ABSTRACT: INTRODUCTION: The seven in absentia homolog 2 (SIAH2) protein plays a significant role in the hypoxic response by regulating the abundance of hypoxia-inducible factor-alpha; however, its role in breast carcinoma is unclear. We investigated the frequency and expression pattern of SIAH2 in two independent cohorts of sporadic breast cancers. METHODS: Immunohistochemical evaluation of SIAH2protein expression was conducted in normal breast tissues and in tissue microarrays comprising ductal carcinoma in situ (DCIS) and a cohort of invasive breast carcinomas. Correlation analysis was performed between SIAH2 and clinicopathological variables and intrinsic breast cancer subgroups and validated in a cohort of 293 invasive ductal carcinomas. Promoter methylation, gene copy number and mRNA expression of SIAH2 were determined in a panel of basal-like tumors and cell lines. RESULTS: There was a significant increase in nuclear SIAH2 expression from normal breast tissues through to DCIS and progression to
The N-end rule pathway is a proteolytic system where its recognition components (N-recognins) recognize destabilizing N-terminal residues of short-lived proteins as an important part of specific degrons called N-degrons. like a scaffold E3 that promotes HR6B/UbcH2-reliant ubiquitylation of H2A and H2B however not H3 and H4 via a system distinct from normal polyubiquitylation. The E3 activity of UBR2 in histone ubiquitylation is activated by dipeptides bearing destabilizing N-terminal residues allosterically. Insufficient monoubiquitylation and polyubiquitylation on UBR2-lacking meiotic chromosomes correlate to problems in dual strand break (DSB) restoration along with other meiotic procedures leading to pachytene arrest at stage IV and apoptosis. A few of these features of UBR2 are found in somatic cells where UBR2 is really a chromatin-binding proteins involved in chromatin-associated ubiquitylation upon DNA damage. UBR2-deficient somatic cells show an array of chromosomal abnormalities ...
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Specifically ubiquitinates Lys-63 in target proteins (By similarity). Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Involved in ubiquitination of ERBB4 intracellular domain E4ICD1 (PubMed:19193720). Predominantly involved in ubiquitination of membrane bound forms of ERBB4 rather than processed precursors and intermediate membrane-anchored 80 kDa fragments (m80HER4), with a lesser role in ubiquitination of ERBB4 intracellular domain E4ICD1 (PubMed:19047365). Promotes ubiquitination of RAPGEF2. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Part of a signaling complex composed of NEDD4, RAP2A and TNIK
The mechanisms underlying neuron death in Parkinsons disease are unknown, but both genetic defects and environmental factors are implicated in its pathogenesis. Mutations in the parkin gene lead to autosomal recessive juvenile Parkinsonism (AR-JP). Here we report that compared to control flies, Drosophila lacking parkin show significantly reduced lifespan but no difference in dopamine neuron numbers when raised on food supplemented with environmental pesticides or mitochondrial toxins. Moreover, chelation of redox-active metals, anti-oxidants and overexpression of superoxide dismutase 1 all significantly reversed the reduced longevity of parkin-deficient flies. Finally, parkin deficiency exacerbated the rough eye phenotype of Drosophila caused by overexpression of the copper importer B (Ctr1B). Taken together, our results demonstrate an important function of parkin in the protection against redox-active metals and pesticides implicated in the etiology of Parkinsons disease. They also ...
SMAD ubiquitination regulatory element 1 (Smurf1) is a Nedd4 family E3 ubiquitin ligase that regulates cell motility, polarity and TGF signaling. and reveals a book discussion for non-calcium-dependent C2 membrane and domains lipids. BL21-DE3 cells and purified utilizing a regular His6-label purification protocol based on the producers guidelines (Qiagen, Hilden, Germany). Proteins manifestation was induced with 0.15 M IPTG at 25 C overnight when the cells reached an optical density at 600 nm (OD600) of 0.6C0.8. The cells were lysed with 0 then.5 mg/mL lysozyme, vortexed and briefly sonicated in 50 mM NaH2PO4 (pH 8.0) containing 300 mM NaCl and 1 mM PMSF. The lysate was handed through 0.8 m and 0.45 m filters and incubated with Ni-NTA resin R428 cell signaling (Qiagen) for 1 h at 4 C on the rocking platform. Beads had been after that packed onto a column and cleaned with 10 column quantities of 10, 20, and 25 mM imidazole in lysis buffer. The proteins was eluted using 50 mM NaH2PO4 (pH 8.0) ...
The SIAH1 gene encodes a RING-type E3 ubiquitin ligase belonging to the Seven in Absentia Homolog (SIAH) family. The enzyme carries out the ubiquitination of a wide variety of targets, either by direct binding or by acting as the essential RING domain subunit for larger E3 ubiquitin ligase complexes. By carrying out its function, the protein marks its targets for proteasomal degradation. Target substrates of SIAH1 include transcription regulators such as ELL2, MYB, POU2AF1, PML and RBBP8, the signal transduction molecules TIEG1 and NUMB, the cell surface receptor DCC and the anti-aopoptotic protein BAG1. It also ubiquitinates SYP, a protein involved in synaptic vesicle function in neurons. The protein is thus involved in the regulation of several key biological processes such as apoptosis, axon guidance, cell cycle, spermatogenesis and nervous system development. ...
UBR5 (ubiquitin protein ligase E3 component n-recognin 5), Authors: Dessen P. Published in: Atlas Genet Cytogenet Oncol Haematol.
SIAH1 antibody for detecting human E3 ubiquitin-protein ligase SIAH1. Validated on up to 12 cell lysates for western blotting. Try a trial size today.
Loss-of-function mutations of the parkin gene are a major cause of early-onset parkinsonism. To explore the mechanism by which loss of parkin function results in neurodegeneration, we are using a genetic approach in Drosophila. Here, we show that Drosophila parkin mutants display degeneration of a subset of dopaminergic (DA) neurons in the brain. The neurodegenerative phenotype of parkin mutants is enhanced by loss-of-function mutations of the glutathione S-transferase S1 (GstS1) gene, which were identified in an unbiased genetic screen for genes that modify parkin phenotypes. Furthermore, overexpression of GstS1 in DA neurons suppresses neurodegeneration in parkin mutants. Given the previous evidence for altered glutathione metabolism and oxidative stress in sporadic Parkinsons disease (PD), these data suggest that the mechanism of DA neuron loss in Drosophila parkin mutants is similar to the mechanisms underlying sporadic PD. Moreover, these findings identify a potential therapeutic approach ...
Parkin is encoded by the PARK2 gene in humans; its precise function is unknown. However, it is known to be part of a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. The ubiquitin-tagged proteins are then degraded by ubiquitin-proteasome complexes. Mutations in the PARK2 gene are associated with familial and autosomal recessive juvenile forms of Parkinson disease. It has been suggested that loss of function of the parkin protein leads to dopaminergic cell death, but the mechanism is not clear. Parkin is also known as Parkinson protein 2, E3 ubiquitin protein ligase; Parkinson disease (autosomal recessive, juvenile) 2, parkin; E3 ubiquitin-protein ligase parkin, Parkinson disease protein 2, PDJ, PRKN, AR-JP, and LPRS2.. ...
