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

The E3 ubiquitin (Ub) ligase Itch is a critical regulator of T helper 2 (Th2) cytokine production through its ability to induce Ub-dependent JunB degradation. After T cell receptor engagement, Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222, which are located within a Pro-rich region. Phosphorylation of these sites is necessary and sufficient for disrupting an inhibitory interaction between the WW domain of Itch and its catalytic HECT (Homologous to E6-AP C Terminus) domain and induces a conformational change that greatly enhances the catalytic activity of Itch, a HECT E3 ligase found to be directly activated upon its phosphorylation.
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PMID:Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change. 1644 28

Nedd4 family ubiquitin ligases regulate trafficking and degradation of numerous target substrates in different cellular compartments, including at the plasma membrane, in endosomes, in the secretory pathway and in the nucleus. WWP1 is a Nedd4 family protein closely related to mouse Itch and Drosophila Su(dx), both of which have been shown to regulate the Notch receptor. To investigate the possibility that WWP1 is also associated with Notch signalling we coexpressed human Notch1 and WWP1 in mouse myoblast cells. We found that WWP1 could localize to both the nucleus and cytoplasm in a context dependent manner. Coexpression of human Notch1 (hN1) depleted WWP1 from the nucleus to colocalise with hN1 in early endosomes, dependent on the presence of the C-terminal HECT domain. Furthermore we found that full-length expressed WWP1 could interact in vitro with the cytoplasmic domain of human Notch1. The Notch receptor has multiple roles in development, mediating a short-range signal that controls cell fate and pattern formation. The canonical Notch signal involves proteolytic release of the soluble Notch intracellular domain and the activation by the latter of the transcription factor Suppressor of Hairless/CBF-1 in the nucleus. This pathway does not however account for all of the activity of Notch. The ability of Notch to regulate the nuclear localization of WWP1 suggests a possible alternative mechanism by which Notch may communicate a signal to the nucleus. Drosophila Notch similarly regulated the nuclear localization of the Drosophila Nedd4 family protein, Suppressor of deltex, implying conservation of this mechanism during evolution.
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PMID:Regulation of the nuclear localization of the human Nedd4-related WWP1 protein by Notch. 1678 10

To elucidate the mechanisms of autoreactive T cell activation and expansion, we used endogenous viral superantigens (VSAg)-reactive T cells as a model of self-antigens in two strains of Foxp3-mutant mice. These two strains, together with wild-type mice, provided us with an advantage to simultaneously study the positively and negatively selected as well as rescued autoreactive T cells. We show here that while both VSAg-reactive and non-VSAg-reactive T cells are equally activated in Foxp3-mutant mice, only the VSAg-reactive T cells are preferentially expanded independently of their selected states in the thymus. The T cell activation appears to be controlled by Foxp3 through transcriptional regulation of early growth response (Egr) genes Egr-2 and Egr-3, and E3 ubiquitin (Ub) ligase genes Cblb, Itch and GRAIL, subsequently affecting degradation of two key signaling proteins, PLCgamma1 and PKC-theta. Physiologically, the positively, but not negatively selected VSAg-reactive T cells are spontaneously activated without significant expansion. The results suggest that autoreactive T cell activation is controlled by Foxp3 through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection.
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PMID:Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection. 1694 88

Itch is a ubiquitin ligase that has been implicated in the regulation of a number of cellular processes. We previously have identified Itch as a binding partner for the endocytic protein Endophilin and found it to be localized to endosomes. Using affinity purification coupled to mass spectrometry, we have now identified the ubiquitin-protease FAM/USP9X as a binding partner of Itch. The association between Itch and FAM/USP9X was confirmed in vitro by glutathione S-transferase pulldown and in vivo through coimmunoprecipation. Itch and FAM partially colocalize in COS-7 cells at the trans-Golgi network and in peripheral vesicles. We mapped the FAM-binding domain on Itch to the WW domains, a region known to be involved in substrate recognition. However, transient overexpression of FAM/USP9X resulted in the deubiquitylation of Itch. Moreover, we show that Itch auto-ubiquitylation leads to its degradation in the proteasome. By examining the amounts of Itch and FAM in various cell lines and rat tissues, a positive correlation was found in the expression of both proteins. This observation suggests that the levels of FAM expression could have an influence on Itch in cells. Experimental decrease in FAM levels by RNA interference leads to a significant reduction in intracellular levels of endogenous Itch, which can be prevented by treatment with the proteasome inhibitor lactacystin. Accordingly, overexpression of FAM/USP9X resulted in a marked increase in endogenous Itch levels. These results demonstrate an intriguing interplay between a ubiquitin ligase and a ubiquitin protease, based on direct interaction between the two proteins.
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PMID:The ubiquitin ligase itch is auto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X. 1703 27

Homozygous itchy mice develop a fatal, late-onset autoimmune-like disease due to a loss of function mutation in an ubiquitin protein ligase. Phylogenetic and in vitro analyses suggest that Itch is a negative regulator of Notch signaling. Since Notch proteins have many important functions in the immune system, we determined whether Itch regulates Notch signaling in vivo. This was accomplished by breeding homozygous itch mice to mice carrying an activated Notch1 transgene that was specifically overexpressed in developing thymocytes. Interestingly, all itch mice carrying this transgene were smaller than their littermates and died by 12 weeks of age. These mice had a similar autoimmune disease to that seen in itch animals. However, the lesions were more severe with a much earlier age of onset, supporting the assertion that these mutations genetically interact. In addition, the combination of these mutations produced novel phenotypes including a perturbation in T cell development, with a reduction in the number of double-positive (DP) and an increase in the number of double-negative and single-positive T cells. TUNEL staining showed reduced apoptosis in the thymus of itch animals that carry the Notch1 transgene. Antibody staining displayed increased levels of full-length Notch1 and phospho-AKT specifically in DP thymocytes but no change in other signaling pathways including MAPK, p38 and JNK. These results provide the first direct demonstration that increased AKT-mediated Notch1 signaling results in autoimmunity and may provide insight into the treatment of a group of diseases that affect a significant proportion of the population.
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PMID:Itch genetically interacts with Notch1 in a mouse autoimmune disease model. 1709 21

