ZAP-70-deficient patients present with nonfunctional CD4+ T cells in the periphery. We find that a subset of primary ZAP-70-deficient T cells, expressing high levels of the related protein-tyrosine kinase Syk, can proliferate in vitro. These cells (denoted herein as Syk(hi)/ZAP-70(-) T cells) provide a unique model in which the contribution of Syk to TCR-mediated responses can be explored in a nontransformed background. Importantly, CD3-induced responses, such as tyrosine phosphorylation of cellular substrates (LAT, SLP76, and PLC-gamma1), as well as calcium mobilization, which are defective in T cells expressing neither ZAP-70 nor Syk, are observed in Syk(hi)/ZAP-70(-) T cells. However, Syk(hi)/ZAP-70(-) T cells differ from control T cells with respect to the T cell antigen receptor (TCR)-mediated activation of the MAPK cascades: extracellular signal-regulated kinase activity and recruitment of the JNK and p38 stress-related MAPK pathways are diminished. This distinct phenotype of Syk(hi)/ZAP-70(-) T cells is associated with a profound decrease in CD3-mediated interleukin 2 secretion and proliferation relative to control T cells. Thus, ZAP-70 and Syk appear to play distinct roles in transducing a TCR-mediated signal.
Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk
Noraz, N.; Schwarz, K.; Steinberg, M.; Dardalhon, V.; Rebouissou, C.; Hipskind, R.; Friedrich, W.; Yssel, H.; Bacon, K.; Taylor, N.
J Biol Chem
2000-05-26 / vol 275 / pages 15832-8
Humans; Calcium/metabolism; Molecular Sequence Data; Phosphorylation; Base Sequence; Mutation; Phosphoproteins/metabolism; Signal Transduction/genetics; Cell Division; Interleukin-2/secretion; ZAP-70 Protein-Tyrosine Kinase; Intracellular Signaling Peptides and Proteins; Jurkat Cells; Carrier Proteins/metabolism; *Adaptor Proteins, Signal Transducing; *Membrane Proteins; Antigens, CD3/metabolism; Enzyme Precursors/*metabolism; Isoenzymes/metabolism; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases/metabolism; Phospholipase C gamma; Phosphotyrosine/metabolism; Protein-Tyrosine Kinases/*deficiency/genetics/*metabolism; Receptors, Antigen, T-Cell/*metabolism; Type C Phospholipases/metabolism