Parkin is encoded by the PARK2 gene in humans; its precise function is unknown. However, it is known to be part of a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. The ubiquitin-tagged proteins are then degraded by ubiquitin-proteasome complexes. Mutations in the PARK2 gene are associated with familial and autosomal recessive juvenile forms of Parkinson disease. It has been suggested that loss of function of the parkin protein leads to dopaminergic cell death, but the mechanism is not clear. Parkin is also known as Parkinson protein 2, E3 ubiquitin protein ligase; Parkinson disease (autosomal recessive, juvenile) 2, parkin; E3 ubiquitin-protein ligase parkin, Parkinson disease protein 2, PDJ, PRKN, AR-JP, and LPRS2.. ...
Attempts to target mutant KRAS have been unsuccessful. Most of the current therapeutic approaches are indirect, mainly via inhibiting KRAS down-stream signaling, which have been marginally successful. Here we report the identification of Smad ubiquitination regulatory factor 2 (SMURF2), a HECT-type ubiquitin ligase (E3) as a critical regulator of mutant KRAS protein stability. We show that the loss of SMURF2 either by si-/sh-RNA mediated gene silencing or by overexpression of a catalytically inactive SMURF2 Cys716Ala (CA) mutant, can cause lysosome-mediated KRAS degradation; whereas, overexpression of wild type SMURF2 enhances KRAS protein stability. Most importantly, we found that mutant KRAS protein is more susceptible to SMURF2 alterations in that mutant protein half-life decreased from ,12h in control siRNA-treated cells to ,3h with Smurf2 siRNA treatment, whereas only marginal differences were noted for wild-type KRAS protein upon similar treatments. Importantly, this loss of mutant KRAS ...
Parkinsons disease (PD) is a neurodegenerative disorder with severe motor and non-motor symptoms. Mutations on several genes associated with various structural and functional components of neurons cause loss of neurons which results in PD. However, two genes PARK2 and PARK6 are found most frequently mutated causing more than 50% of the familial form of the disease. PARK2 gene encodes an E3 ubiquitin ligase Parkin, and PARK6 encodes PTEN-induced Kinase 1 (PINK1). Parkin is an auto-inhibited enzyme mediated by its ubiquitin like (UBL) domain. During stress condition, PINK1 is stabilised on mitochondria and phosphorylates Ser65 on UBL domain of Parkin and ubiquitin. Phosphorylation of Parkin and ubiquitin results in fully active Parkin which clears the damaged mitochondria, however, underlying molecular mechanism of PINK1 and Parkin signalling is poorly understood. I have determined human Parkin structures in both in-active state (apo-Parkin) & active state (phospho-mimic Parkin & in complex with ...
Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. BCR complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the BCR complex depends on the BTB domain-containing protein as the substrate recognition component. BCR(KLHL42) is involved in ubiquitination of KATNA1. BCR(SPOP) is involved in ubiquitination of BMI1/PCGF4, BRMS1, H2AFY and DAXX, GLI2 and GLI3. Can also form a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing
Protein target information for Chain A, E3 ubiquitin-protein ligase UBR2 (human). Find diseases associated with this biological target and compounds tested against it in bioassay experiments.
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E3 ubiquitin ligases have a significant role in carcinogenesis and include a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome. ubiquitin ligases for GC are discussed IPI-493 in the review. (a very interesting new gene) fingers IPI-493 and U-box domains[21]. There are about 30 proteins containing the HECT domain. The fingers and U-box quitin ligases contain the new gene (finger domain but only a small part functions as an E3 ubiquitin ligase. Unlike RING proteins most HECT proteins if not all are believed to function as E3 ubiquitin ligases. RING and HECT E3 ubiquitin ligases use different catalytic mechanisms to promote the transfer of ubiquitin to targeted substrates. RING E3 ubiquitin ligases can promote the direct transfer of ubiquitin from E2 to the targeted substrate whereas HECT E3 ubiquitin ligases interact with the cognate E2 followed by the formation of a thiolester linkage with ubiquitin and subsequent ...
The PARK2 gene encodes the Parkin protein. It is one of three genes that protect from young-onset Parkinson disease (PD); in Parkins absence, symptoms and signs usually begin before the age of forty. Despite the genes discovery in 1998 by Kitada et al., few Parkin-specific antibodies exist. The antibodies available do not readily detect specific, modified forms of Parkin and higher-order variants that are found in the human brain. The lack of variant-specific tools has limited progress and understanding of Parkins functions in the human brain in both healthy and diseased states.. Hypothesis: ...
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. It probably triggers the ubiquitin-mediated degradation of different substrates.
The parkin gene, PARK2, contains 12 exons and 1.5 Mb [2]. PARK2 is located on a region of chromosome 6 that is known to be fragile and unstable; making it prone to mutations and deletions [1]. Genetically acquiring a mutation in PARK2 can lead to developing early onset autosomal recessive Parkinsons Disease (PD). The protein is an E3 ubiquitin ligase, which functions as a component of the ubiquitin proteasome degradation system. It consists of 465 amino acids, an ubiquitin-like domain, and two RING finger domains [1]. Ubiquitination (and polyubiquitination) marks proteins to be degraded by the proteasome. Mutations of parkin can result in the loss of this function and endanger the cell. Studies have shown that improper protein degradation can cause a build-up of parkin substrates and neuronal death of the cells producing dopamine. Mitochondrion function and integrity is also upheld by the parkin protein, but the link between parkin, mitochondria, and PD is still being investigated [4]. Overall, ...
Read Overexpression of OsRDCP1 , a rice RING domain-containing E3 ubiquitin ligase, increased tolerance to drought stress in rice ( Oryza sativa L.), Plant Science on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
The familial form of Parkinsons disease (PD) is linked to mutations in specific genes. The mutations in parkin are one of the most common causes of early-onset PD. Mitochondrial dysfunction is an emerging active player in the pathology of neurodegenerative diseases, because mitochondria are highly dynamic structures integrated with many cellular functions. Herein, we overview and discuss the role of the parkin protein product, Parkin E3 ubiquitin ligase, in the cellular processes related to mitochondrial function, and how parkin mutations can result in pathology in vitro and in vivo.
Nedd4-family E3 ubiquitin ligases regulate signaling in intracellular pathways that control cancer, blood pressure, iron metabolism, and inflammation. These E3 ligases are catalytically active, and share a highly conserved, modular architecture. How Nedd4 family members are differentially regulated, despite their high degree of homology, is unclear. A regulatory mechanism that maintains an inactive state, common to Nedd4 family members, is autoinhibition. The majority of Nedd4 family members are autoinhibited by an intramolecular interaction between the N terminal C2 domain and the HECT domain. One subfamily of Nedd4 family members that includes the E3 ligase Itch does not appear to be regulated by a C2 domain interaction. The molecular mechanism regulating activation of these E3 ligases is unclear. Here I present findings that illustrate a novel intramolecular interaction regulating Itch and related Nedd4 family member activation that distinguish these E3s as functionally distinct from other Nedd4
SIAH2 (seven in absentia homolog 2 (Drosophila)), Authors: Jianfei Qi, Zeev Ronai. Published in: Atlas Genet Cytogenet Oncol Haematol.
