SYK (spleen tyrosine kinase)

2016-03-01   Barnabas Nyesiga , Anette Gjörloff Wingren 

Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden.


Atlas Image
Figure 1. Mapping of SYK gene on chromosome 9q22.2 (from GeneCards Syk gene).



The spleen tyrosine kinase (SYK) gene encodes a member of the family of non-receptor type Tyr protein kinases ( The cDNA clone encoding porcine SYK was identified by Taniguchi et al (Taniguchi 1991; Yamada 1993), and thereafter the SYK cDNA for mouse and human, respectively, was cloned (Hutchcroft 1991; Hutchcroft 1992; Müller 1994; Ku 1994). Initially, a smaller porcine SYK protein product was purified and was found to be proteolytically cleaved from the mature SYK protein (Kobayashi 1990). The PTK72 was at the same time found to be identical with the cloned SYK (LePrince 1993; Law 1994).


The transcript encodes 635 amino acids with a mass of 72,066 Da. Two isoforms have been described, isoform long (L) and isoform short (S) ( Isoform 1 (full-length); Isoform 2 (283-305 missing)



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. When mice deficient for recombination-activating gene 1 (RAG1) were reconstituted with fetal liver from SYK-deficient embryos, the pool of pre-B cells formed was reduced. This suggests that SYK is required for the proper signalling from the pre-BCR to generate or maintain the pool of pre-B cells. Indeed, it has been shown that SYK is an essential transducer of BCR signals required for the transition of immature into recirculating B cells (Turner 2000). Moreover, SYK-deficient mice die due to embryonic and perinatal death (Turner 1995; Cheng 1995).


SYK can also be inactivated by epigenetic modifications (i.e. hypermethylation)

Implicated in

Entity name
found in Peripheral T-cell lymphoma (Streubel et al. 2006).
Hybrid gene
N-terminal ITK (bp 1-577) fused in frame with C-terminal SYK cDNA
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found in a case of myelodysplastic syndrome (Kuno et al. 2001).
ETV6-SYK is constituvely tyrosine phosphorylated
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Breast cancer
SYK mRNA and protein expression in a panel of well-characterized breast cancer cell lines, normal mammary gland tissue, and a normal breast epithelial cell line has been investigated by Coopman et al (Coopman 2000). They readily detected SYK expression in normal mammary tissue and epithelium, as well as in non-invasive breast carcinoma cell lines. SYK expression was however observed to be reduced or absent in the invasive breast tumor cell lines. Hypermethylation of the SYK locus during breast cancer progression was found to cause a loss of SYK protein expression in highly invasive and metastatic human mammary carcinomas (Coopman 2000,Yuan 2001). Moreover, Wang et al have shown that full-length SYK can enter the nucleus and thereby suppress invasion (Wang 2003). The sequences confined to a region of the SYK molecule near the junction of the linker B and catalytic domain were determined to be responsible for its distribution between the nucleus and cytoplasm (Zhou 2006). It was further demonstrated that the distribution of SYK between the nucleus and cytoplasm was regulated by signals sent downstream from the activated BCR and require the receptor-mediated activation of protein kinase C (PKC) and the induction of new protein synthesis.
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Colon carcinoma
Expression of the SYK gene in human colon carcinoma cells is known to be suppressed in a p53-dependent manner, an indication that loss of p53 function during tumorigenesis can lead to deregulation of SYK activity (Okamura 1999). As reviewed recently by Krisenko et al,the levels of SYK mRNA in many cancerous tissues, including colon, are higher than in normal corresponding tissue (Krisenko 2015).
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Gastric cancer
An inverse correlation between nuclear SYK and lymph node metastasis was observed in gastric cancer patients (Wang 2004).
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Ovarian cancer
Ovarian tumors of low malignant grade have low levels of SYK compared to aggressive grades, which have the highest levels (Prinos 2011). Interestingly, when SYK expression was silenced, anchorage-independent growth was inhibited, and apoptosis was induced in SYK-expressing ovarian cancer cells.
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Lung cancer
Primary tumors of small cell lung cancer (SCLC) was examined and found to express higher levels of SYK compared to normal alveolar epithelium (reviewed by Krisenko 2015).
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Chronic lymphocytic leukemia (CLL)
Both SYK and ZAP70 are present in CLL in B cells and may compete in facilitating BCR signaling (reviewed in Au-Yeung 2009). CLL fall into two classes, an indolent milder form and an aggressive form that is particularly dependent on SYK activity for survival (Buchner 2009).
DLBCL can exhibit tonic or chronic signaling from the BCR that results in constitutive phosphorylation of SYK on activation loop tyrosines (Chen 2008). In a study from 2011 by Cheng et al, 44% of DLBCL samples showed elevated levels of phosphorylated SYK (Cheng 2011).
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Constitutive activation of SYK has been reported in FL, were primary cells are hyperresponsive to BCR engagement as compared to nonmalignant B cells (Leseux 2006; Irish 2006).
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Constitutive activation of SYK has been reported in MCL as well, with a frequent overexpression of SYK due to gene amplification in both cell lines and primary tumors (Rinaldi 2006).
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Ruiz-Ballesteros reported upregulation of SYK in splenic MZL, potentially due to downregulation of microRNAs predicted to modulate SYK gene transcription (Ruiz-Ballesteros 2005).
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B cell acute lymphocytic leukemia (B-ALL)
B-ALL cells are derived from pro-B cells that lack pre-BCR or BCR complexes, but still these cells have elevated levels of constitutively active phosphorylated SYK (Perova 2014).
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Rheumatoid arthritis (RA)
It is likely that SYK is widely expressed in a range of haemopoietic cell lineages in RA synovium. Inhibition of Syk suppresses both inflammation and bone erosion in animal models of RA (Singh Najjar 2014). Indeed, Syk has been shown to be necessary for emerging pathology in several animal models of arthritis.


