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An Obligatory Role of Mind Bomb-1 in Notch Signaling of Mammalian Development  [PDF]
Bon-Kyoung Koo, Mi-Jeong Yoon, Ki-Jun Yoon, Sun-Kyoung Im, Yoon-Young Kim, Cheol-Hee Kim, Pann-Ghill Suh, Yuh Nung Jan, Young-Yun Kong
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0001221
Abstract: Background The Notch signaling pathway is an evolutionarily conserved intercellular signaling module essential for cell fate specification that requires endocytosis of Notch ligands. Structurally distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), cooperatively regulate the endocytosis of Notch ligands in Drosophila. However, the respective roles of the mammalian E3 ubiquitin ligases, Neur1, Neur2, Mib1, and Mib2, in mammalian development are poorly understood. Methodology/Principal Findings Through extensive use of mammalian genetics, here we show that Neur1 and Neur2 double mutants and Mib2?/? mice were viable and grossly normal. In contrast, conditional inactivation of Mib1 in various tissues revealed the representative Notch phenotypes: defects of arterial specification as deltalike4 mutants, abnormal cerebellum and skin development as jagged1 conditional mutants, and syndactylism as jagged2 mutants. Conclusions/Significance Our data provide the first evidence that Mib1 is essential for Jagged as well as Deltalike ligand-mediated Notch signaling in mammalian development, while Neur1, Neur2, and Mib2 are dispensable.
Ubiquitin-Mediated Regulation of Endocytosis by Proteins of the Arrestin Family
Michel Becuwe,Antonio Herrador,Rosine Haguenauer-Tsapis,Olivier Vincent,Sébastien Léon
Biochemistry Research International , 2012, DOI: 10.1155/2012/242764
Abstract: In metazoans, proteins of the arrestin family are key players of G-protein-coupled receptors (GPCRS) signaling and trafficking. Following stimulation, activated receptors are phosphorylated, thus allowing the binding of arrestins and hence an “arrest” of receptor signaling. Arrestins act by uncoupling receptors from G proteins and contribute to the recruitment of endocytic proteins, such as clathrin, to direct receptor trafficking into the endocytic pathway. Arrestins also serve as adaptor proteins by promoting the recruitment of ubiquitin ligases and participate in the agonist-induced ubiquitylation of receptors, known to have impact on their subcellular localization and stability. Recently, the arrestin family has expanded following the discovery of arrestin-related proteins in other eukaryotes such as yeasts or fungi. Surprisingly, most of these proteins are also involved in the ubiquitylation and endocytosis of plasma membrane proteins, thus suggesting that the role of arrestins as ubiquitin ligase adaptors is at the core of these proteins' functions. Importantly, arrestins are themselves ubiquitylated, and this modification is crucial for their function. In this paper, we discuss recent data on the intricate connections between arrestins and the ubiquitin pathway in the control of endocytosis.
Two Distinct E3 Ubiquitin Ligases Have Complementary Functions in the Regulation of Delta and Serrate Signaling in Drosophila  [PDF]
Roland Le Borgne,Sylvie Remaud,Sophie Hamel,Fran?ois Schweisguth
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0030096
Abstract: Signaling by the Notch ligands Delta (Dl) and Serrate (Ser) regulates a wide variety of essential cell-fate decisions during animal development. Two distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), have been shown to regulate Dl signaling in Drosophila melanogaster and Danio rerio, respectively. While the neur and mib genes are evolutionarily conserved, their respective roles in the context of a single organism have not yet been examined. We show here that the Drosophila mind bomb (D-mib) gene regulates a subset of Notch signaling events, including wing margin specification, leg segmentation, and vein determination, that are distinct from those events requiring neur activity. D-mib also modulates lateral inhibition, a neur- and Dl-dependent signaling event, suggesting that D-mib regulates Dl signaling. During wing development, expression of D-mib in dorsal cells appears to be necessary and sufficient for wing margin specification, indicating that D-mib also regulates Ser signaling. Moreover, the activity of the D-mib gene is required for the endocytosis of Ser in wing imaginal disc cells. Finally, ectopic expression of neur in D-mib mutant larvae rescues the wing D-mib phenotype, indicating that Neur can compensate for the lack of D-mib activity. We conclude that D-mib and Neur are two structurally distinct proteins that have similar molecular activities but distinct developmental functions in Drosophila.