Here, we show that cardiomyocyte Parkin is essential to mitochondrial and cardiac hemostasis in Drosophila. This warrants re-evaluation of the notion, derived from absence of a basal cardiac phenotype in parkin null mice,16 that Parkin is dispensable to normal heart function. By interrogating genetic epistasis between Drosophila Parkin and mitofusin (MARF), we uncover a completely new mechanism for end-organ dysfunction produced by Parkin insufficiency: ongoing mitochondrial fusion contributes to mitochondrial contagion when Parkin signaling (and presumably Parkin-dependent mitophagic elimination of abnormal organelles) is impaired. These findings suggest that general mitochondrial health and end-organ function could be preserved in mitophagically impaired tissues through chronic suppression of fusion-induced mitochondrial contamination.. The PINK1-Parkin interaction is central to mitophagic quality control in most tissues, but published studies provide an inconsistent picture of the role of ...
The most common mode of healthcare delivery is through personal, face-to-face contact between a healthcare provider and a beneficiary (patient). There is, however, an increasing trend towards the provision of healthcare in the absence of personal contact. This limit of contact during patient care is known as in absentia health care. In Absentia healthcare, or distance medicine, occurs when the patient and care giver are at different locations, but still communicate by audio and video, or sometimes without any personal contact. A face-to-face contact is often a necessary prelude to rendering health care. This, however, may not be necessary for care; in fact current technologies permit with no prior or concurrent contact.[1][2] Some people argue that this type of in absentia medical care may derail the traditional sequences of examination, diagnosis and treatment, and that such a detour may challenge existing values of modern medicine. In absentia care assumes heightened relevance today because ...
Mutations in the parkin gene, which encodes a ubiquitin ligase, has been implicated as one of causative factor for genetic parkinsonism. Interestingly, parkin role has also been implicated in cancer as a putative tumor suppressor with the gene been frequently targeted by deletion and inactivation in several human malignant tumors. Here, we demonstrated a potential tumor suppressor role for parkin in gliomas. We found that parkin expression was dramatically reduced in glioma cells and that the restoration of parkin expression promoted G1 phase cell-cycle arrest and mitigated the proliferation rate of glioma cells in vitro and in vivo. Furthermore, parkin-expressing glioma cells showed a reduction in levels of cyclin D1, but not cyclin E, and a selective downregulation of Akt serine-473 phosphorylation and VEGF receptor levels. In accordance, cells derived from a parkin-null mouse model exhibited increased levels of cyclin D1, VEGF receptor, and Akt phosphorylation, and divided significantly ...
E3 ubiquitin-protein ligase which binds polysumoylated chains covalently attached to proteins and mediates Lys-6-, Lys-11-, Lys-48- and Lys-63-linked polyubiquitination of those substrates and their subsequent targeting to the proteasome for degradation. Regulates the degradation of several proteins including PML and the transcriptional activator PEA3. Involved in chromosome alignment and spindle assembly, it regulates the kinetochore CENPH-CENPI-CENPK complex by targeting polysumoylated CENPI to proteasomal degradation. Regulates the cellular responses to hypoxia and heat shock through degradation of respectively EPAS1 and PARP1. Alternatively, it may also bind DNA/nucleosomes and have a more direct role in the regulation of transcription for instance enhancing basal transcription and steroid receptor-mediated transcriptional activation ...
The E3 Ubiquitin-protein Ligases Are Associated To Various Processes Such As Cell Cycle Control And Diverse Developmental Pathways. Arabidopsis Thaliana SEVEN IN ABSENTIA Like 7, Which Has Ubiquitin Ligase Activity, Is Located In The Nucleus And Cytosol
Heart failure is a major complication of cardiovascular disease that frequently involves initial cardiac hypertrophy that provides transient compensation for decreased heart function. Eventually, decompensation leads to compromised cardiac structure and progression into heart failure. Investigation of the downstream effector pathways for these growth factors has identified molecules involved in the progression of cardiac hypertrophy and heart failure, including phosphoinositide 3-kinase (PI3K) and Akt (Protein Kinase B). MG53, a tripartite motif (TRIM) protein family member designated as TRIM72, is highly expressed in skeletal and cardiac muscle and is known to have cardioprotective effects through modulation of PI3K signaling mechanisms. It is essential for the activation of PI3K-mediated intracellular signaling in cardiomyocytes and TRIM72 overexpression is sufficient to induce PI3K signaling. As TRIM72 regulates PI3K signaling it may play a role in regulation of heart failure, which is ...
TY - JOUR. T1 - Post-translational regulation of FLC is mediated by an E3 ubiquitin ligase activity of SINAT5 in Arabidopsis. AU - Park, Bong Soo. AU - Sang, Wan Gyu. AU - Yeu, Song Yion. AU - Choi, Yang Do. AU - Paek, Nam Chon. AU - Kim, Min Chul. AU - Song, Jong Tae. AU - Seo, Hak Soo. PY - 2007/8/1. Y1 - 2007/8/1. N2 - Suppression of Flowering Locus C (FLC) is critical for the transition from the vegetative to reproductive phase in Arabidopsis. FLC represses the expression of several genes involved in floral induction and its transcription is positively or negatively regulated by FRIGIDA or by vernalization, respectively. However, the regulatory mechanisms for the level and stability of FLC protein throughout development are unknown. Here, we show that SINAT5 colocalizes with FLC in the nuclear bodies and that its zinc finger motif interacts directly with the MADS-box domain of FLC. In addition, it is shown that SINAT5 has an E3 ubiquitin ligase activity towards FLC as a substrate, suggesting ...
The TRIM37 (also known as MUL) gene is located in the 17q23 chromosomal region, which is amplified in up to approximately 40% of breast cancers. TRIM37 contains a RING finger domain, a hallmark of E3 ubiquitin ligases, but its protein substrate(s) is unknown. Here we report that TRIM37 mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. We find that in human breast cancer cell lines containing amplified 17q23, TRIM37 is upregulated and, reciprocally, the major H2A ubiquitin ligase RNF2 (also known as RING1B) is downregulated. Genome-wide chromatin immunoprecipitation (ChIP)-chip experiments in 17q23-amplified breast cancer cells identified many genes, including multiple tumour suppressors, whose promoters were bound by TRIM37 and enriched for ubiquitinated H2A. However, unlike RNF2, which is a subunit of polycomb repressive complex 1 (PRC1), we find that TRIM37 associates with polycomb repressive complex 2 (PRC2). TRIM37, PRC2 and PRC1 are co-bound to
The IBR (In Between Ring fingers) domain is often found to occur between pairs of ring fingers. This domain has also been called the C6HC domain and DRIL (for double RING finger linked) domain [ (PUBMED:10422847) ]. Proteins that contain two Ring fingers and an IBR domain (these proteins are also termed RBR family proteins) are thought to exist in all eukaryotic organisms. RBR family members play roles in protein quality control and can indirectly regulate transcription [ (PUBMED:15152079) ]. Evidence suggests that RBR proteins are often parts of cullin-containing ubiquitin ligase complexes. The ubiquitin ligase Parkin is an RBR family protein whose mutations are involved in forms of familial Parkinsons disease [ (PUBMED:15152079) ]. IBR domain is a cysteine-rich (C6HC) zinc finger domain that is present in Triad1, and which is conserved in other proteins encoded by various eukaryotes. The C6HC consensus pattern is:. ...
