Abstract
c-Cbl is an adaptor protein that negatively regulates signal transduction events involved in thymic-positive selection. To further characterize the function of c-Cbl in T cell development, we analyzed the effect of c-Cbl inactivation in mice deficient in the scaffolding molecule SLP-76. SLP-76-deficient mice show a high frequency of neonatal lethality; and in surviving mice, T cell development is blocked at the DN3 stage. Inactivation of c-cbl completely reversed the neonatal lethality seen in SLP-76-deficient mice and partially reversed the T cell development arrest in these mice. SLP-76(-/-) Cbl(-/-) mice exhibited marked expansion of polarized T helper type (Th)1 and Th2 cell peripheral CD4(+) T cells, lymphoid infiltrates of parenchymal organs, and premature death. This rescue of T cell development is T cell receptor dependent because it does not occur in recombination activating gene 2(-/-) SLP-76(-/-) Cbl(-/-) triple knockout mice. Analysis of the signal transduction properties of SLP-76(-/-) Cbl(-/-) T cells reveals a novel SLP-76- and linker for activation of T cells-independent pathway of extracellular signal-regulated kinase activation, which is normally down-regulated by c-Cbl.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Animals, Newborn
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Separation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Flow Cytometry
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Interferon-gamma / metabolism
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Interleukin-2 / metabolism
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Interleukin-4 / metabolism
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Liver / cytology
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Liver / metabolism
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Lung / cytology
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Lung / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-cbl
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / physiology
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Spleen / cytology
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Survival Rate
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T-Lymphocyte Subsets / physiology
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T-Lymphocytes / physiology*
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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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Carrier Proteins
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DNA-Binding Proteins
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Interleukin-2
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Lat protein, mouse
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Membrane Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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Rag2 protein, mouse
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Receptors, Antigen, T-Cell
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SLP-76 signal Transducing adaptor proteins
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V(D)J recombination activating protein 2
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Interleukin-4
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Interferon-gamma
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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CBL protein, human
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Cbl protein, mouse