Abstract
E3 ubiquitin ligase Cbl-b plays a crucial role in T cell activation and tolerance induction. However, the molecular mechanism by which Cbl-b inhibits T cell activation remains unclear. Here, we report that Cbl-b does not inhibit PI3K but rather suppresses TCR/CD28-induced inactivation of Pten. The elevated Akt activity in Cbl-b(-/-) T cells is therefore due to heightened Pten inactivation. Suppression of Pten inactivation in T cells by Cbl-b is achieved by impeding the association of Pten with Nedd4, which targets Pten K13 for K63-linked polyubiquitination. Consistent with this finding, introducing Nedd4 deficiency into Cbl-b(-/-) mice abrogates hyper-T cell responses caused by the loss of Cbl-b. Hence, our data demonstrate that Cbl-b inhibits T cell activation by suppressing Pten inactivation independently of its ubiquitin ligase activity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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CD28 Antigens / metabolism
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Endosomal Sorting Complexes Required for Transport / deficiency
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Endosomal Sorting Complexes Required for Transport / genetics
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Endosomal Sorting Complexes Required for Transport / metabolism*
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Female
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Lymphocyte Activation / physiology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Models, Animal
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Molecular Sequence Data
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Nedd4 Ubiquitin Protein Ligases
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PTEN Phosphohydrolase / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-cbl / deficiency
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism*
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / physiology
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T-Lymphocytes / metabolism*
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T-Lymphocytes / pathology
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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CD28 Antigens
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Cblb protein, mouse
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Endosomal Sorting Complexes Required for Transport
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Receptors, Antigen, T-Cell
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Nedd4 Ubiquitin Protein Ligases
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Nedd4l protein, mouse
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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Pten protein, mouse
Associated data
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GENBANK/BC032851
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GENBANK/BC138813
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GENBANK/NM008960