Exit from mitosis requires the degradation of regulatory proteins including the mitotic cyclins and securin through ubiquitination by the anaphase promoting complex bound to Cdc20 or Cdh1. Cdc20-APC is regulated through inhibition by the spindle assembly checkpoint protein MAD2. Knowledge of Cdh1-APC regulation is limited to the phosphorylation-dependent dissociation of Cdh1 from APC. A novel means of regulating Cdh1 by the MAD2-related gene, MAD2L2, is reported. MAD2L2 specifically binds and inhibits Cdh1-APC, paralleling the effect of MAD2 on Cdc20. It is suggested that MAD2L2 and MAD2 inhibit the release of substrates from APC and a mechanism of inhibition is proposed (Pfleger, 2001a). The specificity of ubiquitin-mediated protein degradation with regard to the selection of substrates to be polyubiquitinated has only been determined rather recently. Substrate targeting by the N-end rule and HECT (homology to E6AP carboxyl terminus) domain ubiquitin ligases occurs through substrate-specific ...
Ndfip1 is an adaptor for the E3 ubiquitin ligase Itch. Both Ndfip1- and Itch-deficient T cells are biased toward Th2 cytokine production. In this study, we demonstrate that lungs from Ndfip1−/− mice showed increased numbers of neutrophils and Th17 cells. This was not because Ndfip1−/− T cells are biased toward Th17 differentiation. In fact, fewer Ndfip1−/− T cells differentiated into Th17 cells in vitro due to high IL-4 production. Rather, Th17 differentiation was increased in Ndfip1−/− mice due to increased numbers of IL-6-producing eosinophils. IL-6 levels in mice that lacked both Ndfip1 and IL-4 were similar to wild-type controls, and these mice had fewer Th17 cells in their lungs. These results indicate that Th2 inflammation, such as that observed in Ndfip1−/− mice, can increase Th17 differentiation by recruiting IL-6-producing eosinophils into secondary lymphoid organs and tissues. This may explain why Th17 cells develop within an ongoing Th2 inflammatory response. ...
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Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also ...
Translation is important in the regulation of gene expression and is implicated in the control of cell growth, proliferation, and differentiation (32-34). In eukaryotes, initiation is the rate-limiting step of translation under most circumstances, and initiation is a major target for regulation (33). Paip1 is a mammalian PABP that binds to eIF4A and eIF3 and stimulates translational initiation. In the present study, we showed that the Paip1 protein was degraded by the HECT ubiquitin ligase WWP2. The following findings from the present study directly support the use of Paip1 as a physiological substrate of WWP2. WWP2 directly interacted with Paip1, and the interaction depended on the integrity of the WW domain of WWP2. The loss of WWP2 impeded Paip1 turnover. WWP2 promoted Paip1 ubiquitination both in vivo and in a reconstituted in vitro system. The ubiquitin ligase activity of WWP2 and the PXXY motif of Paip1 were critical for ubiquitination and degradation. Previous studies have demonstrated ...
E3 Ubiquitin-Protein Ligase XIAP (Baculoviral IAP Repeat-Containing Protein 4 or IAP-Like Protein or X-Linked Inhibitor Of Apoptosis Protein or XIAP or EC
TY - JOUR. T1 - Muscle RING finger-1 promotes a maladaptive phenotype in chronic hypoxia-induced right ventricular remodeling. AU - Campen, Matthew J.. AU - Paffett, Michael L.. AU - Colombo, E. Sage. AU - Lucas, Selita N.. AU - Anderson, Tamara. AU - Nysus, Monique. AU - Norenberg, Jeffrey P.. AU - Gershman, Ben. AU - Hesterman, Jacob. AU - Hoppin, Jack. AU - Willis, Monte. PY - 2014/5/8. Y1 - 2014/5/8. N2 - Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while ...
TY - JOUR. T1 - The ubiquitin-conjugating enzyme UBCH7 acts as a coactivator for steroid hormone receptors. AU - Verma, Seema. AU - Ismail, Ayesha. AU - Gao, Xiuhua. AU - Fu, Guilian. AU - Li, Xiaotao. AU - OMalley, Bert W.. AU - Nawaz, Zafar. PY - 2004/10/1. Y1 - 2004/10/1. N2 - We investigated the role of the ubiquitin-conjugating enzyme UBCH7 in nuclear receptor transactivation. Using transient transfection assays, we demonstrated that UBCH7 modulates the transcriptional activity of progesterone receptor (PR) and glucocorticoid, androgen, and retinoic acid receptors in a hormone-dependent manner and that the ubiquitin conjugation activity of UBCH7 is required for its ability to potentiate transactivation by steroid hormone receptors (SHR). However, UBCH7 showed no significant effect on the transactivation functions of p53 and VP-16 activation domain. Depletion of endogenous UBCH7 protein by small interfering RNAs suggests that UBCH7 is required for the proper function of SHR. Furthermore, a ...
TY - JOUR. T1 - Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome. AU - Berg, E. L.. AU - Pride, M. C.. AU - Petkova, S. P.. AU - Lee, R. D.. AU - Copping, N. A.. AU - Shen, Y.. AU - Adhikari, A.. AU - Fenton, T. A.. AU - Pedersen, L. R.. AU - Noakes, L. S.. AU - Nieman, B. J.. AU - Lerch, J. P.. AU - Harris, S.. AU - Born, H. A.. AU - Peters, M. M.. AU - Deng, P.. AU - Cameron, D. L.. AU - Fink, K. D.. AU - Beitnere, U.. AU - OGeen, H.. AU - Anderson, A. E.. AU - Dindot, S. V.. AU - Nash, K. R.. AU - Weeber, E. J.. AU - Wöhr, M.. AU - Ellegood, J.. AU - Segal, D. J.. AU - Silverman, J. L.. PY - 2020/1/27. Y1 - 2020/1/27. N2 - Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, ...
Autosomal recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular in the E3 ubiquitin ligase Parkin (PARK2), and in its upstream protein kinase PINK1 (PARK6). PINK1 phosphorylates ubiquitin and the Parkin ubiquitin-like domain on structurally protected Ser65 to trigger mitophagy. We here report a crystal structure of a nanobody-stabilised complex between Pediculus humanus corporis (Ph)PINK1 with ubiquitin in the C-terminally retracted (Ub-CR) conformation. The structure reveals many peculiarities of PINK1, including the architecture of the C-terminal region, and reveals how the PINK1 N-lobe binds ubiquitin via a unique insertion ...
Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group
EN] Seed longevity is important to preserve crops and wild plants and it is limited by progressive cellular damage (aging) during storage. The induction of cellular stress defenses and the formation of the seed coat are crucial protecting events during seed development, a process mediated in Arabidopsis thaliana by the transcription factors LEC1, LEC2, FUS3 and the abscisic acid-activated ABI3. In order to identify novel determinants of seed longevity we have screened an activation-tagging mutant collection of Arabidopsis and isolated a dominant mutant with increased seed longevity under both natural and accelerated aging conditions. Molecular characterization indicates that the mutant phenotype is caused by over-expression of the At2g26130 gene encoding a RING-type zinc finger putative ubiquitin ligase. Loss of function of this gene in a T-DNA insertion mutant resulted in decreased seed longevity. We named this important gene for seed longevity RSL1 (from Ring finger of Seed Longevity1) and we ...
