he activation of tyrosine kinases is an early and essential event in the transduction of signals from immune receptors, including the B and T-cell receptors for antigen, activatory natural killer (NK)-cell receptors, the mast cell and basophil receptor for IgE and the widely distributed receptors for the Fc portion of IgG (Fig. 1). Immune receptors control checkpoints in lymphocyte development and serve to integrate the responses of innate and acquired immunity. Although the extracellular domains of immune receptors are quite different, they share the ability to associate with invariant subunits, which contain an immunoreceptor tyrosinebased activation motif (ITAM) in their cytoplasmic domains. This motif is characterized by a consensus sequence that includes two tyrosines, typically 10-12 amino acids apart, which are rapidly phosphorylated following engagement of the immune receptor. The phosphorylated ITAM mediates association of the receptor complex with signalling molecules containing SH2 domains.
Several classes of non-receptor tyrosine kinases expressed by cells of the immune system have been shown to interact with ITAMs; these include members of the SRC family and the Bruton's tyrosine kinase (BTK)/TEC family. A third class of tyrosine kinase, SYK and ZAP-70, contain two SH2 domains (Fig. 2). SYK is expressed by all haematopoietic cells; it is essential for lymphocyte development and signal transduction via immune receptors in non-lymphoid cells. This review will focus on discussion of the cell types and physiological processes that require SYK.
Structure of SYK and ZAP-70
SYK family tyrosine kinases contain a C-terminal kinase domain and tandem N-terminal SH2 domains that bind phosphorylated ITAMs (Fig. 2). A 'linker' region, designated interdomain B, that contains multiple tyrosines separates the SH2 domains from the kinase domain. These tyrosines, when phosphorylated, act as docking sites for proteins such as phospholipase Cβ₯1 (PLCβ₯1), VAV and CBL, which might be substrates for SYK and ZAP-70 (Refs 1-3). Beyond the catalytic domain lie tyrosine residues which, when mutated to phenylalanine, give rise to gain-of-function mutants 4 . The mechanism by which these C-terminal tyrosines mediate their inhibitory effect is not known but might involve the binding of a phosphatase which dephosphorylates SYK.
Though similar in overall structure, there are important differences between SYK and ZAP-70. In particular, the most abundant form of SYK contains a 23 amino acid insert in the linker region, which is not found in ZAP-70. A less abundant, alternatively spliced form of SYK, SYKB, does not contain this insert and is thus more similar to ZAP-70 (Fig. 2). Recent experiments have shown functional consequences of this difference: SYK couples the Fcβ₯RI receptor of mast cells to downstream intracellular signalling pathways much more efficiently than SYKB (Ref. 5). This difference correlates with a higher binding affinity of SYK to phosphorylated ITAMs compared with SYKB. In accordance with these findings, ZAP-70 behaved much more like SYKB -it was inefficient at coupling Fcβ₯RI signalling and bound less avidly to phosphorylated ITAMs than SYK.