Pubmed IDLast YearTitleAuthors
155074312004A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase.Atwell S et al
192909202009The structure, regulation, and function of ZAP-70.Au-Yeung BB et al
157975112005Src and Syk kinases: key regulators of phagocytic cell activation.Berton G et al
159236112005Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases.Brdicka T et al
14236211992ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.Chan AC et al
81762011994Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling.Chan AC et al
180486472008ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemia.Chen L et al
74773531995Syk tyrosine kinase required for mouse viability and B-cell development.Cheng AM et al
220255272011SYK inhibition and response prediction in diffuse large B-cell lymphoma.Cheng S et al
109636012000The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells.Coopman PJ et al
75185611994Activation of p56lck by p72syk through physical association and N-terminal tyrosine phosphorylation.Couture C et al
93145521997A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages.Crowley MT et al
175124072007Structural basis for the inhibition of tyrosine kinase activity of ZAP-70.Deindl S et al
184657722008Redundant role for Zap70 in B cell development and activation.Fallah-Arani F et al
180454592007Spleen tyrosine kinase Syk is critical for sustained leukocyte adhesion during inflammation in vivo.Frommhold D et al
96985671998Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide.Fütterer K et al
193068982009Syk and pTyr'd: Signaling through the B cell antigen receptor.Geahlen RL et al
195213992009Signalling through C-type lectin receptors: shaping immune responses.Geijtenbeek TB et al
76591561995Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor.Hatada MH et al
168728482006Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy.Hirahashi J et al
15691061992Association of the 72-kDa protein-tyrosine kinase PTK72 with the B cell antigen receptor.Hutchcroft JE et al
168353852006Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells.Irish JM et al
23319841990Purification and characterization of a cytosolic protein-tyrosine kinase from porcine spleen.Kobayashi T et al
83347021993T cell activation by clustered tyrosine kinases.Kolanus W et al
75384401995Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase.Kong GH et al
254476752015Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer.Krisenko MO et al
80828941994Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans.Ku G et al
183693152008The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development.Kulathu Y et al
111595362001Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12).Kuno Y et al
75130171994Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling.Kurosaki T et al
81635361994Molecular cloning of human Syk. A B cell protein-tyrosine kinase associated with the surface immunoglobulin M-B cell receptor complex.Law CL et al
84750641993CD22 associates with the human surface IgM-B-cell antigen receptor complex.Leprince C et al
169122212006Syk-dependent mTOR activation in follicular lymphoma cells.Leseux L et al
111601902001Visualization of Syk-antigen receptor interactions using green fluorescent protein: differential roles for Syk and Lyn in the regulation of receptor capping and internalization.Ma H et al
176696742008Syk inhibitors as treatment for allergic rhinitis.Masuda ES et al
163399992006Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation.Matsubara S et al
204674262010The SYK tyrosine kinase: a crucial player in diverse biological functions.Mócsai A et al
81688541994Molecular cloning of the human homologue to the pig protein-tyrosine kinase syk.Müller B et al
85900011995Solution structure of the C-terminal SH2 domain of the human tyrosine kinase Syk complexed with a phosphotyrosine pentapeptide.Narula SS et al
238615342013Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis.Nijjar JS et al
106910301999Identification of seven genes regulated by wild-type p53 in a colon cancer cell line carrying a well-controlled wild-type p53 expression system.Okamura S et al
212110672010Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases.Pamuk ON et al
114936822001Ubiquitination and degradation of Syk and ZAP-70 protein tyrosine kinases in human NK cells upon CD16 engagement.Paolini R et al
248280762014Therapeutic potential of spleen tyrosine kinase inhibition for treating high-risk precursor B cell acute lymphoblastic leukemia.Perova T et al
202252182010Novel insights into the mechanism of decreased expression of type X collagen in human mesenchymal stem cells from patients with osteoarthritis cultured on nitrogen-rich plasma polymers: implication of cyclooxygenase-1.Petit A et al
215522592011Alternative splicing of SYK regulates mitosis and cell survival.Prinos P et al
164092952006Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma.Rinaldi A et al
159145632005Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis.Ruiz-Ballesteros E et al
112507392001Syk: a new player in the field of breast cancer.Stewart ZA et al
163410442006Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma.Streubel B et al
18747351991Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis.Taniguchi T et al
167543222006Complement-mediated phagocytosis--the role of Syk.Tohyama Y et al
114123032001Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling.Toyabe S et al
188182022008Molecular mechanism of the Syk activation switch.Tsang E et al
107317002000Purification of a 72-kDa protein-tyrosine kinase from rat liver and its identification as Syk: involvement of Syk in signaling events of hepatocytes.Tsuchida S et al
74773521995Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk.Turner M et al
106893032000Tyrosine kinase SYK: essential functions for immunoreceptor signalling.Turner M et al
129076552003Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer.Wang L et al
151885132004Hypermethylation of Syk gene in promoter region associated with oncogenesis and metastasis of gastric carcinoma.Wang S et al
152126162004Targeting Syk as a treatment for allergic and autoimmune disorders.Wong BR et al
116764692001Syk expression and novel function in a wide variety of tissues.Yanagi S et al
114547072001Hypermethylation leads to silencing of the SYK gene in human breast cancer.Yuan Y et al
109318392000Phosphorylation of Syk activation loop tyrosines is essential for Syk function. An in vivo study using a specific anti-Syk activation loop phosphotyrosine antibody.Zhang J et al
166119902006Nucleocytoplasmic trafficking of the Syk protein tyrosine kinase.Zhou F et al