TY - JOUR. T1 - Hect E3 ubiquitin ligase Tom1 controls Dia2 degradation during the cell cycle. AU - Kim, Dong Hwan. AU - Koepp, Deanna M.. PY - 2012/11/1. Y1 - 2012/11/1. N2 - The ubiquitin proteasome system plays a pivotal role in controlling the cell cycle. The budding yeast F-box protein Dia2 is required for genomic stability and is targeted for ubiquitin-dependent degradation in a cell cycle-dependent manner, but the identity of the ubiquitination pathway is unknown. We demonstrate that the Hect domain E3 ubiquitin ligase Tom1 is required for Dia2 protein degradation. Deletion of DIA2 partially suppresses the temperature-sensitive phenotype of tom1 mutants. Tom1 is required for Dia2 ubiquitination and degradation during G1 and G2/M phases of the cell cycle, whereas the Dia2 protein is stabilized during S phase. We find that Tom1 binding to Dia2 is enhanced in G1 and reduced in S phase, suggesting a mechanism for this proteolytic switch. Tom1 recognizes specific, positively charged residues ...
Linear ubiquitin chains are important regulators of cellular signalling pathways that control innate immunity and inflammation through nuclear factor (NF)-κB activation and protection against tumour necrosis factor-α-induced apoptosis. They are synthesized by HOIP, which belongs to the RBR (RING-bet …
We have probed the interactions between HOIP and NEMO by solving a cocrystal structure of NZF1 of human HOIP and CoZi of mouse NEMO, while our mutational studies have been performed using mouse HOIP. However, the surface residues from HOIP that interact with NEMO are fully conserved in human and mouse species (Fig. 3J). Our mutational analyses based on the structure of the cocrystal show that direct recognition of NEMO by HOIP plays a major role in NF-κB activation following conjugation of linear chains to NEMO. Although the RING-IBR-RING region of HOIP is the catalytic center for linear polyubiquitination by LUBAC (7), recent results obtained using an in vitro ubiquitin assay have suggested that the RING2 domain of HOIL-1L plays a role in linear polyubiquitination of NEMO (38). However, given that the HOIP-SHARPIN complex effectively linearly polyubiquitinates NEMO in vitro and activates NF-κB in cells (12), any involvement of the RING2 domain of HOIL-1L in linear polyubiquitination of NEMO ...
The ubiquitin E1, E2, and E3 ligase enzymes are the enzymatic core of the ubiquitination pathway. The E2-E3 complex interacts with the substrate, catalyzing ubiquitin addition to the substrate. Thus, the expression, activity, localization, and selectivity of ubiquitin E2s and E3s are important parameters that can serve to regulate ubiquitination. The E2-E3 combination used in the ubiquitination reaction can also influence the fate of the substrate through determining the extent and nature of ubiquitin addition. The majority of substrates observed to date are modified by the attachment of a Lys-48-linked ubiquitin chain, which targets the substrate for degradation by the 26S proteasome. Substrates modified with other types of polyubiquitin chains linked via ubiquitin Lys-6, -11, -29, and -63, or modified with a single ubiquitin, face different or unknown fates. For example, the heterodimeric E2 UBC13/methyl methane sulfonate sensitivity 2 functions with the RING E3 TNF receptor-associated factor ...
Protein neddylation is essential for the viability of most organisms and is widely involved in the regulation of immunity, DNA damage and repair, cell signaling and cell cycle. Unlike RING-type neddylation ligases, HECT-type neddylation ligase remains less defined. Here, we show that Itch is a novel HECT-type neddylation E3 ligase and we identify JunB as a substrate of Nedd8 modification by Itch. JunB neddylation attenuates its transcriptional activity. In addition, JunB neddylation mediated by Itch promotes its ubiquitination-dependent degradation. Therefore, these findings define a new HECT-type neddylation ligase and its neddylation substrate.
E3 ubiquitin ligases catalyze ubiquitination, which can target specific proteins for degradation. Although a growing number of E3 ubiquitin ligases and their targets have been identified, much less is known about the mechanisms that regulate their activity. A convergence of data indicate that phosphorylation regulates the binding of Nedd4-2, a HECT (homologous to the E6-AP C terminus) domain E3 ubiquitin ligase, to its target, the epithelial Na+ channel ENaC. Nedd4-2 phosphorylation is emerging as a central convergence point for the regulation of epithelial Na+ transport.. ...
The gene encoding deleted in breast cancer 2′ ((Rho-related BTB domain-containing protein 2), is classified being a tumor suppressor gene. for everyone natural procedures almost, including Nelfinavir Mesylate supplier cell development, apoptosis and differentiation.1 Dysregulation of the phenomenon qualified prospects to irreversible shifts in protein stability and will directly or indirectly promote a number of pathological conditions, including tumor.1 The procedure of ubiquitination involves multiple guidelines mediated by E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and substrate-specific E3 ubiquitin ligases.2 One of the most predominant course of E3 ligases may be the category of really interesting brand-new gene (Band)-finger domain-containing protein. These protein are subdivided into two groupings: the monomeric RING-type E3 ligases as well as the multimeric RING-type E3 ligases, like the Cullin-3 (CUL3)-structured E3 ligases.2 The substrate specificity of CUL E3 ...
TY - JOUR. T1 - Effects of the combination of a proteasome inhibitor (PSI) and an inhibitor of ubiquitin-ligases (Leu-Ala) on the ultrastructure of human leukemic U937 cells. AU - Biały, P.. AU - Ziemba, H.. AU - Pleban, E.. AU - Wójcik, Cezary. PY - 2002/1/1. Y1 - 2002/1/1. N2 - We have used the dipeptide Leu-Ala in an attempt to prevent the formation of ubiquitin-protein conjugates in U937 cells by inhibition of cellular E3 enzymes (ubiquitin ligases). Proteasome inhibitors induce the formation of perinuclear aggregates for ubiquitinated proteins and proteasomes (aggresomes) in the area of the proteolytic center of the cell. Leu-Ala did not prevent the formation of those aggregates under the action of PSI (peptidyl aldehyde, selective inhibitor of the chymotrypsin-like activity of the proteasome), however it induced an accumulation of lipid droplets in treated cells, suggesting a previously unknown involvement of Leu-Ala in lipid metabolism. We conclude, that either Leu-Ala is not able to ...
A second member of the E3 ubiquitin ligases, Fbxo7, is also mutated in early-onset Parkisonism [91-97]. In contrast with Parkin, which functions as a single-polypeptide E3 ligase, Fbxo7 is a component of a multisubunit E3 ligase of the Cullin-RING ligase family (CRL). CRLs are a large class of multisubunit E3 ubiquitin ligases that feature a scaffolding protein, termed a cullin, and associate with a RING-box protein (reviewed in refs [98,99]). The archetypal CRL is the SCF-type ligase family, which comprises Cullin1, Skp1, the RING protein Rbx1, and an F-box. Skp1 associates with substrate adaptor proteins that contain F-boxes (Skp1-Cullin1-Fbox), which recruits substrates to the CRL for ubiquitylation.. Until recently, Fbxo7 had only four identified substrates. The first of these is HURP (hepatoma up-regulated protein) [100]. HURP is found at high levels in hepatocellular carcinomas and is required during mitotic spindle assembly for correct alignment of chromosomes [101]. As such, it is ...
