ReviewTyrosine kinase SYK: essential functions for immunoreceptor signalling
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 CD4−CD8− 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.
References (54)
- et al.
Association of p72 Syk with the SRC homology-2 (SH2) domains of PLC-γ1 in B lymphocytes
J. Biol. Chem.
(1995) Identification of the major sites of autophosphorylation of the murine protein-tyrosine kinase Syk
Biochim. Biophys. Acta
(1997)T cell activation induced by novel gain-of-function mutants of Syk and ZAP-70
J. Biol. Chem.
(1998)T cell activation by clustered tyrosine kinases
Cell
(1993)ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain
Cell
(1992)A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development
Immunity
(1997)Restoration of thymocyte development and function in zap-70−/− mice by the Syk protein tyrosine kinase
Immunity
(1997)Signal transduction during natural killer cell activation: inside the mind of a killer
Immunity
(1997)FcR gamma chain deletion results in pleiotrophic effector cell defects
Cell
(1994)B-cell receptor regulation of peripheral B cells
Curr. Opin. Immunol.
(1998)
The Fc(epsilon)RIbeta subunit functions as an amplifier of Fc(epsilon)RIgamma-mediated cell activation signals
Cell
Initial events in Fc epsilon RI signal transduction
J. Allergy. Clin. Immunol
Signal transduction by lymphocyte antigen receptors
Cell
The molecular dissection of Fc gamma receptor mediated phagocytosis
Blood
Collagen receptor signalling in platelets: extending the role of the ITAM
Immunol Today
Genetic and pharmacological analyses of Syk function in alphaIIbbeta3 signaling in platelets
Blood
Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76
Cell
Syk activation and dissociation from the B-cell antigen receptor is mediated by phosphorylation of tyrosine 130
J. Biol. Chem.
Phospholipase C-gamma1 interacts with conserved phosphotyrosyl residues in the linker region of Syk and is a substrate for Syk
Mol. Cell. Biol
The unique insert in the linker domain of Syk is necessary for its function in immunoreceptor signalling
EMBO J
The Syk family of protein tyrosine kinases in T-cell activation and development
Immunol. Rev
Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases
Science
The Syk protein tyrosine kinase can function independently of CD45 or Lck in T cell antigen receptor signaling
EMBO J
Syk activation by the SRC-family tyrosine kinase in the B cell receptor signaling
J. Exp. Med
Activation of p56lck by p72syk through physical association and N-terminal tyrosine phosphorylation
Mol. Cell. Biol.
Protein tyrosine kinases Syk and ZAP-70 display distinct requirements for SRC family kinases in immune response receptor signal transduction
J. Immunol.
Syk protein-tyrosine kinase is regulated by tyrosine-phosphorylated Ig alpha/Ig beta immunoreceptor tyrosine activation motif binding and autophosphorylation
J. Biol. Chem.
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