scholarly journals Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vincenza Simona Delvecchio ◽  
Claudia Fierro ◽  
Sara Giovannini ◽  
Gerry Melino ◽  
Francesca Bernassola
Keyword(s):  
Hematological Malignancies ◽  
Apoptotic Cell ◽  
Ubiquitin Ligases ◽  
Covalent Attachment ◽  
E3 Ubiquitin Ligases ◽  
Comprehensive Overview ◽  
Altered Expression ◽  
Hect Domain ◽  
Cellular Processes ◽  
Substrate Proteins

AbstractUbiquitination-mediated proteolysis or regulation of proteins, ultimately executed by E3 ubiquitin ligases, control a wide array of cellular processes, including transcription, cell cycle, autophagy and apoptotic cell death. HECT-type E3 ubiquitin ligases can be distinguished from other subfamilies of E3 ubiquitin ligases because they have a C-terminal HECT domain that directly catalyzes the covalent attachment of ubiquitin to their substrate proteins. Deregulation of HECT-type E3-mediated ubiquitination plays a prominent role in cancer development and chemoresistance. Several members of this subfamily are indeed frequently deregulated in human cancers as a result of genetic mutations and altered expression or activity. HECT-type E3s contribute to tumorigenesis by regulating the ubiquitination rate of substrates that function as either tumour suppressors or oncogenes. While the pathological roles of the HECT family members in solid tumors are quite well established, their contribution to the pathogenesis of hematological malignancies has only recently emerged. This review aims to provide a comprehensive overview of the involvement of the HECT-type E3s in leukemogenesis.

scholarly journals Targeting the Ubiquitin System in Glioblastoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Nico Scholz ◽  
Kathreena M. Kurian ◽  
Florian A. Siebzehnrubl ◽  
Julien D. F. Licchesi
Keyword(s):  
Drug Targets ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Primary Brain Tumor ◽  
E3 Ubiquitin Ligases ◽  
Deubiquitinating Enzymes ◽  
Comprehensive Overview ◽  
Ubiquitin System ◽  
Novel Therapeutic Strategies ◽  
Promising Source

Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.

scholarly journals 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 ◽  
2016 ◽  
Vol 11 (6) ◽  
pp. e0156718 ◽  
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

scholarly journals E3 ubiquitin ligase components in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Elena Faccenda ◽  
Robert Layfield
Keyword(s):  
Cell Cycle Progression ◽  
Protein Complexes ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Post Translational Modification ◽  
Protein Substrates ◽  
Cellular Processes ◽  
Ubiquitin Molecule ◽  
E2 Enzymes ◽  
Ubiquitin Conjugating Enzymes

Ubiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [19]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction. E3 ubiquitin ligases, of which there are >600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex.

scholarly journals Functional Significance of the E3 Ubiquitin Ligases in Disease and Therapeutics

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.

scholarly journals Post-translational regulation of ubiquitin signaling

2019 ◽  
Vol 218 (6) ◽  
pp. 1776-1786 ◽  
Author(s):  
Lei Song ◽  
Zhao-Qing Luo
Keyword(s):  
Translational Regulation ◽  
Covalent Attachment ◽  
Immune Disorders ◽  
Post Translational Modification ◽  
Polyubiquitin Chains ◽  
Cellular Processes ◽  
Lysine Residues ◽  
Substrate Proteins ◽  
Ubiquitination Machinery ◽  
Integrate Development

Ubiquitination regulates many essential cellular processes in eukaryotes. This post-translational modification (PTM) is typically achieved by E1, E2, and E3 enzymes that sequentially catalyze activation, conjugation, and ligation reactions, respectively, leading to covalent attachment of ubiquitin, usually to lysine residues of substrate proteins. Ubiquitin can also be successively linked to one of the seven lysine residues on ubiquitin to form distinctive forms of polyubiquitin chains, which, depending upon the lysine used and the length of the chains, dictate the fate of substrate proteins. Recent discoveries revealed that this ubiquitin code is further expanded by PTMs such as phosphorylation, acetylation, deamidation, and ADP-ribosylation, on ubiquitin, components of the ubiquitination machinery, or both. These PTMs provide additional regulatory nodes to integrate development or insulting signals with cellular homeostasis. Understanding the precise roles of these PTMs in the regulation of ubiquitin signaling will provide new insights into the mechanisms and treatment of various human diseases linked to ubiquitination, including neurodegenerative diseases, cancer, infection, and immune disorders.

scholarly journals Mechanisms, regulation and consequences of protein SUMOylation

