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These authors show clear evidence that c-Cbl mediates CD3ζ chain ubiquitination. They also show that this function depends on Zap-70, which acts as a linker between c-Cbl and CD3ζ. These data provide an explanation of how c-Cbl selectively promotes ubiquitination of the activated TCR complex.
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•] suggest that c-Cbl regulates the Lck activation in T cells by eliminating it from the lipid rafts and promoting its ubiquitination and degradation.
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Zhang J., Bardos T., Li D., Gal I., Vermes C., Xu J., Mikecz K., Finnegan A., Lipkowitz S., Glant T.T. Cutting edge: regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination. J. Immunol. 169:2002;2236-2240 This paper shows that co-stimulation by TCR and CD28 promotes ubiquitination and degradation of Cbl-b, thus providing an explanation for how CD28 co-stimulation enhances the T-cell response following TCR engagement.
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This paper describes that ubiquitination of p85, the regulatory subunit of PI-3 kinase, in T cells is mediated by Cbl-b. It also shows that ubiquitination of p85 prevents the recruitment of p85 to CD3 and CD28, leading to a low PI-3 kinase activity upon TCR engagement. In the absence of Cbl-b, p85 ubiquitination is reduced, resulting in an increased association of p85 with CD3 and CD28, as well as an enhanced PI-3 kinase activity. As PI-3 kinase functions upstream of Vav activation in T cells, these data thus provide an explanation how Vav activation is regulated by Cbl-b.
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Fang D., Liu Y.C. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat. Immunol. 2:2001;870-875 This paper describes that ubiquitination of p85, the regulatory subunit of PI-3 kinase, in T cells is mediated by Cbl-b. It also shows that ubiquitination of p85 prevents the recruitment of p85 to CD3 and CD28, leading to a low PI-3 kinase activity upon TCR engagement. In the absence of Cbl-b, p85 ubiquitination is reduced, resulting in an increased association of p85 with CD3 and CD28, as well as an enhanced PI-3 kinase activity. As PI-3 kinase functions upstream of Vav activation in T cells, these data thus provide an explanation how Vav activation is regulated by Cbl-b.
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This paper reports the first case in which Cbl-b is found to be a major factor responsible for the susceptibility of the type one diabetes in an existing autoimmune animal model.
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Yokoi N., Komeda K., Wang H.Y., Yano H., Kitada K., Saitoh Y., Seino Y., Yasuda K., Serikawa T., Seino S. Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat. Genet. 31:2002;391-394 This paper reports the first case in which Cbl-b is found to be a major factor responsible for the susceptibility of the type one diabetes in an existing autoimmune animal model.
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Thien C.B., Langdon W.Y. Cbl: many adaptations to regulate protein tyrosine kinases. Nat. Rev. Mol. Cell Biol. 2:2001;294-307.
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Dysregulation of T lymphocyte function in itchy mice: A role for Itch in TH2 differentiation
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This paper describes a mutant mouse strain in which mutation in the Itch gene, an E3 ubiquitin ligase, leads to severe inflammatory disorder and constant itching of the skin. It is found that Itch mutant mice produce a high level of IgE in vivo, and Itch mutant T cells exhibit a biased differentiation potential toward Th2 cells in vitro. Transcription factor JunB is associated with the Itch protein, suggesting that Itch might regulate Th2 differentiation by controlling JunB ubiquitination.
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Fang D., Elly C., Gao B., Fang N., Altman Y., Joazeiro C., Hunter T., Copeland N., Jenkins N., Liu Y.C. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat. Immunol. 3:2002;281-287 This paper describes a mutant mouse strain in which mutation in the Itch gene, an E3 ubiquitin ligase, leads to severe inflammatory disorder and constant itching of the skin. It is found that Itch mutant mice produce a high level of IgE in vivo, and Itch mutant T cells exhibit a biased differentiation potential toward Th2 cells in vitro. Transcription factor JunB is associated with the Itch protein, suggesting that Itch might regulate Th2 differentiation by controlling JunB ubiquitination.
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