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J Biol Chem, Vol. 274, Issue 8, 4883-4889, February 19, 1999

Dual Regulation of T Cell Receptor-mediated Signaling by Oncogenic Cbl Mutant 70Z

Zhihong Zhang, Chris Elly, Amnon Altman, and Yun-Cai Liu

From the Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121

We previously showed that an oncogenic Cbl mutant (70Z) is constitutively active in transcriptional activation of nuclear factor at activated T cells (NFAT). However, the mechanism underlying this effect remains unclear. Here we analyzed the effects of 70Z mutations at an amino-terminal loss of function site (Gly-306) and at carboxyl-terminal potential tyrosine or serine phosphorylation sites on association with signaling proteins and on NFAT activation. Mutation at Gly-306 of 70Z disrupted its association with Zap-70 and almost completely abolished its ability to induce NFAT activation under basal and ionomycin-stimulated conditions. However, mutations at potential tyrosine or serine phosphorylation sites had little effect. In fact, expression of 70Z with Tyr-700, Tyr-731, or Tyr-774 mutated to Phe increased NFAT activity in comparison with unmutated 70Z. These findings suggest that an amino terminus-mediated interaction of 70Z with Zap-70 plays a positive role and that a carboxyl terminus-mediated, phosphotyrosine-dependent interaction with their binding proteins plays a negative role in 70Z-mediated NFAT activation. In support of this notion are the observations that 70Z reduced T cell receptor-induced NFAT activation and that wild-type Cbl further inhibited this event, suggesting that both 70Z and wild-type Cbl employ a similar mechanism by which Cbl proteins dually regulate T cell receptor-mediated signaling.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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