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  • Review Article
  • Published:

The SYK tyrosine kinase: a crucial player in diverse biological functions

Key Points

  • Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that has long been thought to exclusively mediate signalling by receptors of the adaptive immune response (B cell receptors (BCRs) and Fc receptors (FcRs)). However, recent studies indicate that it also participates in innate immunity and non-immune functions.

  • SYK activation proceeds through binding of its two SRC homology 2 (SH2) domains to phosphorylated tyrosine residues in immunoreceptor tyrosine-based activation motifs (ITAMs) or ITAM-like sequences in C-type lectins. Binding to phosphorylated ITAMs relieves SYK from an intramolecular autoinhibition and triggers its association with receptor-proximal signalling molecules.

  • SYK mediates integrin signalling in neutrophils, macrophages and platelets, signalling by P-selectin glycoprotein ligand 1 (PSGL1), as well as the development of osteoclasts. These responses are mediated by ITAM-containing adaptor molecules (mostly DAP12 and FcRγ).

  • SYK participates in innate recognition of fungal and other microbial pathogens, as well as of tissue damage, by C-type lectins. SYK activation by C-type lectins activates the caspase-recruitment domain 9–B cell lymphoma 10–mucosa-associated lymphoid tissue lymphoma translocation protein 1 (CARD9–BCL-10–MALT1) pathway and it is also required for NLR family, pyrin domain-containing 3 (NLRP3) inflammasome activation following fungal infection.

  • The phosphorylated ITAM-mediated activation of the SYK homologue SH2 domain ankyrin repeat kinase (SHARK) is required to remove cellular debris in Drosophila melanogaster. This finding indicates an ancient origin of the ITAM–SYK signalling pathway.

  • SYK is required for the separation of newly formed lymphatic vessels from the blood vasculature. This function is probably mediated by the SYK-coupled receptor CLEC2 in platelets.

  • SYK has a central role in the development of allergic and autoimmune diseases, as well as in haematological malignancies such as B cell lymphomas. A new SYK inhibitor has shown beneficial effects in human rheumatoid arthritis and B cell lymphomas.

Abstract

Spleen tyrosine kinase (SYK) is known to have a crucial role in adaptive immune receptor signalling. However, recent reports indicate that SYK also mediates other, unexpectedly diverse biological functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. SYK is activated by C-type lectins and integrins, and activates new targets, including the CARD9–BCL-10–MALT1 pathway and the NLRP3 inflammasome. Studies using Drosophila melanogaster suggest that there is an evolutionarily ancient origin of SYK-mediated signalling. Moreover, SYK has a crucial role in autoimmune diseases and haematological malignancies. This Review summarizes our current understanding of the diverse functions of SYK and how this is being translated for therapeutic purposes.

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Figure 1: General mechanism of SYK-mediated signalling.
Figure 2: Structural basis of SYK activation.
Figure 3: The role of SYK in integrin and PSGL1 signalling.
Figure 4: SYK-dependent innate pathogen and damage recognition pathways.
Figure 5: Non-immune functions of SYK.
Figure 6: The role of spleen tyrosine kinase (SYK) in B cell development and malignancies of the B cell lineage.

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Acknowledgements

We apologize to the many colleagues whose work could not be discussed owing to space constraints, as well as for the focus of this Review on mouse knockout studies. We thank the members of our laboratories for discussions and M. Kahn for sharing unpublished results. The authors' laboratories are supported by the European Research Council, the Wellcome Trust and the Hungarian Office for Research and Technology (A.M.), the Deutsche Forschungsgemeinschaft and the Deutsche Krebshilfe (J.R.), as well as by the UK Medical Research Council (V.L.J.T.).

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Victor Tybulewicz's homepage

SYK in the UCSD-Nature Molecule Pages

SYK in the Mouse Genome Informatics Database

Glossary

Immunoreceptor tyrosine-based activation motif

(ITAM). A short peptide motif containing two tyrosine residues that is found in the cytoplasmic tail of several signalling adaptor proteins and is necessary to recruit proteins that are involved in triggering activating signalling proteins. The consensus sequence is Tyr-X-X-(Leu/Ile)-X6–12-Tyr-X-X-(Leu/Ile), where X denotes any amino acid.

