Cbl promotes ubiquitination of the T cell receptor zeta through an adaptorfunction of Zap-70

Triggering of the T cell antigen receptor (TCR). CD3 complex induces its ub iquitination, However, the molecular events that lead to ubiquitin conjugat ion to these cell surface molecules have not been defined, Here we report t hat Cbl, a RING-type E3 ubiquitin-protein ligase, promotes ubiquitination o f TCR zeta chain, which requires its functional variant Src homology 2 doma in and an intact RING finger. The tyrosine kinase Zap-70, which binds to bo th TCR zeta and Cbl, plays an adaptor role in these events, Mutations in TC R zeta, Zap-70, or Cbl that disrupt the interaction between TCR zeta and Za p-70 or between Zap-70 and Cbl reduce ubiquitination of TCR zeta Our result s suggest a novel mechanism by which Cbl negatively regulates T cell develo pment and activation by inducing ubiquitination of the TCR CD3 components.