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J Biol Chem, Vol. 273, Issue 25, 15445-15452, June 19, 1998

T Cell Activation Induced by Novel Gain-of-function Mutants of Syk and ZAP-70

Lutz ZeitlmannDagger , Thomas KnorrDagger , Michael KnollDagger , Charles Romeo§, Pinar SirimDagger , and Waldemar KolanusDagger

From the Dagger  Laboratorium für Molekulare Biologie, Genzentrum der Universität München, Feodor Lynen Strasse 25, D-81377 München, Germany and the § NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

The Syk family tyrosine kinases play a crucial role in antigen receptor-mediated signal transduction, but their regulation and cellular targets remain incompletely defined. Following receptor engagement, phosphorylation of tyrosine residues within ZAP-70 and Syk is thought to control both kinase activity and recruitment of modulatory factors. We report here the characterization of novel mutants of ZAP-70 and Syk, in which conserved C-terminal tyrosine residues have been replaced by phenylalanines (ZAP YF-C, Syk YF-C). Both mutant kinases display a prominent gain-of-function phenotype in Jurkat T cells, as demonstrated by lymphokine promoter activation, tyrosine phosphorylation of potential targets in vivo, and elevated intracellular calcium mobilization. While the presence of p56-Lck was required for ZAP YF-C-induced signaling, Syk YF-C showed enhanced functional activity in Lck-deficient JCaM1 Jurkat cells. Our results implicate the C terminus of Syk family kinases as an important regulatory region modulating T cell activation.


Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.



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