Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0033774 (pruritus)
14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Itch, an E3 protein ubiquitin ligase (E3), which belongs to the homologous to E6-AP carboxy terminus (HECT)-type subfamily, catalyzes its own ubiquitylation. The precise nature of Itch-mediated self-modification and its biological outcome are not completely understood. Here, we show that Itch auto-ubiquitylation is an intermolecular reaction generating Lys63-linkages, rather than the Lys48-linked polyubiquitin chains that target proteins for proteasomal degradation. As a result, Itch is a relatively high stable protein, whose levels are not significantly affected by treatment by either proteasome or lysosome inhibitors. Furthermore, we demonstrate that the decay rate of a catalytic inactive Itch mutant, which is devoided of self-ubiquitylating activity, is barely indistinguishable from the one of the wild-type protein. These data definitely establish a nondegradative role for Lys63-linked Itch self-ubiquitylation.
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PMID:Itch self-polyubiquitylation occurs through lysine-63 linkages. 1871 49

Itchy mice possess a loss-of-function mutation in a HECT-domain-containing ubiquitin ligase (E3), Itch. Homozygous itchy mice develop a systemic and progressive autoimmune disease that proves lethal beginning at 6 months of age. Numerous targets of Itch-mediated ubiquitination have been identified, and some of these have defined physiological roles for Itch signaling in Tcell anergy and T cell differentiation. Studies of itchy mice have also allowed for the identification of a novel pathway involved in autoimmunity: noncanonical Notch signaling. In itchy mice carrying an activated Notch1 transgene, there are increased amounts of full-length Notch1, which can complex with p56(lck) and PI3K to activate a cell survival signal that is mediated by phospho-AKT. This, in turn, leads to a reduction in apoptosis in the thymus and may have consequences in T cell tolerance. A role for noncanonical Notch signaling in autoimmune disease is also supported by numerous mouse knockout studies, and suggests possible new therapeutic approaches for the treatment of autoimmune disease.
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PMID:Itchy mice: the identification of a new pathway for the development of autoimmunity. 1872 93

E3 ubiquitin ligases catalyze the final step in the ubiquitylation cascade and therefore determine the specificity of this important cellular metabolic pathway. Although first thought to be constitutively active, increasing evidence demonstrates the existence of a wide variety of posttranslational modifications that regulate the activity of these enzymes. Here we show that upon induction of apoptosis the ubiquitin ligase Itch is processed by caspases both in vitro and ex vivo in cells from patients with chronic lymphocytic leukemia (CLL). The specific cleavage site was mapped to residue Asp240. Interestingly, cleavage of Itch by active caspases does not inhibit the catalytic activity of Itch, but results in the loss of an N-terminal Itch fragment that contains a negative regulatory region. Our data suggests that caspase-dependent Itch cleavage might be an important regulator of Itch at the endogenous level under both physiological and stressed conditions.
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PMID:Caspase cleavage of Itch in chronic lymphocytic leukemia cells. 1907 38

Death receptor-mediated host cell apoptosis, a defense strategy for elimination by the immune system of parasite-infected cells, is inhibited by Trypanosoma cruzi, the causative agent of Chagas' disease. It has previously been reported by us that, in infected cells, T. cruzi upregulates and exploits cFLIP(L), a mammalian inhibitor of death receptor signaling. Here it is shown that ubiquitination of cFLIP(L,) leading to proteasomal degradation, is inhibited in parasite-infected cells. The extent of expression of Itch, a protein thought to be an ubiquitin ligase for cFLIP(L), was found to be equivalent in T. cruzi-infected and in uninfected cells. However, co-immunoprecipitation analysis showed that the interaction between cFLIP(L) and Itch is strongly inhibited in T. cruzi-infected cells. This unique parasite strategy, which has not been reported in any other pathogen-infected cells, may allow the host cell to accumulate cFLIP(L), eventually resulting in the inhibition of apoptosis of T. cruzi-infected cells.
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PMID:Interaction between cFLIP and Itch, a ubiquitin ligase, is obstructed in Trypanosoma cruzi-infected human cells. 1909 Aug 33

