Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes.

Abstract

SummaryAccumulating data show that the tyrosine protein kinase Zap-70 plays an essential role in T cell receptor-mediated signal transduction. However, the mode of action, as well as the physiologically relevant substrates of Zap-70, have not been determined. We have attempted to identify a 120-kD tyrosine-phosphorylated protein (p120) that associates with Zap-70 in activated T lymphocytes. The results of our analyses showed that p120 is largely encoded by the c-cbl protooncogene. Furthermore, the association of Zap-70 with c-Cbl was shown to be induced by T cell receptor stimulation, implying that it required posttranslational modification of one or both of these products. FynT, but not Lck, also associated with c-Cbl in activated T cells. Finally, using a heterologous system, it was demonstrated that the ability of Zap-70 to cause tyrosine phosphorylation of p120 c-cbl was dependent on Lck-or FynT-mediated signals. As c-Cbl can associate with several other signaling molecules, it may couple Zap-70 to downstream es lectors during T cell activation.

Tissue Hyperplasia and Enhanced T-Cell Signalling via ZAP-70 in c-Cbl-Deficient Mice

“…This implied that a kinase other than Lck may be responsible for inappropriate activation of ZAP-70 in CD3-cross-linked c-Cbl Ϫ/Ϫ thymocytes. Several reports have described an interaction between c-Cbl and the CD3⑀ chain-associated Src family kinase, Fyn (14,16,55). Although it is possible that the loss of c-Cbl increases the availability of Fyn to phosphorylate ZAP-70 following CD3⑀ cross-linking, we have found no evidence of this (data not shown).…”

Selective Defect in Antigen-Induced TCR Internalization at the Immune Synapse of CD8 T Cells Bearing the ZAP-70(Y292F) Mutation

“…Tyrosine-292 in ZAP-70, when phosphorylated upon TCR activation, is a binding site for c-cbl and cbl-b via the cbl tyrosine kinase binding domain (22)(23)(24). Contrasting results were reported for thymocytes of mice expressing an altered c-cbl mutated in its tyrosine kinase binding domain, because this led to constitutive activation of rac without affecting ZAP-70 phosphorylation (25).…”

PTPN22 and rheumatoid arthritis: Gratifying replication

“…In addition, although PTPN22 binds to the intracellular kinase Csk, there is also evidence that PTPN22 can bind to other proteins such as c-Cbl and Grb2 (18,19). Baseline tyrosine phosphorylation is reduced in COS cells overexpressing Lyp/PEP, indicating that PEP may regulate the function of Cbl-associated proteins, such as ZAP-70 (20). Lyp also binds Grb2, a signaling adaptor molecule that is involved in CD28-mediated costimulation and T cell activation (19).…”