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lüll The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system Rao N; Dodge I; Band HJ Leukoc Biol 2002[May]; 71 (5): 753-63The Cbl family of proteins are evolutionarily conserved negative regulators of activated tyrosine kinase-coupled receptors. Antigen receptors are prominent targets of negative regulation by the Cbl family members, Cbl and Cbl-b, which proteins function as ubiquitin ligases. Cbl and Cbl-b contain substrate recognition domains that interact specifically with activated protein tyrosine kinases of the Src and Syk/ZAP-70 families. Cbl-mediated ubiquitination of these kinases leads to their degradation, resulting in attenuation of receptor signals. Cbl may also control activation-induced monoubiquitination of antigen receptors, thus facilitating their delivery to lysosomes for subsequent degradation. Finally, the interactions of Cbl proteins with downstream targets of tyrosine kinases, such as PI-3-kinase and Vav, could provide an additional mechanism to attenuate receptor signaling. By targeting multiple components of antigen receptor signaling for degradation, the Cbl protein family provides a critical mechanism to ensure an appropriate immune response. The hyperresponsiveness of Cbl(-/-) and Cbl-b(-/-) lymphocytes and the autoimmune phenotype of Cbl-b(-/-) mice lend strong support for this proposal. The ability to control early receptor signals through regulated protein degradation provides a novel paradigm of immunoregulation.|Animals[MESH]|Down-Regulation[MESH]|Ligases/chemistry/*physiology[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Models, Biological[MESH]|Protein Structure, Tertiary[MESH]|Protein-Tyrosine Kinases/*antagonists & inhibitors[MESH]|Proto-Oncogene Proteins c-cbl[MESH]|Proto-Oncogene Proteins/chemistry/genetics/*physiology[MESH]|Receptors, Antigen/*metabolism[MESH]|Receptors, Cell Surface/metabolism[MESH]|Signal Transduction[MESH]|Ubiquitin-Protein Ligases[MESH]|Ubiquitin/metabolism[MESH] |