Review
Tyrosine kinase SYK: essential functions for immunoreceptor signalling

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Abstract

The tyrosine kinase SYK plays critical roles in signalling through immune receptors. Gene-targeting studies have identified the cell types that require SYK for development and function, and the receptors that use SYK as well as their downstream signalling effectors. There is also evidence of a role for SYK in non-immune cells and in the maintenance of vascular integrity.

Section snippets

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 Cγ1 (PLCγ1), VAV and CBL, which might be substrates for SYK and ZAP-70 (1, 2, 3). Beyond the catalytic domain lie tyrosine residues which,

Dependence on SRC-family kinases and ITAM interaction

Several studies suggest that SYK is less dependent upon SRC-family kinases for function than ZAP-70 (Ref. 6). T-cell hybrids expressing a CD16–ZAP-70 chimaeric receptor required co-crosslinking of the receptor with the SRC-family kinases FYN or LCK to activate their cytotoxic potential. By contrast, crosslinking of the CD16–SYK chimera alone activated cytotoxicity7. Furthermore, mutant Jurkat T-cell lines that lack LCK (Ref. 8) or the tyrosine phosphatase CD45 (Ref. 9), which is implicated in

αβ T cells

SYK was initially characterized as an abundant protein tyrosine kinase in thymus and spleen. During T-cell ontogeny, SYK is expressed by CD4CD8 double-negative (DN) and CD4+CD8+ double-positive (DP) thymocytes, but expression levels are markedly reduced in CD4+ and CD8+ single-positive (SP) thymocytes and peripheral T cells17. By contrast, ZAP-70 is expressed throughout thymocyte development and at high levels in peripheral T cells17. These expression profiles suggest that SYK and ZAP-70 play

γδ T cells

In conventional TCRαβ-bearing T cells, SYK, like ZAP-70, is thought to couple the receptor to downstream pathways through its association with the ζ chain of the CD3 complex. By contrast, in some γδ T cells, particularly γδ intraepithelial lymphocytes (IELs), SYK can be coupled to downstream pathways via the FcRγ chain23. Previous studies have suggested that the development of some γδ IELs requires SYK (24, 25). Analysis of Syk−/− fetal thymi revealed a deficiency in the development of γδ

NK cells

NK cells are bone-marrow-derived lymphocytes that do not express rearranged TCRs or B-cell receptors (BCRs). NK cells mediate cytotoxic killing without prior sensitization: their ontogeny and the pathways leading to NK-cell activation are, however, only partly understood28. The first evidence of a non-essential role for SYK in the differentiation of NK cells comes from studies of SYK−/− to RAG2/γc haematopoietic chimeras. Phenotypically mature SYK−/− NK cells develop and demonstrate normal

B cells

The development of B cells proceeds through a well-characterized set of stages defined by the extent of antigen receptor rearrangement and the expression of particular cell surface markers. The functional assembly of a pre-B-cell receptor (pre-BCR), comprising the nascent heavy chain, the surrogate light chains λ5 and VpreB, and CD79α and β (Igα and β), is essential for the development of a normal-sized pool of pre-B cells in which rearrangement of light chains occurs. When RAG1-deficient mice

Myeloid cells and Fc receptors

Activation of mast cells by antigen–IgE complexes stimulates the release of inflammatory mediators in the form of secretory granule contents, cytokines and arachidonic acid metabolites. The receptor for antigen–IgE complexes, FcϵRI, contains an IgE binding α subunit complexed with a β chain and a dimer of γ chains that each contain an ITAM. The γ chain binds SYK whereas the β ITAM binds the SRC-family kinase LYN and acts as an amplifier by recruiting and activating SYK to the γ chain39. Several

Platelets

In platelets, biochemical and pharmacological evidence has implicated SYK in signalling through a large number of receptors including the ADP, thrombin, von Willebrand factor, FcγRIIA and GPVI collagen receptors and the integrin αIIbβ3. Analysis of Syk−/− platelets has allowed a direct assessment of the role of SYK in signalling from a variety of receptors49. Signalling through the GPVI collagen receptor was shown to require both SYK and FcRγ, because platelets deficient in either of these

Concluding remarks

Gene targeting studies have demonstrated an essential role for SYK in signalling through a variety of immune receptors in both lymphoid and myeloid cells. In some circumstances SYK has unique functions, but in others, the related kinase ZAP-70 is able to compensate functionally. Finally, studies have shown that SYK plays a role in signalling from receptors not thought of as belonging to the ‘immune receptor’ family, thus extending the function of these kinases to a broader range of signalling

Acknowledgements

We thank D. Alexander, G. Butcher, G. Doody, L. Martensson and L. Webb for commenting on draft versions of this manuscript.

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