Two Distinct E3 Ubiquitin Ligases Have Complementary Functions in the Regulation of Delta and Serrate Signaling in Drosophila
Le Borgne Roland,Remaud Sylvie,Hamel Sophie,Schweisguth Fran?ois
PLOS Biology , 2005, DOI: 10.1371/journal.pbio.0030096.20050521
Abstract: Signaling by the Notch ligands Delta (Dl) and Serrate (Ser) regulates a wide variety of essential cell-fate decisions during animal development. Two distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), have been shown to regulate Dl signaling in Drosophila melanogaster and Danio rerio, respectively. While the neur and mib genes are evolutionarily conserved, their respective roles in the context of a single organism have not yet been examined. We show here that the Drosophila mind bomb (D-mib) gene regulates a subset of Notch signaling events, including wing margin specification, leg segmentation, and vein determination, that are distinct from those events requiring neur activity. D-mib also modulates lateral inhibition, a neur- and Dl-dependent signaling event, suggesting that D-mib regulates Dl signaling. During wing development, expression of D-mib in dorsal cells appears to be necessary and sufficient for wing margin specification, indicating that D-mib also regulates Ser signaling. Moreover, the activity of the D-mib gene is required for the endocytosis of Ser in wing imaginal disc cells. Finally, ectopic expression of neur in D-mib mutant larvae rescues the wing D-mib phenotype, indicating that Neur can compensate for the lack of D-mib activity. We conclude that D-mib and Neur are two structurally distinct proteins that have similar molecular activities but distinct developmental functions in Drosophila.
Two Distinct E3 Ubiquitin Ligases Have Complementary Functions in the Regulation of Delta and Serrate Signaling in Drosophila  [PDF]
Roland Le Borgne,Sylvie Remaud,Sophie Hamel,Fran?ois Schweisguth
PLOS Biology , 2005, DOI: 10.1371/journal.pbio.0030096
Abstract: Signaling by the Notch ligands Delta (Dl) and Serrate (Ser) regulates a wide variety of essential cell-fate decisions during animal development. Two distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), have been shown to regulate Dl signaling in Drosophila melanogaster and Danio rerio, respectively. While the neur and mib genes are evolutionarily conserved, their respective roles in the context of a single organism have not yet been examined. We show here that the Drosophila mind bomb (D-mib) gene regulates a subset of Notch signaling events, including wing margin specification, leg segmentation, and vein determination, that are distinct from those events requiring neur activity. D-mib also modulates lateral inhibition, a neur- and Dl-dependent signaling event, suggesting that D-mib regulates Dl signaling. During wing development, expression of D-mib in dorsal cells appears to be necessary and sufficient for wing margin specification, indicating that D-mib also regulates Ser signaling. Moreover, the activity of the D-mib gene is required for the endocytosis of Ser in wing imaginal disc cells. Finally, ectopic expression of neur in D-mib mutant larvae rescues the wing D-mib phenotype, indicating that Neur can compensate for the lack of D-mib activity. We conclude that D-mib and Neur are two structurally distinct proteins that have similar molecular activities but distinct developmental functions in Drosophila.
