Syk

Syk (spleen tyrosine kinase) is a non-receptor protein tyrosine kinase that has, at the N-terminus, a tandem pair of Src homology 2 (SH2) domains separated by a long linker (linker B) from the C-terminal catalytic domain. Syk is one of two members of the Syk-family of kinases, the other being ZAP-70. An alternatively spliced variant of Syk, SykB, lacks a stretch of 23 amino acids from linker B. Syk prefers to phosphorylate substrates on tyrosines surrounded by acidic amino acids. Syk is expressed in most hematopoietic cells including B cells, thymocytes, erythrocytes, monocytes, macrophages, leukocytes, natural killer cells, eosinophils, mast cells and basophils, but is largely absent from mature T cells. It is also expressed in epithelial cells and in some neuron-like cells, hepatocytes, and endothelial cells. SykB is found most abundantly in bone marrow-derived B cells and epithelial cells.

In hematopoietic cells, Syk is required for transducing signals from a wide variety of cell surface receptors involved in the recognition of antigens or antigen-antibody complexes. In Syk-deficient mice, B cell development is blocked due to a lack of signaling from pre-B and B cell antigen receptors. Syk-deficient mast cells are unable to degranulate when triggered through the high-affinity IgE receptor, FcεRI. Phagocytosis through Fcγ receptors is blocked in Syk-deficient macrophages as is the FcγR-stimulated production of reactive oxygen species. FcR-dependent immune complex internalization is blocked in dendritic cells from Syk-deficient mice as is the activation and aggregation of platelets via the collagen receptor. Syk associates with the B cell and T cell antigen receptors, FcεRI, FcγRI, FcγRIIa, FcγRIIIa, NK cell activating receptors and collagen receptor through the binding of its tandem SH2 domains to a conserved pair of tyrosines present within an immunoreceptor tyrosine-based activation motif (ITAM) found on the cytoplasmic tails of receptor components. ITAMs bear the consensus sequence E/DXXYXX(L/I)X6-8YXX(L/I) and bind Syk when both tyrosines are phosphorylated, typically by a Src-family kinase in conjunction with Syk, itself. In addition, Syk associates with β-integrins and the receptors for IL-2, G-CSF, GM-CSF, IL-3, IL-5, IL-15, and tumor necrosis factor (TNF). In Syk-deficient mice, integrin-dependent signaling in monocytes and neutrophils is defective. Syk-deficient mice exhibit a perinatal lethality resulting from a failure of the circulatory and lymphatic systems to separate during development.

Syk is localized in resting cells in both the nucleus and cytoplasm and is recruited from both compartments to the site of the aggregated, ITAM-containing receptor. The binding of Syk to phosphorylated ITAMs on cross-linked receptors leads to its activation and its phosphorylation on multiple tyrosines. The phosphorylation of tyrosines in the activation loop of the catalytic domain are important for receptor-mediated signaling. The phosphorylation of linker B region tyrosines provides docking sites for downstream effectors that bear SH2 or related domains. The binding of c-Cbl, an E3 ubiquitin ligase, to phosphotyrosine-317 (mouse) inhibits Syk-dependent signaling. The C-terminal SH2 domain of the p85 subunit of phosphoinositide 3-kinase can also bind here. Tyrosines-342 and -346 constitute a multi-functional binding site that interacts with SH2 domains from the guanine nucleotide exchange factor, Vav1, phospholipase C-γ (PLCγ) and the Src-family kinase, c-Fgr. Vav1 can bind phosphotyrosine-342 alone while PLCγ binds only when both tyrosines are phosphorylated. Syk also binds CrkL and Gab2.

Syk is expressed in normal breast epithelial cells and in relatively benign breast cancer cells, but is missing from highly metastatic cells due to gene methylation. Re-expression of Syk in malignant breast cancer cells reduces their tumorigenicity, decreases cell motility and enhances cell-cell adhesion. Syk functions, in part, through its ability to associate with and inhibit signaling from the EGF receptor.

 

The Table below contains accepted modulators and additional information.

