Abstract
Protein-tyrosine kinases p56(Lck), SYK, and ZAP-70 and downstream adaptors LAT and SLP-76 have been implicated as essential components in T-cell activation. Another lymphoid-specific adaptor FYB/SLAP has also been identified as a predominant binding partner of SLP-76 and the Src kinase FYN-T, although its role in the activation process has been unclear. In this study, we demonstrate that FYN-T selectively phosphorylates FYB providing a template for the recruitment of FYN-T and SLP-76 SH2 domain binding. This interaction is unusual in its distinct cytoplasmic localization and its long term stable kinetics of phosphorylation. Furthermore, we demonstrate for the first time that the co-expression of all three components of the FYN-T-FYB-SLP-76 matrix can synergistically up-regulate T-cell receptor-driven interleukin 2 transcription activity. These findings document the existence of a T-cell receptor-regulated FYN-T-FYB pathway that interfaces with the adaptor SLP-76 and up-regulates lymphokine production in T-cells.
Highlights
Ligation of CD4/CD8-p56Lck and the T-cell receptor complex (TcR1/CD3) activates Src protein-tyrosine kinases p56Lck and p59Fyn-T [1] leading to the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) of the TcR and CD3 chains [2,3,4]
We demonstrate that the Src kinase FYN-T regulates the binding of the FYN-T and SLP-76 Src homology 2 (SH2) domains to distinct sites on FYB
As an internal control for expression, FYB and SLP-76 (Fig. 1, A and B, lower panels), and the kinases (Lck, FYN-T, and ZAP-70) in each co-transfectant was expressed at significant levels
Summary
Ligation of CD4/CD8-p56Lck and the T-cell receptor complex (TcR1/CD3) activates Src protein-tyrosine kinases p56Lck and p59Fyn-T [1] leading to the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) of the TcR and CD3 chains [2,3,4]. We demonstrate that the Src kinase FYN-T (but not LCK or ZAP-70) regulates the binding of the FYN-T and SLP-76 SH2 domains to distinct sites on FYB. As an internal control for expression, FYB and SLP-76 (Fig. 1, A and B, lower panels), and the kinases (Lck, FYN-T, and ZAP-70) in each co-transfectant was expressed at significant levels (data not shown).
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