Glycoprotein VI

(GPVI). One of several collagen receptors expressed on platelets. GPVI is a transmembrane glycoprotein that is closely related to Fcα receptors (FcαRs). It associates with, and signals through, the ITAM-containing adaptor FcR γ-chain.

Petechia

A small red spot on the skin that results from localized bleeding owing to broken blood vessels. A large number of petechiae usually indicates a platelet defect. Note that, in contrast to the original assumptions, the red spots of SYK-deficient embryos are not bona fide petechiae as they are caused by a vascular developmental defect.

Osteoclasts

Large multinucleated cells that arise from macrophage precursors and are specialized for bone resorption. Once firmly adhered to the bone surface, osteoclasts release hypochlorous acid and hydrolytic enzymes to digest the bone tissue.

C-type lectins

Carbohydrate-recognizing proteins (lectins) that require Ca2+ ions for their proper function. A characteristic feature of their structure is a carbohydrate recognition domain. C-type lectins include soluble molecules such as the complement-activating mannose binding lectin, as well as cell surface receptors such as various CLEC proteins.

Paracaspase

A group of proteolytic enzymes distinct from, but closely related to, the caspases. The most important mammalian paracaspase is MALT1.

E3 ubiquitin ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation by the proteasome, sort them to specific subcellular compartments or modify their biological activity.

Pro-B cells

Cells in the earliest stage of B cell development in the bone marrow. They are characterized by incomplete immunoglobulin heavy-chain rearrangements and are defined as CD19+ cytoplasmic IgM or sometimes as B220+CD43+ (by the Hardy classification scheme).

Pre-B cells

Cells in a stage of B cell development in the bone marrow that are characterized by complete immunoglobulin heavy-chain rearrangement in the absence of immunoglobulin light-chain rearrangement. They express the pre-B cell receptor, which comprises a pseudo light chain and a heavy chain.

Transitional type 0 stage

Transitional B cells are recent emigrants from the bone marrow that are in the process of maturing into follicular and marginal zone B cells. They can be found in the spleen and typically have a half-life of a few days. Transitional B cells have been subdivided into subsets type 0 to type 3 based on expression of IgM, IgD, CD93 and CD23. Type 0 B cells are the earliest migrants from the bone marrow and are located in the red pulp of the spleen.

Pre-BCR

(Pre-B cell receptor). A receptor that is formed at the surface of pre-B cells by the pairing of rearranged immunoglobulin heavy chains with surrogate light chains and the heterodimer of Igα and Igβ. Signalling by the pre-BCR occurs in the absence of known ligands and is a crucial event in B cell development.

Pre-TCR

(Pre-T cell receptor). A cell surface receptor complex consisting of TCRβ, pre-TCRα and CD3 that is expressed by immature CD4CD8 thymocytes. Signalling through this complex is essential for maturation to the CD4+CD8+ stage.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). A cytotoxic mechanism by which an antibody-coated target cell is directly killed by a leukocyte that expresses Fc receptors, such as a natural killer cell, macrophage or neutrophil.

HemITAM

A peptide motif in the cytoplasmic tail of various C-type lectins, characterized by the presence of a single Tyr-X-X-Leu sequence (in contrast to the two such sequences present in consensus ITAMs). Phosphorylation of the tyrosine residue in the hemITAMs leads to binding to the SYK SH2 domains in a 2/1 stoichiometry.

Phosphomimetic

An amino acid of which the conformation resembles that of a phosphate residue, or that of the phosphorylated form of another amino acid. Owing to their negative charge, the most important phosphomimetic amino acids are glutamate and aspartate.

Vasculopathy

A disorder of blood vessels, such as inflammation of the vessel wall.

