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Volume 272, Number 1, Issue of January 3, 1997 pp. 168-173
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Ras-dependent, Ca²⁺-stimulated Activation of Nuclear Factor of Activated T Cells by a Constitutively Active Cbl Mutant in T Cells

(Received for publication, July 9, 1996, and in revised form, October 2, 1996)

Yun-Cai Liu , Chris Elly , Wallace Y. Langdon and Amnon Altman

From the Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121 and  Department of Pathology, University of Western Australia, Nedlands, West Australia 6009, Australia

T cell receptor (TCR) stimulation induces rapid tyrosine phosphorylation of cellular proteins, including Cbl, a protooncogene product whose function remains unclear. As a first step toward elucidating the function of Cbl in TCR-initiated signaling, we evaluated the ability of wild-type Cbl or a transforming Cbl mutant (70Z/3) to induce transcriptional activation of a nuclear factor of activated T cells (NFAT) element derived from the interleukin 2 (IL2) promoter in transiently cotransfected Jurkat-TAg T cells. 70Z/3, but not Cbl, caused NFAT activation which was significantly enhanced by stimulation with calcium ionophore, and was drastically reduced by cyclosporin A pretreatment. A point mutation of a potential phosphatidylinositol 3-kinase (PI3-K) binding site (Y⁷³¹EAM to Y⁷³¹EAC) in 70Z/3 disrupted the association of PI3-K with 70Z/3, but did not reduce the induction of NFAT activity, suggesting that the interaction between Cbl and PI3-K is not required in the 70Z/3-mediated induction of NFAT. Additional mapping studies indicated that defined deletions of C-terminal 70Z/3 sequences affected to a variable degree its ability to stimulate NFAT activity. Strikingly, deletion of 346 C-terminal residues augmented this activity, whereas removal of 20 additional residues abolished it. Coexpression of dominant negative Ras abrogated the basal or ionomycin-stimulated, 70Z/3-mediated NFAT activation, suggesting a functional Ras is required for this activation. These results implicate Cbl in Ras-dependent signaling pathways which lead to NFAT activation.

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