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

• Published in: The Journal of biological chemistry Vol. 273; no. 25; pp. 15445 - 15452
• Main Authors: Zeitlmann, L, Knorr, T, Knoll, M, Romeo, C, Sirim, P, Kolanus, W
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 19-06-1998
• Subjects: Amino Acid Sequence; Calcium - metabolism; Catalysis; Enzyme Precursors - genetics; Enzyme Precursors - metabolism; Humans; Interleukin-2 - genetics; Intracellular Signaling Peptides and Proteins; Jurkat Cells; Lymphocyte Activation; Molecular Sequence Data; Mutation; Promoter Regions, Genetic; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Receptors, Antigen, B-Cell - metabolism; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Recombinant Fusion Proteins - metabolism; Signal Transduction; Syk Kinase; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; ZAP-70 Protein-Tyrosine Kinase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.25.15445

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of novel mutants of ZAP-70 and Syk, in which conserved C-terminal tyrosine residues have been replaced by phenylalanines (ZAP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.