Chronic lymphocytic leukemia (CLL) is characterized by cells that exhibit dysfunctional apoptosis. Here, we show that deacetylase inhibition led to the E2F1- and myc-mediated transcriptional activation of the microRNA miR106b in primary CLL cells. Induction of miR106b was associated with a down-regulation in the levels of the E3-ubiquitin ligase Itch. Decreases in Itch protein levels were associated with a reciprocal accumulation of its proapoptotic substrate, TAp73 (p73), and induction of p53 up-regulated modulator of apoptosis (PUMA) mRNA and protein. This event was accompanied by mitochondrial dysfunction, processing of caspase-9, and apoptosis of CLL cells. Ectopic expression of miR106b in CLL cells demonstrated that Itch was a direct target of miR106b such that miR106b-induced decreases in Itch resulted in an accumulation of p73. Thus, our results identify a novel regulatory mechanism wherein microRNA regulate cell survival by mediating the posttranscriptional down-regulation of an ubiquitin ligase, leading to the induction of a proapoptotic regulator in malignant cells. Silencing of miRNA expression in CLL may selectively suppress proapoptotic pathways, providing such tumors with a survival advantage. Consequently, chemotherapeutic drugs that activate miR106b could initiate a p53-independent mechanism that targets CLL cells.
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PMID:Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase Itch for degradation. 1954 40

EGF-mediated stimulation of the EGF receptor activates a plethora of signaling cascades followed by receptor down regulation. Preventing down regulation leads to increased mitogenic signaling and potentially, cancer. Cbl and Endophilin are two key proteins required for EGF receptor down regulation and both become ubiquitylated and subject to proteasome-mediated degradation following EGF activation, providing a negative feedback loop for EGF receptor down regulation. The mechanism of this pathway is unknown. Here, we demonstrate that treatment of cells with EGF leads to JNK-dependent phosphorylation of the ubiquitin ligase Itch, stimulating Itch ligase activity. EGF-stimulated JNK activation causes an increased interaction between Itch and the de-ubiquitylating enzyme FAM, limiting the influence of Itch auto-ubiquitylation on its own degradation. Finally, JNK activation stimulates the association of Itch with its substrates. These effects combine to cause increased ubiquitylation of Itch substrates including Endophilin and Cbl, resulting in the proteasome-dependent down regulation of these key trafficking proteins. Thus, Itch is a key regulatory locus for EGF receptor degradation.
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PMID:Reciprocal regulation of the ubiquitin ligase Itch and the epidermal growth factor receptor signaling. 1934 94

The turnover rate of many transcription factors such as c-Jun, a member of the AP-1 family of transcription factors, is regulated by phosphorylation events. Phosphorylation on serine residues 63 and 73 (S63/73) by the c-Jun-N-terminal kinases (JNKs) regulates c-Jun's turnover, and is critical for its ability to regulate cell death and proliferation. Recently, biochemical evidence indicated that the c-Abl and Csk kinases were able to phosphorylate the tyrosine 170 (Y170) residue of c-Jun - which lies within the recognition motif of the Itch ubiquitin ligase - and also regulate its stability independent of the JNK phosphorylation sites. We have investigated here the relevance of Y170 residue by substituting it to either an unphosphorylable phenylanine or a pseudo-phosphorylated aspartic acid residue, and re-expressing the mutants stably in c-jun(-/-) embryonic fibroblasts. Our results indicate that Y170 residue is not a critical determinant of c-Jun stability. Itch was able to bind and degrade both wild-type and the c-Jun(170F)/c-Jun(170D) mutants, albeit to varying extents. Moreover, both Csk and c-Abl were also not defective in binding to these mutants, although Csk and c-Abl were either unable to degrade or increased the steady-state levels of all c-Jun mutants respectively. Phosphorylation on S63/73 upon exposure to genotoxic stresses was also not affected by the status of Y170, although cell death and proliferation were slightly affected regardless of the substituted residue. These data therefore proposes that altering the Y170 residue does not affect c-Jun's turnover and does not abolish its functions in regulating cellular proliferation and cell survival.
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PMID:Tyrosine 170 is dispensable for c-Jun turnover. 1981 98