During ubiquitination, Ub is initially activated by an ATP‐dependent E1 enzyme before it is passed to one of several distinct Ub‐conjugating enzymes (E2s). The E2 subsequently acts to either transfer Ub to a HECT (homologous to the E6AP carboxyl terminus)‐type Ub ligase (E3), or to catalyse substrate ubiquitination in conjunction with RING (really interesting new gene)‐type or U‐box E3 enzymes. An exception to this is the process of coupled monoubiquitination, through which E2 enzymes can catalyse the ubiquitination of Ub‐binding domain (UBD)‐containing proteins independently of E3 (Hoeller et al, 2006, 2007).. Ubiquitin ligases seem to be the crucial determinants of substrate selection and are also considered to be important components in controlling Ub‐chain formation on a substrate. For example, different HECT‐type E3s can specify both the linkage of a Ub chain and the process of its assembly. E6AP can form a Lys 48‐linked chain on its active cysteine residue (Scheffner & ...
A multiethnic series of patients with early-onset Parkinsons disease (EOP) was studied to assess the frequency and nature of parkin/PARK2 gene mutations and to investigate phenotype-genotype relationships. Forty-six EOP probands with an onset age of | 45 years, and 14 affected relatives were ascertained from Italy, Brazil, Cuba, and Turkey. The genetic screening included direct sequencing and exon dosage using a new, cost-effective, real-time polymerase chain reaction method. Mutations were found in 33% of the indexes overall, and in 53% of those with family history compatible with autosomal recessive inheritance. Fifteen parkin alterations (10 exon deletions and five point mutations) were identified, including four novel mutations: Arg402Cys, Cys418Arg, IVS11-3C | G, and exon 8-9-10 deletion. Homozygous mutations, two heterozygous mutations, and a single heterozygous mutation were found in 8, 6, and 1 patient, respectively. Heterozygous exon deletions represented 28% of the mutant alleles. The
TY - JOUR. T1 - Vps9p CUE domain ubiquitin binding is required for efficient endocytic protein traffic. AU - Davies, Brian A.. AU - Topp, Justin D.. AU - Sfeir, Agnel J.. AU - Katzmann, David J.. AU - Carney, Darren S.. AU - Tall, Gregory G.. AU - Friedberg, Andrew S.. AU - Deng, Li. AU - Chen, Zhijian. AU - Horazdovsky, Bruce F.. PY - 2003/5/30. Y1 - 2003/5/30. N2 - Rab5 GTPases are key regulators of protein trafficking through the early stages of the endocytic pathway. The yeast Rab5 ortholog Vps21p is activated by its guanine nucleotide exchange factor Vps9p. Here we show that Vps9p binds ubiquitin and that the CUE domain is necessary and sufficient for this interaction. Vps9p ubiquitin binding is required for efficient endocytosis of Ste3p but not for the delivery of the biosynthetic cargo carboxypeptidase Y to the vacuole. In addition, Vps9p is itself monoubiquitylated. Ubiquitylation is dependent on a functional CUE domain and Rsp5p, an E3 ligase that participates in cell surface receptor ...
MKRN2 is a novel ubiquitin E3 ligase for the p65 subunit of NF-κB and negatively regulates inflammatory responses.MKRN2 is a novel ubiquitin E3 ligase for the p65 subunit of NF-κB and negatively regulates inflammatory responses. ...
Misfolded proteins of the endoplasmic reticulum (ER) are targeted to the cytoplasm for proteasomal degradation. Key components of this process are ER membrane-bound ubiquitin ligases. These ligases associate with the cytoplasmic AAA-ATPase Cdc48p/p97, which is thought to support the release of malfolded proteins from the ER. Here, we characterize a yeast protein complex containing the ubiquitin ligase Hrd1p and the ER membrane proteins Hrd3p and Der1p. Hrd3p binds malfolded proteins in the ER lumen enabling their delivery to downstream components. Therefore, we propose that Hrd3p acts as a substrate recruitment factor for the Hrd1p ligase complex. Hrd3p function is also required for the association of Cdc48p with Hrd1p. Moreover, our data demonstrate that recruitment of Cdc48p depends on substrate processing by the Hrd1p ligase complex. Thus, the Hrd1p ligase complex unites substrate selection in the ER lumen and polyubiquitination in the cytoplasm and links these processes to the release of ER ...
Background RBR ubiquitin ligases are components of the ubiquitin-proteasome system present in all eukaryotes. They are characterized by having the RBR (RING - IBR - RING) supradomain. In this study, the patterns of emergence of RBR genes in plants are described. Methodology/Principal Findings Phylogenetic and structural data confirm that just four RBR subfamilies (Ariadne, ARA54, Plant I/Helicase and Plant II) exist in viridiplantae. All of them originated before the split that separated green algae from the rest of plants. Multiple genes of two of these subfamilies (Ariadne and Plant II) appeared in early plant evolution. It is deduced that the common ancestor of all plants contained at least five RBR genes and the available data suggest that this number has been increasing slowly along streptophyta evolution, although losses, especially of Helicase RBR genes, have also occurred in several lineages. Some higher plants (e. g. Arabidopsis thaliana, Oryza sativa) contain a very large number of RBR genes
Project title: Regulation and control of linear ubiquitin chian synthesis: Structure, function and mechanism of linear ubiquitin chian assembly complex LUBAC. Summary: The linear ubiquitin chain assembly complex LUBAC is E3 ubiquitin ligase that plays pivotal roles in the innitiation of innate and adpative immune response, especially in the activation of nuclear factor-kappa B, which is a transcription factor that induces transcription of inflammatory genes. Abberrant LUBAC activity has been known as a contributor to diffuse large B-cell lymphoma (DLBL), which is a bone marrow malignancy. More importantly, individuals carrying congenital mutaions in LUBAC protein domains (i.e. HOIP, HOIL-1, SHARPIN) manifest devastating immunodeficiency and/or autoinflammatory symptoms. All those add up to the fact that LUBAC is really interesting and important. This project aims to unveal regulatory mechanisms for LUBAC activity with aid from biochemical and structural biology techiniques (i.e. in vitro protein ...
We report the map-based cloning of the SLY1 gene of Arabidopsis. SLY1 is a positive regulator of GA response. Recessive mutations in SLY1 affect the full range of GA phenotypes, including feedback regulation of the GA3ox1 biosynthetic gene (Figure 1). Thus, the fact that SLY1 encodes a putative F-box protein suggests that the GA signal is transmitted via an SCFSLY1 E3 ubiquitin ligase.. Ubiquitylation controls target protein activity at multiple levels, including proteolysis and the potentiation of transcriptional activation domains (Conaway et al., 2002). Major members of the SCF complex include homologs of SKP1, cullin, and the RING-finger domain protein Rbx1 (Zheng et al., 2002). The F-box subunit directs the interaction of the complex with a specific target for ubiquitylation. The conserved F-box domain allows the protein to interact with the SKP1 subunit of the SCF. SKP1 tethers the F-box protein to the N terminus of cullin. The RING-finger protein Rbx1 binds the C terminus of cullin and ...