What Has the Study of the K3 and K5 Viral Ubiquitin E3 Ligases Taught Us about Ubiquitin-Mediated Receptor Regulation?  [PDF]
Jessica M. Boname,Paul J. Lehner
Viruses , 2011, DOI: 10.3390/v3020118
Abstract: Cells communicate with each other and the outside world through surface receptors, which need to be tightly regulated to prevent both overstimulation and receptor desensitization. Understanding the processes involved in the homeostatic control of cell surface receptors is essential, but we are not alone in trying to regulate these receptors. Viruses, as the ultimate host pathogens, have co-evolved over millions of years and have both pirated and adapted host genes to enable viral pathogenesis. K3 and K5 (also known as MIR1 and MIR2) are viral ubiquitin E3 ligases from Kaposi’s Sarcoma Associated Herpesvirus (KSHV) which decrease expression of a number of cell surface receptors and have been used to interrogate cellular processes and improve our understanding of ubiquitin-mediated receptor endocytosis and degradation. In this review, we summarize what has been learned from the study of these viral genes and emphasize their role in elucidating the complexity of ubiquitin in receptor regulation.
Possible role of death receptor-mediated apoptosis by the E3 ubiquitin ligases Siah2 and POSH
Perry A Christian, Michael V Fiandalo, Steven R Schwarze
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-57
Abstract: Data from the high-throughput screen revealed that targeting the RING-finger containing E3 ligase Siah2 as well as the signaling platform molecule POSH (SH3RF1) conferred robust caspase-8 activation in response to TRAIL stimulus. Silencing Siah2 or POSH in prostate cancer cells led to increased caspase activity and apoptosis in response to both TRAIL and Fas ligand. The E3 activity of Siah2 was responsible for mediating apoptosis resistance; while POSH protein levels were critical for maintaining viability. Further characterization of Siah2 revealed it to function downstream of early death receptor events in the apoptotic pathway. The observed apoptosis resistance provides one biological explanation for the induction of Siah2 and POSH reported in lung and prostate cancer, respectively. Expanding on an initial yeast-two-hybrid screen we have confirmed a physical interaction between E3 ligases Siah2 and POSH. Utilizing a yeast-two-hybrid mapping approach we have defined the spacer region of POSH, more specifically the RPxAxVxP motif encompassing amino acids 601-607, to be the site of Siah2 binding.The data presented here define POSH and Siah2 as important mediators of death receptor mediated apoptosis and suggest targeting the interaction of these two E3 ligases is a promising novel cancer therapeutic strategy.Tight regulation of apoptosis is essential for maintaining tissue homeostasis. Altering this balance in favor of apoptosis resistance is a common feature in cancer cells [1], and overcoming cell death barriers is a primary goal of many chemotherapeutic treatments used in the clinic today. One proven strategy to induce apoptosis is through blocking components of the ubiquitin proteasome system (UPS).The ubiquitin proteasome system is the major cellular pathway for regulated protein turnover. Ubiquitination and protein degradation allows the cell to respond quickly to extra- or intracellular signals, thereby maintaining cellular homeostasis. The addition of multip
Animal HECT ubiquitin ligases: evolution and functional implications
Ignacio Marín
BMC Evolutionary Biology , 2010, DOI: 10.1186/1471-2148-10-56
Abstract: I show that the current classification of HECT E3s into three groups (NEDD4-like E3s, HERCs and single-HECT E3s) is fundamentally incorrect. First, the existence of a "Single-HECT E3s" group is not supported by phylogenetic analyses. Second, the HERC proteins must be divided into two subfamilies (Large HERCs, Small HERCs) that are evolutionarily very distant, their structural similarity being due to convergence and not to a common origin. Sequence and structural analyses show that animal HECT E3s can be naturally classified into 16 subfamilies. Almost all of them appeared either before animals originated or in early animal evolution. More recently, multiple gene losses have occurred independently in some lineages (nematodes, insects, urochordates), the same groups that have also lost genes of another type of E3s (RBR family). Interestingly, the emergence of some animal HECT E3s precedes the origin of key cellular systems that they regulate (TGF-β and EGF signal transduction pathways; p53 family of transcription factors) and it can be deduced that distantly related HECT proteins have been independently co-opted to perform similar roles. This may contribute to explain why distantly related HECT E3s are involved in the