HECT E3 Ligases: A Tale With Multiple Facets

Weber, Janine; Polo, Simona; Maspero, Elena

doi:10.3389/fphys.2019.00370

Cited by 117 publications

(88 citation statements)

References 96 publications

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“…With new research and discoveries becoming available, there is mounting evidence that the lesser known HECT E3 ubiquitin ligases play critical roles in regulating intracellular processes and their dysfunction have been suggested to contribute to the onset of many diseases and disorders [4,[29][30][31][32]. Here we discuss the latest discoveries on these lesser known members of the HECT E3 ubiquitin ligases and on their emerging roles in developmental and neurological abnormalities, cancers, and embryogenesis.…”

Section: The "Other" Hect E3 Ubiquitin Ligases: Important Players Inmentioning

confidence: 97%

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Kane¹,

Spratt²

2020

Ubiquitin - Proteasome Pathway

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HECT E3 ubiquitin ligases selectively recognize, bind, and ubiquitylate their substrate proteins to target them for 26S proteasomal degradation. There is increasing evidence that HECT E3 ubiquitin ligase dysfunction due to misfolding and/or the gene encoding the protein being mutated is responsible for the development of different diseases. Apart from the more prominent and well-characterized E6AP and members of the NEDD4 family, new studies have begun to reveal how other members of the HECT E3 ubiquitin ligase family function as well as their links to disease and developmental disorders. This chapter provides a comprehensive discussion on the more mysterious members of the HECT E3 ubiquitin ligase family and how they control intracellular processes. Specifically, AREL1, HACE1, HECTD1, HECTD4, G2E3, and TRIP12 will be examined as these enzymes have recently been identified as contributors to disease development.2 covalently attach ubiquitin on to a lysine residue of the substrate protein forming a stable isopeptide bond between the C-terminus of ubiquitin and the ε-amine of the substrate lysine [3,5,6]. This process can be repeated numerous times to form different polyubiquitin chain linkages with the specific HECT E3 ubiquitin ligase dictating the type(s) of ubiquitin linkages that are built [2,7]. Chain typesLinker Proposed function Monoubiquitylation Monoubiquitylation/ multi-monoubiquitylation Endocytosis [9] DNA damage repair [10-15] Histone regulation [10-15] Mitophagy [10-15] Protein localization [10-15] Protein interactions [10-15] Protein transportation [10-15] Transcription activation [10-15] Polyubiquitylation Chain (homotypic) M1 Innate immunity [2, 9, 16] Linear chain formation [9] NF-κB activation [9, 16] Signaling cascades [9, 16] K6 DNA damage response [14] NF-κB regulation [14] Mitophagy [14] K11 Cell cycle regulation [17] DNA damage response [18] Mitophagy [17] NF-κB activation [16] Protein degradation [17] K27 DNA damage response [18] Kinase activation [19] Protein degradation [20] Protein scaffolding [21] Protein trafficking [22] K29 DNA damage response [18] Kinase activation [19] Protein degradation [9] K33 DNA damage response [10-15, 18] Kinase activation [23] Post-golgi trafficking [24] T-cell signaling [23] K4 8 Protein degradation [1, 2, 25] K63 DNA damage response [9, 18] NF-κB activation [9, 16] Protein trafficking [9] Chain (heterotypic; branched) M1 /K63 NF-κB activation [16] K11 /K4 8 Protein degradation [26, 27] K29/K48 Protein degradation [26] K48/K63 Protein degradation [26] K11 /K63 Endocytosis [28]

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Section: The "Other" Hect E3 Ubiquitin Ligases: Important Players Inmentioning

confidence: 97%

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Kane¹,

Spratt²

2020

Ubiquitin - Proteasome Pathway

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“…The human proteome encodes more than 600 E3 ligases that fall into three main groups: the really interesting new gene (RING) class comprising ∼600 members, the homologous to E6AP C terminus (HECT) class which includes at least 28 members and the RING between RING (RBR) class encompassing 14 members [59][60][61]. A detailed ubiquitin taxonomy, specifically, a precise mapping of the enzyme to substrate, is currently lacking, however, the sheer number of ligases points strongly a high degree of specificity.…”