Evidence suggests that regulated ubiquitination of proteins plays a critical role in the development and plasticity of the central nervous system. We have previously identified the ubiquitin ligase Praja1 as a gene product induced during fear memory consolidation. However, the neuronal function of this enzyme still needs to be clarified. Here, we investigate its involvement in the nerve growth factor (NGF)-induced differentiation of rat pheochromocytoma (PC12) cells. Praja1 co-localizes with cytoskeleton components and the neurotrophin receptor interacting MAGE homologue (NRAGE). We observed an enhanced expression of Praja1 after 3 days of NGF treatment and a suppression of neurite formation upon Praja1 overexpression in stably transfected PC12 cell lines, which was associated with a proteasome-dependent reduction of NRAGE levels. Our data suggest that Praja1, through ubiquitination and degradation of NRAGE, inhibits neuronal differentiation. The two murine isoforms, Praja1.1 and Praja1.2, appear to be
TY - JOUR. T1 - The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation. AU - Omerovic, Jasminka. AU - Santangelo, Laura. AU - Puggioni, Eleonora Maria Rosaria. AU - Marrocco, Jordan. AU - DallArmi, Claudia. AU - Palumbo, Camilla. AU - Belleudi, Francesca. AU - Di Marcotullio, Lucia. AU - Frati, Luigi. AU - Torrisi, Maria Rosaria. AU - Cesareni, Gianni. AU - Gulino, Alberto. AU - Alimandi, Maurizio. PY - 2007/9. Y1 - 2007/9. N2 - The ErbB-4 receptors are unique in the EGFR/ErbB family for the ability to associate with WW domain-containing proteins. To identify new ligands of the cytoplasmic tail of ErbB-4, we panned a brain cDNA phage library with ErbB-4 peptides containing sequence motifs corresponding to putative docking sites for class-I WW domains. This approach led to identification of AIP4/Itch, a member of the Nedd4-like family of E3 ubiquitin protein ligases, as a protein that specifically interacts with and ubiquitinates ErbB-4 in vivo. Interaction with the ErbB-4 ...
HPK1, a member of mammalian Ste20-like serine/threonine kinases, is lost in |95% pancreatic cancer through proteasome-mediated degradation. However, the mechanism of HPK1 loss has not been defined. The aims of this study are to identify the ubiquitin ligase and to examine the mechanisms that targets HPK1 degradation. We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome. The ubiquitination of HPK1 required its kinase activity and autophosphorylation. Wild-type protein phosphatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 with HPK1 and Fbxw8-mediated ubiquitination of HPK1. In addition, we showed that Thr-355 of HPK1 is a key PP4 dephosphorylation site, through which CUL7/Fbxw8 ubiquitin ligase and PP4 regulates HPK1 stability. Knockdown of Fbxw8 restores endogenous HPK1 protein expression and inhibits cell proliferation of pancreatic cancer cells. Our study demonstrated that targeted degradation of HPK1 by
Polycomb group proteins Bmi-1 and Ring1B are core subunits of the PRC1 complex, which plays important roles in the regulation of Hox gene expression, X-chromosome inactivation, tumorigenesis, and stem cell self-renewal. The RING finger protein Ring1B is an E3 ligase that participates in the ubiquitination of lysine 119 of histone H2A, and the binding of Bmi-1 stimulates the E3 ligase activity. We have mapped the regions of Bmi-1 and Ring1B required for efficient ubiquitin transfer and determined a 2.5-A structure of the Bmi-1-Ring1B core domain complex. The structure reveals that Ring1B hugs Bmi-1 through extensive RING domain contacts and its N-terminal tail wraps around Bmi-1. The two regions of interaction have a synergistic effect on the E3 ligase activity. Our analyses suggest a model where the Bmi-1-Ring1B complex stabilizes the interaction between the E2 enzyme and the nucleosomal substrate to allow efficient ubiquitin transfer.. ...
The herpes simplex virus type 1 (HSV-1) encoded E3 ubiquitin ligase, infected cell protein 0 (ICP0), is required for efficient lytic viral replication and regulates the switch between the lytic and latent states of HSV-1. As an E3 ubiquitin ligase, ICP0 directs the proteasomal degradation of several cellular targets, allowing the virus to counteract different cellular intrinsic and innate immune responses. In this review, we will focus on how ICP0s E3 ubiquitin ligase activity inactivates the host intrinsic defenses, such as nuclear domain 10 (ND10), SUMO, and the DNA damage response to HSV-1 infection. In addition, we will examine ICP0s capacity to impair the activation of interferon (innate) regulatory mediators that include IFI16 (IFN γ-inducible protein 16), MyD88 (myeloid differentiation factor 88), and Mal (MyD88 adaptor-like protein). We will also consider how ICP0 allows HSV-1 to evade activation of the NF-κB (nuclear factor kappa B) inflammatory signaling pathway. Finally, ICP0s ...
TY - JOUR. T1 - Ubiquitin ligases. T2 - Cell-cycle control and cancer. AU - Nakayama, Keiichi I.. AU - Nakayama, Keiko. PY - 2006/5/1. Y1 - 2006/5/1. N2 - A driving force of the cell cycle is the activation of cyclin-dependent kinases (CDKs), the activities of which are controlled by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors. Two ubiquitin ligases, the SKP1-CUL1-F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), are responsible for the specific ubiquitylation of many of these regulators. Deregulation of the proteolytic system might result in uncontrolled proliferation, genomic instability and cancer. Cumulative clinical evidence shows alterations in the ubiquitylation of cell-cycle regulators in the aetiology of many human malignancies. A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.. AB - A ...
MalaCards based summary : Itch E3 Ubiquitin Ligase Deficiency, also known as autoimmune disease, syndromic multisystem, is related to autoimmune disease, multisystem, with facial dysmorphism and autoimmune disease. An important gene associated with Itch E3 Ubiquitin Ligase Deficiency is ITCH (Itchy E3 Ubiquitin Protein Ligase). Affiliated tissues include liver and thyroid ...
A multitude of studies have demonstrated that the early phases of DNA replication are regulated by ubiquitylation. For instance, the E3 ubiquitin ligase complexes cullin-RING ligase-1 (CRL1) and cullin-RING ligase-4 (CRL4) prevent re-replication and the occurrence of genome instability by targeting pre-RC components for proteasomal degradation (reviewed in Truong et al.2). Cullin-RING ligases (CRLs) constitute a protein family of ,200 modular E3s and are composed of eight distinct subfamilies containing different cullins, namely CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7 and CUL9.3 Cullins work as molecular scaffolds assembling the different complex subunits, that is, a RING-finger protein (RBX1 or RBX2), which interacts with the ubiquitin-conjugating enzyme, an adaptor protein and one of many substrate-receptor subunits. The activity of CRLs is primarily controlled at the level of substrate recruitment. The direct recognition of the target protein by the substrate-receptor subunit and its ...
PINK1 regulation of neuronal and mitochondrial homeostasis PROJECT SUMMARY. Mutations in PTEN-induced kinase 1 (PINK1) cause familial autosomal recessive parkinsonism. As PINK1 plays a neuroprotective role in a wide range of genetic and toxin-induced Parkinsons disease (PD) models, studying its function in neurons may offer particular insights into potential therapeutic strategies. In the prior project period, we found that endogenous PINK1 exists in mitochondrial and cytosolic compartments. Moreover, these pools of PINK1 played divergent roles in regulating mitochondrial fission-fusion, mitophagy, calcium homeostasis and dendritic morphogenesis. Using primary neurons, differentiated neuronal cell lines and Pink1 knockout and control mice, the current proposal focuses on studying mechanisms by which PINK1 regulates neuron differentiation and the maintenance of extended axo-dendritic arbors. Based on preliminary data, we hypothesize that PINK1 interacts with cytosolic targets to regulate neuron ...
