The Cbl family of ubiquitin ligases: Critical negative regulators of tyrosine kinase signaling in the immune system

Navin Rao, Ingrid Dodge, Hamid Band

Research output: Contribution to journalReview articlepeer-review

135 Scopus citations

Abstract

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 hyper-responsiveness 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.

Original languageEnglish (US)
Pages (from-to)753-763
Number of pages11
JournalJournal of Leukocyte Biology
Volume71
Issue number5
StatePublished - May 1 2002

Keywords

  • Antigen receptors
  • Immunoregulation
  • PI-3K
  • SFK Syk/ZAP-70

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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