Upon DNA damage signaling, p73, a member of the p53 tumor suppressor family, accumulates to support transcription of downstream apoptotic genes. p73 interacts with Yes-associated protein 1 (Yap1) through its PPPY motif, and increases p73 transactivation of apoptotic genes. The ubiquitin E3 ligase Itch, like Yap1, interacts with p73. Given the fact that both Itch and Yap1 bind p73 via the PPPY motif, we hypothesized that Yap may also function to stabilize p73 by displacing Itch binding to p73. We show that the interaction of Yap1 and p73 was necessary for p73 stabilization. Yap1 competed with Itch for binding to p73, and prevented Itch-mediated ubiquitination of p73. Treatment of cells with cisplatin leads to an increase in p73 accumulation and induction of apoptosis, but both were dramatically reduced in the presence of Yap1 siRNA. Altogether, our findings attribute a central role to Yap1 in regulating p73 accumulation and function under DNA damage signaling.
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PMID:The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73. 1711 Sep 58

Hedgehog pathway is crucial for the maintenance and self-renewal of neural stem cells and for tumorigenesis. Hedgehog signaling is limited by multiple E3 ubiquitin ligases that process the downstream transcription factors Gli. Cullin family-based ubiquitination results in either Cullin1-Slimb/betaTrCP- or Cullin3-HIB/Roadkill/SPOP-dependent proteolytic processing or degradation of Drosophila Cubitus interruptus or mammalian Gli proteins. We have recently identified Itch as an additional HECT family E3 ligase, able to ubiquitinate and degrade Gli1. A functional link with the influence of Hedgehog signaling on cell development and tumorigenesis is suggested by the identification of Numb as a promoter of such an Itch-dependent ubiquitination process that leads to Gli1 degradation, thus suppressing its transcriptional function. Numb is an evolutionary conserved developmental protein that, during progenitor division, asymmetrically segregates to daughter cells thereby determining distinct binary cell fates. Numb is downregulated in cerebellar progenitors and their malignant derivatives (i.e. medulloblastoma cells). Furthermore, Numb has anti-proliferative and pro-differentiation effects on both cerebellar progenitors and medulloblastoma cells, due to its suppression of functional Gli1. These findings unveil a novel Numb/Itch-dependent regulatory loop that limits the extent and duration of Hedgehog signaling during neural progenitor differentiation. Its subversion emerges as a relevant event in brain tumorigenesis.
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PMID:Multiple ubiquitin-dependent processing pathways regulate hedgehog/gli signaling: implications for cell development and tumorigenesis. 1731 94

Tagging a small molecule ubiquitin to a protein substrate, or protein ubiquitination, plays an important role in the immune responses. This process is catalyzed by a cascade of enzymatic reactions, with the E3 ubiquitin ligases being the critical enzymes that determine the specificity of substrate recognition. The E3 ligase Itch was identified from a mutant mouse which displays skin scratching and abnormal immune disorders. In the past few years, much progress has been made in our understanding of Itch-promoted protein ubiquitination, modulation of its ligase activity by upstream kinases, and the kinase-ligase interaction in T cell differentiation and tolerance induction.
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PMID:The E3 ubiquitin ligase Itch in T cell activation, differentiation, and tolerance. 1743 11

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 receptors occurs via the WW domains of AIP4/Itch. Functional analyses demonstrate that AIP4/Itch is recruited to the ErbB-4 receptor to promote its polyubiquitination and degradation, thereby regulating stability of the receptor and access of receptor intracellular domains to the nuclear compartment. These findings expand our understanding of the mechanisms contributing to the integrity of the ErbB signaling network and mechanistically link the cellular ubiquitination pathway of AIP4/Itch to the ErbB-4 receptor.
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PMID:The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation. 1746 26

A growing body of literature indicates that the Notch pathway can influence the activation and differentiation of peripheral murine T cells, though comparatively little is known about the effects of Notch signaling in human T cells. In the present report we demonstrate that Jagged-1-induced Notch signaling (using immobilized Jagged-1 fusion protein) during stimulation of purified human CD4+ and CD8+ T cells potently inhibits T cell proliferation and effector function, including both Th1- and Th2-associated cytokines. Inhibition of T cell activation is not due to apoptosis or disruption of proximal TCR signaling, but is associated with up-regulation of GRAIL (gene related to anergy in lymphocytes) in CD4+ T cells, with modest effects on other E3 ubiquitin ligases such as c-Cbl and Itch. When evaluated for its effects on CD4+ T cell differentiation, Jagged-1-mediated signaling inhibits T cell cytokine secretion with no significant effect on proliferative responses. Collectively, these data demonstrate that Notch signaling in human T cells induced by Jagged-1 promotes a novel form of T cell hyporesponsiveness that differs from anergy, whereby primary T cell proliferation and cytokine secretion are potently inhibited, and effector function but not proliferative capacity are ameliorated upon secondary stimulation.
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PMID:Up-regulation of gene related to anergy in lymphocytes is associated with Notch-mediated human T cell suppression. 1747 42


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