Background: RING is one of the largest E3 ubiquitin ligase families and C3H2C3 type is the largest subfamily of RING, playing an important role in plants development and growth and their biotic and abiotic stress responses. Results: A total of 143 RING...
TY - JOUR. T1 - In vitro reconstitution defines the minimal requirements for Cdc48-dependent disassembly of the CMG helicase in budding yeast. AU - Mukherjee, Progya. AU - Labib, Karim. N1 - We gratefully acknowledge the support of the Medical Research Council (core grant MC_UU_12016/13 to KL) and the Wellcome Trust (reference 102943/Z/13/Z for an Investigator award to KL).. PY - 2019/9/10. Y1 - 2019/9/10. N2 - Disassembly of the replisome is the final step of chromosome duplication in eukaryotes. In budding yeast and metazoa, cullin ubiquitin ligases are required to ubiquitylate the Cdc45-MCM-GINS (CMG) helicase that lies at the heart of the replisome, leading to a disassembly reaction that is dependent upon the ATPase known as Cdc48 or p97. Here, we describe the reconstitution of replisome disassembly, using a purified complex of the budding yeast replisome in association with the cullin ligase SCF Dia2. Upon addition of E1 and E2 enzymes, together with ubiquitin and ATP, the CMG helicase is ...
Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that is essential for the survival of multiple cell lineages and that is highly amplified in human cancer. Under physiological conditions, Mcl-1 expression is tightly regulated at multiple levels, involving transcriptional, post-transcriptional and post-translational processes. Ubiquitination of Mcl-1, that targets it for proteasomal degradation, allows for rapid elimination of the protein and triggering of cell death, in response to various cellular events. In the last decade, a number of studies have elucidated different pathways controlling Mcl-1 ubiquitination and degradation. Four different E3 ubiquitin-ligases (e.g., Mule, SCFβ-TrCP, SCFFbw7 and Trim17) and one deubiquitinase (e.g., USP9X), that respectively mediate and oppose Mcl-1 ubiquitination, have been formerly identified. The interaction between Mule and Mcl-1 can be modulated by other Bcl-2 family proteins, while recognition of Mcl-1 by the other E3 ubiquitin-ligases and
PTEN-induced putative kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene. It is thought to protect cells from stress-induced mitochondrial dysfunction. PINK1 activity causes the parkin protein to bind to depolarized mitochondria to induce autophagy of those mitochondria. PINK1 is processed by healthy mitochondria and released to trigger neuron differentiation. Mutations in this gene cause one form of autosomal recessive early-onset Parkinsons disease. PINK1 is synthesized as a 63000 Da protein which is often cleaved by PARL, between the 103-Alanine and the 104-Phenylalanine residues, into a 53000 Da fragment. PINK1 contains an N-terminal mitochondrial localization sequence, a putative transmembrane sequence, a Ser/Thr kinase domain, and a C-terminal regulatory sequence. The protein has been found to localize to the outer membrane of mitochondria, but can also be found throughout the cytosol. Experiments suggest the Ser/Thr kinase domain faces outward ...
Background: Although neuronal extracellular sensing is emerging as crucial for brain wiring and therefore plasticity, little is known about these processes in neurodevelopmental disorders. Ubiquitin protein ligase E3A (UBE3A) plays a key role in neurodevelopment. Lack of UBE3A leads to Angelman syndrome (AS), while its increase is among the most prevalent genetic causes of autism (e.g., Dup15q syndrome). By using microstructured substrates that can induce specific directional stimuli in cells, we previously found deficient topographical contact guidance in AS neurons, which was linked to a dysregulated activation of the focal adhesion pathway. Methods: Here, we study axon and dendrite contact guidance and neuronal morphological features of wild-type, AS, and UBE3A-overexpressing neurons (Dup15q autism model) on micrograting substrates, with the aim to clarify the role of UBE3A in neuronal guidance. Results: We found that loss of axonal contact guidance is specific for AS neurons while UBE3A ...
TY - JOUR. T1 - The isolated N terminus of Ring1B is a well-folded, monomeric fragment with native-like structure. AU - Martínez-Gómez, Ana Isabel. AU - Villegas, Sandra. AU - Aguado-Llera, David. AU - Bacarizo, Julio. AU - Cámara-Artigas, Ana. AU - Vidal, Miguel. AU - Neira, José L.. PY - 2014/1/1. Y1 - 2014/1/1. N2 - The Polycomb group (PcG) proteins assemble into Polycomb repressive complexes (PRCs), PRC1 and PRC2, which act as general transcriptional repressors. PRC1 comprises a variety of biochemical entities endowed with histone H2A monoubiquitylation activity conferred by really interesting new gene (RING) finger E3 ubiquitin ligases Ring1A and Ring1B. All PRC1 complexes contain Ring1 proteins which are essential for Polycomb epigenetic regulation. We have been able to express the isolated N-terminal region of Ring1B, N-Ring1B, comprising the first 221 residues of the 334-residue-long Ring1B. This fragment contains the 41-residue-long RING finger motif, and flanking sequences that ...
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Ubiquitin regulation appears to have an important but not well-understood role in C. elegans embryonic polarization. One of the earliest discoveries was that PAR-2 has homology to RING domain E3 ubiquitin ligases, suggesting that ubiquitin ligase activity may be important for excluding anterior PARs from the posterior [5], [37]. Hao and colleagues showed that the PAR-2 RING domain is required for robust transgene rescue of embryos lacking endogenous PAR-2, indicating that it is likely to be an active ubiquitin ligase in vivo, although this activity is not absolutely essential for function [25]. Biochemical targets of PAR-2, however, are unknown. Other results that relate ubiquitin-based regulation to polarization include the finding that PAR-6 levels are affected by activity of the ubiquitin ligase CUL-2 and its adapter protein FEM-3 [44], and that mutations of C. elegans homologs of the BRAT family of ubiquitin ligases have been shown to be able to suppress weak par-2 phenotypes [45]. Weak ...
Recently, it has become known that current treatments of advanced PCa, based on androgen ablation therapies such as surgical and chemical castration, are very effective treatments initially, but almost all cases progress to CRPC eventually. Accumulating evidence has revealed that in nearly all cases resumption of AR transcription activity contributes to CRPC progression [25]. A recently identified mechanism, in which E3 ubiquitin ligase Siah2 regulates a subset of AR bound to corepressor NCoR1, results in removal of transcriptionally-inactive AR from chromatin and allows p300-bound AR binding to AREs, the mechanism of which has become the center of attention in PCa treatment investigations [14].. Interestingly, NO inhibition of AR-function in PCa cells was first described in vitro using the NO-donor DETA/NO. This study showed that NO inhibited AR-mediated genomic function by preventing its DNA-binding activity while not decreasing AR protein concentrations or decreasing nuclear AR translocation ...