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The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system
Author(s) -
Rao Navin,
Dodge Ingrid,
Band Hamid
Publication year - 2002
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.71.5.753
Subject(s) - biology , microbiology and biotechnology , receptor tyrosine kinase , ubiquitin , syk , receptor protein tyrosine kinases , tyrosine kinase , signal transduction , proto oncogene tyrosine protein kinase src , biochemistry , gene
The 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.