Moloney murine leukemia virus (MoMLV) Gag utilizes its late (L) domain motif PPPY to bind members of the Nedd4-like ubiquitin ligase family. These interactions recruit components of the cell's budding machinery that are critical for virus release. MoMLV Gag contains two additional L domains, PSAP and LYPAL, that are believed to drive residual MoMLV release via interactions with cellular proteins Tsg101 and Alix, respectively. We found that overexpression of Tsg101 or Alix failed to rescue the release of PPPY-deficient MoMLV via these other L domains. However, low-level expression of the ubiquitin ligase Itch potently rescued the release and infectivity of MoMLV lacking PPPY function. In contrast, other ubiquitin ligases such as WWP1, Nedd4.1, Nedd4.2, and Nedd4.2s did not rescue this release-deficient virus. Efficient rescue required the ubiquitin ligase activity of Itch and an intact C2 domain but not presence of the endophilin-binding site. Additionally, we found Itch to immunoprecipitate with MoMLV Gag lacking the PPPY motif and to be incorporated into rescued MoMLV particles. The PSAP and LYPAL motifs were dispensable for Itch-mediated virus rescue, and their absence did not affect the incorporation of Itch into the rescued particles. Itch-mediated rescue of release-defective MoMLV was sensitive to inhibition by dominant-negative versions of ESCRT-III components and the VPS4 AAA ATPase, indicating that Itch-mediated correction of MoMLV release defects requires the integrity of the host vacuolar sorting protein pathway. RNA interference knockdown of Itch suppressed the residual release of the MoMLV lacking the PPPY motif. Interestingly, Itch stimulation of the PPPY-deficient MoMLV release was accompanied by the enhancement of Gag ubiquitination and the appearance of new ubiquitinated Gag proteins in virions. Together, these results suggest that Itch can facilitate MoMLV release in an L domain-independent manner via a mechanism that requires the host budding machinery and involves Gag ubiquitination.
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PMID:Late domain-independent rescue of a release-deficient Moloney murine leukemia virus by the ubiquitin ligase itch. 1986 77

Ubiquitin ligases play an important role in the regulation of the immune system. Absence of Itch E3 ubiquitin ligase in mice has been shown to cause severe autoimmune disease. Using autozygosity mapping in a large Amish kindred, we identified a linkage region on chromosome 20 and selected candidate genes for screening. We describe, in ten patients, identification of a mutation resulting in truncation of ITCH. These patients represent the first reported human phenotype associated with ITCH deficiency. These patients not only have multisystem autoimmune disease but also display morphologic and developmental abnormalities. This disorder underscores the importance of ITCH ubiquitin ligase in many cellular processes.
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PMID:Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. 2017 Aug 97

The truncated C-terminal portion of Bid (tBid) is an important intermediate in ligand-induced apoptosis. tBid has been shown to be sensitive to proteasomal inhibitors and downregulated by activation of the epidermal growth factor (EGF) pathway. Here, we provide evidence that tBid is a substrate of the ubiquitin ligase Itch, which can specifically interact with and ubiquitinate tBid, but not intact Bid. Consistently, overexpression of Itch increases cell survival and inhibits caspase 3 activity, whereas downregulation of Itch by RNA interference has the opposite effect, increasing cell death and apoptosis. Treatment with EGF increases Itch phosphorylation and activity, and Itch expression is important for the ability of EGF to increase cell survival after tumour necrosis factor-related apoptosis-inducing ligand treatment. Our findings identify Itch as a key molecule between EGF signalling and resistance to apoptosis through downregulation of tBid, providing further details on how EGF receptor and proteasome inhibitors can contribute to the induction of apoptosis and the treatment of cancer.
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PMID:The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid. 2039 6


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