genesis of multiple types of cancer.The complex evolutionary history of HECT ubiquitin ligases in animals has been deciphered. The most appropriate model animals to study them and new theoretical and experimental lines of research are suggested by these results.Ubiquitination is a critical process in all eukaryotic organisms. It is involved in multiple essential functions, from its best-known role in the regulation of protein levels to additional, precise roles in endocytosis, cellular signaling, DNA repair or the regulation of gene expression [1-3]. Ubiquitin ligases (E3s), a numerous and highly diverse group of enzymes able to transfer ubiquitin to target proteins, are fundamental components of the ubiquitination system [3]. E3 enzymes can be classifie
Genome-Wide and Functional Annotation of Human E3 Ubiquitin Ligases Identifies MULAN, a Mitochondrial E3 that Regulates the Organelle's Dynamics and Signaling  [PDF]
Wei Li, Mario H. Bengtson, Axel Ulbrich, Akio Matsuda, Venkateshwar A. Reddy, Anthony Orth, Sumit K. Chanda, Serge Batalov, Claudio A. P. Joazeiro
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001487
Abstract: Specificity of protein ubiquitylation is conferred by E3 ubiquitin (Ub) ligases. We have annotated ~617 putative E3s and substrate-recognition subunits of E3 complexes encoded in the human genome. The limited knowledge of the function of members of the large E3 superfamily prompted us to generate genome-wide E3 cDNA and RNAi expression libraries designed for functional screening. An imaging-based screen using these libraries to identify E3s that regulate mitochondrial dynamics uncovered MULAN/FLJ12875, a RING finger protein whose ectopic expression and knockdown both interfered with mitochondrial trafficking and morphology. We found that MULAN is a mitochondrial protein – two transmembrane domains mediate its localization to the organelle's outer membrane. MULAN is oriented such that its E3-active, C-terminal RING finger is exposed to the cytosol, where it has access to other components of the Ub system. Both an intact RING finger and the correct subcellular localization were required for regulation of mitochondrial dynamics, suggesting that MULAN's downstream effectors are proteins that are either integral to, or associated with, mitochondria and that become modified with Ub. Interestingly, MULAN had previously been identified as an activator of NF-κB, thus providing a link between mitochondrial dynamics and mitochondria-to-nucleus signaling. These findings suggest the existence of a new, Ub-mediated mechanism responsible for integration of mitochondria into the cellular environment.
Ubiquitin ligases and beyond
Ivan Dikic, Miranda Robertson
BMC Biology , 2012, DOI: 10.1186/1741-7007-10-22
Abstract: Pickart's article marked the expansion of ubiquitination from what most regarded as a niche preoccupation, with implications only for housekeeping protein turnover and the destruction of damaged ribosomal products, to seize the attention and excite the imagination of researchers in every area of cell biology. Comparisons to phosphorylation are rife - specific ubiquitin ligases promote ubiquitination and deubiquitinating enzymes terminate its effects of ubiquitination just as ubiquitination just as kinases and phosphatases induce and terminate the effects of phosphorylation - though ubiquitination, unlike phosphorylation, can operate irreversibly, by delivering its targets to the proteasome: hence its vital role in the progression of the cell cycle.It was already clear in 2004 that the number of ubiquitinating and deubiquitinating enzymes was very large, and that ubiquitin tags can be attached to proteins either as monomers or as poly-ubiquitin chains. But it had only recently been discovered that there are at least seven different kinds of poly-ubiquitin chains, and how the diversity of poly-ubiquitin signals is generated and interpreted in cells was in large part territory still to be explored.In a series of articles the first three of which are published this month, we review what is now known about some of the central issues in research on ubiquitination, revisiting the questions of how ubiquitin signals are conjugated to and removed from specific targets, and how they are recognized and contribute to the regulation of central processes in cells.Ubiquitin is a protein of 76 amino acids whose structure is shown in Figure 1. It is attached to a lysine in its target proteins either as a monomer or as a poly-ubiquitin chain each monomer of which is linked through its carboxy-terminal glycine to (usually) a lysine in the preceding ubiquitin in the chain. Three enzymes, known generically as E1, E2 and E3, act in series to catalyze ubiquitination (Figure 2). The E1 is t
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