Heterologous expression systems

An experimental approach that relies on forced expression of a protein in cells (usually long-propagated cell lines). The approach is powerful but can lead to artefactual results owing to the expression of proteins in a 'unnatural' environment.

Slow rolling

The reduction of leukocyte rolling velocity in an inflammatory environment. Under normal conditions, leukocytes roll on the surface of endothelial cells at a speed of 40 μm per second, mainly determined by the low level expression of endothelial P-selectins. At sites of inflammation, E-selectins are expressed at high densities on the endothelial surface, leading to slowing down of the rolling cells to 5 μm per second.

Inside-out signalling

The process by which intracellular signalling mechanisms result in the activation of a cell surface receptor, such as integrins. By contrast, outside-in signalling is the process by which ligation of a cell surface receptor activates signalling pathways inside the cell.

T helper 17 (TH17) cell

A subset of CD4+ T helper cells that produce IL-17 and that are thought to be important in inflammatory and autoimmune diseases, as well as host defence against certain infectious pathogens. Their generation involves IL-23 and IL-21, as well as the transcription factors RORγt (retinoic acid receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

Inflammasome

A molecular complex of several proteins that following assembly leads to caspase 1-mediated cleavage of precursor proteins for IL-1β and IL-18, thereby producing the mature active cytokines.

Zymosan

A protein–carbohydrate complex prepared from yeast wall extract. Its polysaccharide components (β-glucans) contain d-glucose monomers that are linked by β-type glycosidic bonds. β-glucans are particularly strong activators of antifungal host defence.

Monosodium urate

A monosodium salt of uric acid that has a tendency to precipitate in needle-shaped crystals in the joints, leading to the inflammatory disease gout.

Receptor activator of NF-κB

(RANK). A cytokine receptor that is closely related to tumour necrosis factor receptors and that is mainly expressed by osteoclast lineage cells. Ligation of RANK on early macrophage precursors by RANK ligand expressed on osteoblasts triggers re-programming of the cell leading to osteoclast development.

Osteoblasts

Bone-lining fibroblast-related cells of non-haematopoietic origin that are specialized for the generation of bone matrix and the regulation of bone metabolism. Through expression of RANK ligand, they also promote the development and activation of osteoclasts.

Nasu-Hakola disease

(Also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL)). An inherited human disease characterized by presenile dementia and bone cysts. It is caused by loss of function mutations in the ITAM-containing adaptor protein DAP12 or the DAP12-associated receptor TREM2. The clinical manifestations probably result from the loss of DAP12 or TREM2 in osteoclasts and microglial cells.

Osteopetrosis

A rare inherited disease characterized by pathological accumulation of mineralized bone matrix in the bones. Despite the increased bone mass, osteopetrotic bones are fragile owing to abnormal bone composition and structure. It is caused by a lack or dysfunction of osteoclasts and therefore can be cured by bone marrow transplantation.

Haemostasis

The combination of events that result in cessation of bleeding. Haemostatic processes include constriction of blood vessels, platelet aggregation and coagulation (clotting) of the blood.

Podoplanin

A 43 kDa sialoglycoprotein originally identified in podocytes of the glomerular membrane but later shown to be expressed by several other cell types including lymphatic endothelial cells and tumour cells. It is a natural ligand of CLEC2 and induces CLEC2-mediated platelet aggregation.

Reverse passive Arthus reaction

An antibody-mediated local hypersensitivity reaction that is triggered by systemic injection of antigen followed by local (subcutaneous) injection of antibody against the injected antigen. The formation of immune complexes results in local oedema and inflammation, which is mediated by Fc receptors and activation of the complement cascade.

Rhodocytin

A snake venom toxin that triggers platelet activation by binding to CLEC2 on platelets. It is a disulphide-linked heterodimer with features common to certain C-type lectins.

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Mócsai, A., Ruland, J. & Tybulewicz, V. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 10, 387–402 (2010). https://doi.org/10.1038/nri2765

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