Section: Targeting E3 Ligasesmentioning

confidence: 99%

Small molecules that target the ubiquitin system

Baker

Ovaa

2020

Biochemical Society Transactions

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Eukaryotic life depends upon the interplay between vast networks of signaling pathways composed of upwards of 109–1010 proteins per cell. The integrity and normal operation of the cell requires that these proteins act in a precise spatial and temporal manner. The ubiquitin system is absolutely central to this process and perturbation of its function contributes directly to the onset and progression of a wide variety of diseases, including cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infectious diseases, and muscle dystrophies. Whilst the individual components and the overall architecture of the ubiquitin system have been delineated in some detail, how ubiquitination might be successfully targeted, or harnessed, to develop novel therapeutic approaches to the treatment of disease, currently remains relatively poorly understood. In this review, we will provide an overview of the current status of selected small molecule ubiquitin system inhibitors. We will further discuss the unique challenges of targeting this ubiquitous and highly complex machinery, and explore and highlight potential ways in which these challenges might be met.

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“…The cullin-RING ligase (CRL) is a kind of multi-subunit RING E3 ligase that can be further divided into the S phase kinase associated protein 1 (SKP1)/cullin 1 (CUL1)/F-box protein complex (SCF), CUL2-elongin B/C-VHL or SOCS proteins (CRL2), CUL3-BTBs, CUL4-DDB1-DCAFs (CRL4), CUL5-elonginB/C-SOCS proteins, and the CUL7/F-box/WD repeat-containing 8 (FBXW8) subfamily of E3 ligases (20,21). HECTs, the second largest E3 ligase family in humans, comprises 28 members and can be categorized into three subfamilies: Neural precursor cell expressed developmentally downregulated protein (NEDD)4 family, HECT domain-containing protein (HERC) family and 'other' HECT ligases (22). Studies to date have suggested that only the NEDD4 family and a member of the Other HECT ligase families are related to GC.…”

Section: Classification Of E3 Ubiquitin Ligasesmentioning

confidence: 99%

Functional roles of E3 ubiquitin ligases in gastric cancer (Review)

Wang

Dai

et al. 2020

Oncol Lett

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To date, >650 E3 ubiquitin ligases have been described in humans, including >600 really interesting new genes (RINGs), 28 homologous to E6-associated protein C-terminus (HECTs) and several RING-in-between-RINGs. They are considered key regulators and therapeutic targets of many types of human cancers, including gastric cancer (GC). Among them, some RING and HECT E3 ligases are closely related to the proliferation, infiltration and prognosis of GC. During the past few years, abnormal expressions and functions of many E3 ligases have been identified in GC. However, the functional roles of E3 ligases in GC have not been fully elucidated. The present article focuses on the functional roles of E3 ligases related to the proteasome in GC. In this comprehensive review, the latest research progress on E3 ligases involved in GC and elaborate their structure, classification, functional roles and therapeutic value in GC was summarized. Finally, 30 E3 ligases that serve essential roles in regulating the development of GC were described. Some of these ligases may serve as oncogenes or tumor suppressors in GC, whereas the pathological mechanism of others needs further study; for example, constitutive photomorphogenic 1. In conclusion, the present review demonstrated that E3 ligases are crucial tumor regulatory factors and potential therapeutic targets in GC. Therefore, more studies should focus on the therapeutic targeting of E3 ligases in GC.

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HECT E3 Ligases: A Tale With Multiple Facets

Cited by 117 publications

References 96 publications

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

New Discoveries on the Roles of “Other” HECT E3 Ubiquitin Ligases in Disease Development

Small molecules that target the ubiquitin system

Functional roles of E3 ubiquitin ligases in gastric cancer (Review)

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