2010 ◽  
Vol 428 (2) ◽  
pp. 133-145 ◽  
Author(s):  
Kevin A. Wilkinson ◽  
Jeremy M. Henley
Keyword(s):  
Protein Function ◽  
Covalent Attachment ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Wide Range ◽  
Lysine Residues ◽  
Ubiquitination Pathway ◽  
Regulate Protein ◽  
Substrate Proteins ◽  
Protein Sumoylation

The post-translational modification SUMOylation is a major regulator of protein function that plays an important role in a wide range of cellular processes. SUMOylation involves the covalent attachment of a member of the SUMO (small ubiquitin-like modifier) family of proteins to lysine residues in specific target proteins via an enzymatic cascade analogous to, but distinct from, the ubiquitination pathway. There are four SUMO paralogues and an increasing number of proteins are being identified as SUMO substrates. However, in many cases little is known about how SUMOylation of these targets is regulated. Compared with the ubiquitination pathway, relatively few components of the conjugation machinery have been described and the processes that specify individual SUMO paralogue conjugation to defined substrate proteins are an active area of research. In the present review, we briefly describe the SUMOylation pathway and present an overview of the recent findings that are beginning to identify some of the mechanisms that regulate protein SUMOylation.

scholarly journals Wrestling and Wrapping: A Perspective on SUMO Proteins in Schwann Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1055
Author(s):  
Iman F. Fergani ◽  
Luciana R. Frick
Keyword(s):  
Schwann Cells ◽  
Posttranslational Modifications ◽  
Cellular Localization ◽  
Covalent Attachment ◽  
Protein Protein Interaction ◽  
Cellular Processes ◽  
Schwann Cell Development ◽  
Demyelinating Neuropathies ◽  
Underlying Mechanisms ◽  
Substrate Proteins

Schwann cell development and peripheral nerve myelination are finely orchestrated multistep processes; some of the underlying mechanisms are well described and others remain unknown. Many posttranslational modifications (PTMs) like phosphorylation and ubiquitination have been reported to play a role during the normal development of the peripheral nervous system (PNS) and in demyelinating neuropathies. However, a relatively novel PTM, SUMOylation, has not been studied in these contexts. SUMOylation involves the covalent attachment of one or more small ubiquitin-like modifier (SUMO) proteins to a substrate, which affects the function, cellular localization, and further PTMs of the conjugated protein. SUMOylation also regulates other proteins indirectly by facilitating non-covalent protein–protein interaction via SUMO interaction motifs (SIM). This pathway has important consequences on diverse cellular processes, and dysregulation of this pathway has been reported in several diseases including neurological and degenerative conditions. In this article, we revise the scarce literature on SUMOylation in Schwann cells and the PNS, we propose putative substrate proteins, and we speculate on potential mechanisms underlying the possible involvement of this PTM in peripheral myelination and neuropathies.

scholarly journals The p97 cofactor Ubxn7 facilitates replisome disassembly during S-phase

2021 ◽  
Author(s):  
Zeynep Tarcan ◽  
Divyasree Poovathumkadavil ◽  
Aggeliki Skagia ◽  
Agnieszka Gambus
Keyword(s):  
Dna Replication ◽  
Molecular Mechanism ◽  
Protein Complexes ◽  
Ubiquitin Ligases ◽  
S Phase ◽  
E3 Ubiquitin Ligases ◽  
Replication Machinery ◽  
Replicative Helicase ◽  
Cellular Processes ◽  
Eukaryotic Dna

Complex cellular processes are driven by the regulated assembly and disassembly of large multi-protein complexes. In eukaryotic DNA replication, whilst we are beginning to understand the molecular mechanism for assembly of the replication machinery (replisome), we still know relatively little about the regulation of its disassembly at replication termination. Over recent years, the first elements of this process have emerged, revealing that the replicative helicase, at the heart of the replisome, is polyubiquitylated prior to unloading and that this unloading requires p97 segregase activity. Two different E3 ubiquitin ligases are now known to ubiquitylate the helicase under different conditions: Cul2Lrr1 and TRAIP. Here we have found two p97 cofactors, Ubxn7 and Faf1, which can interact with p97 during replisome disassembly in S-phase. Only Ubxn7 however facilitates efficient replisome disassembly through its interaction with both Cul2Lrr1 and p97. Our data therefore characterise Ubxn7 as the first substrate-specific p97 cofactor regulating replisome disassembly in vertebrates.

scholarly journals Regulation of E3 ubiquitin ligases by homotypic and heterotypic assembly

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 88 ◽  
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.

scholarly journals Control of the activity of WW‐HECT domain E3 ubiquitin ligases by NDFIP proteins

EMBO Reports ◽  
2009 ◽  
Vol 10 (5) ◽  
pp. 501-507 ◽  
Author(s):  
Thomas Mund ◽  
Hugh R B Pelham
Keyword(s):  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Hect Domain
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