 

Family Members Syk ZAP-70
Other Names Spleen tyrosine kinase Syk-related protein kinase
SRK
Molecular Weight
(kDa)
72 kDa; 635 aa (human)

70 kDa 
Structural Data 629 aa (mouse) 619 aa
Isoforms SykA
SykB
Not Known
Species Human, mouse, rat, pig Human, mouse
Domain
Organization
C-terminal SH2 domain
N-terminal SH2 domain
kinase domain
C-terminal SH2 domain
kinase domain
N-terminal SH2 domain
Phosphorylation
Sites (mouse)
Tyr130
Tyr290
Tyr317
Tyr342
Tyr346
Tyr358
Tyr519
Tyr520
Tyr623
Tyr624
Tyr126
Tyr292
Tyr315
Tyr319
Tyr492
Tyr493
Tissue
Distribution
Spleen, thymus, peripheral blood cells,
mammary gland, liver, lung
T-cells, natural killer cells
Subcellular
Localization
Cytoplasmic membrane, cytoplasm, nucleus Cytoplasmic membrane, cytoplasm
Binding Parters/
Associated Proteins
NFAM-1
Cbl
FcRγ
CD3ζ
CD69a
CD69b
DAP-12
β-integrins
PLCγ
Vav
PI3K
c-Fgr
NFAM-1
CBL
SLA
CD3Z
Upstream
Activators
TNF receptor
β-integrins
Lyn
FcεRI
FcγRI
FcγRIIa
FcγRIIIa
BCR
TCR
GM-CSF
G-CSF
TCR-Z
LCK
Downstream
Activation
PLCγ2
Vav
PI3K
Btk
Not Known
Substrates Vav
Cbl
PLCγ
HS1
Band 3
α-tubulin
BLNK/SLP-65
LAT
3BP2
Cortactin
SH3P7
B cell receptor
PKCβI
PKCα
BCAP
FcγR γ-chain
Btk
CD19
Not Known
Activators Not Known
Not Known
Inhibitors Piceatannol (P0453)
ER-27319 (E0656)
BAY 61-3606 (B9685)
Syk inhibitor 574711
Not Known
Selective
Activators
Not Known
Not Known
Physiological
Function
B cell development and activation
FcR-mediated phagocytosis
Platelet activation
Eosinophil activation and survival
Mast cell activation
Neutrophil/ monocyte spreading and migration
Epithelial cell adhesion and motility
T-cell activation regulator
Disease
Relevance
Asthma
Allergy
Leukemia
Breast cancer
Human immunodeficiency
selective T-type defect

 

Abbreviations

3BP2: SH3 binding protein 2
574711: 3-(1-Methyl-1H-indol-3-yl-methylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide
Band 3: Erythrocyte anion transport channel
BAY 61-3606: 2-[7-(3,4-Dimethoxyphenyl)-imadizo[1,2-c]pyrimidin-5-ylamino]-nictotinamide dihydrochloride
BCAP: B cell adaptor protein
BCR: B cell antigen receptor
BLNK: B cell linker protein
Btk: Bruton’s tyrosine kinase
Cbl: Casitas B-lineage lymphoma oncoprotein
c-Fgr: Cellular homolog of transforming protein of Gardner-Rasheed feline sarcoma virus
CrkL: v-Crk sarcoma virus CT10 oncogene homolog-like
EGF: Epidermal growth factor
ER-27319: 3,4-Dimethyl-10-(3-aminopropyl)-9-acridone oxalate
FcεRI: High affinity receptor for IgE
FcγR: Receptor for IgG
GAB2: Growth factor receptor binding protein-2 (Grb2)-associated binding protein-2
G-CSF: Granulocyte colony stimulating factor
GM-CSF: Granulocyte/macrophage colony stimulating factor
HS1: Hematopoietic specific protein-1
IL: Interleukin
ITAM: Immunoreceptor tyrosine-based activation motif
LAT: Linker of activated T cells
NFAM-1: NFAT activating molecule 1
NK: Natural killer
PI3K: Phosphoinositide 3-kinase
PKC: Protein kinase C
PLCγ: Phospholipase C-γ
SH2: Src homology 2
SH3P7: SH3 domain containing protein 7
SLP65: SH2 domain-containing leukocyte protein of 65 kDa
Syk: Spleen tyrosine kinase
TNF: Tumor necrosis factor
ZAP70: ζ chain associated protein of 70 kDa

 

References