A direct interaction between the adaptor protein Cbl-b and the kinase Zap-70 induces a positive signal in T cells

Engagement of the T-cell receptor (TCR)-CD3 complex induces a rapid increas e in the activities of Src-family and Syk/Zap-70-family kinases [1,2]. Thes e activated kinases then induce the tyrosine phosphorylation of multiple in tracellular proteins, eventually leading to T-cell activation. One of the p rominent substrates for these kinases is the adaptor protein Chi [3] and re cent studies suggest that Cbl negatively regulates upstream kinases such as Syk and Zap-70 [4,5]. Cbl-b, a homologue of Chl, is widely expressed in ma ny tissues and cells including hematopoietic cells [6,7]. Cbl-b undergoes r apid tyrosine phosphorylation upon stimulation of the TCR and cytokine rece ptors [8,9]. The role of Cbl-b is unclear, however. Here, we show that over expression of Cbl-b in T cells induced the constitutive activation of the t ranscription factor nuclear factor of activated T cells (NFAT). A loss-of-f unction mutation in Cbl-b disrupted the interaction between Cbl-b and Zap-7 0 and nearly completely abrogated the Cbl-b-mediated activation of NFAT. Un like the proposed role of Cbl as a negative regulator, our results suggest that the Cbl homologue Cbl-b has a positive role in T-cell signaling, most likely via a direct interaction with the upstream kinase Zap-70.