and summarize examples of associated ubiquitylation pathways and mechanisms.

Download Full-text