Other Information

Locus ID:

NCBI: 6850
MIM: 600085
HGNC: 11491
Ensembl: ENSG00000165025


dbSNP: 6850
ClinVar: 6850
TCGA: ENSG00000165025


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Natural killer cell mediated cytotoxicityKEGGko04650
B cell receptor signaling pathwayKEGGko04662
Fc epsilon RI signaling pathwayKEGGko04664
Natural killer cell mediated cytotoxicityKEGGhsa04650
B cell receptor signaling pathwayKEGGhsa04662
Fc epsilon RI signaling pathwayKEGGhsa04664
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Platelet activationKEGGhsa04611
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Antigen activates B Cell Receptor (BCR) leading to generation of second messengersREACTOMER-HSA-983695
Innate Immune SystemREACTOMER-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosisREACTOMER-HSA-2029480
FCGR activationREACTOMER-HSA-2029481
Regulation of actin dynamics for phagocytic cup formationREACTOMER-HSA-2029482
Role of phospholipids in phagocytosisREACTOMER-HSA-2029485
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
FCERI mediated Ca+2 mobilizationREACTOMER-HSA-2871809
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
C-type lectin receptors (CLRs)REACTOMER-HSA-5621481
CLEC7A (Dectin-1) signalingREACTOMER-HSA-5607764
Dectin-2 familyREACTOMER-HSA-5621480
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Regulation of signaling by CBLREACTOMER-HSA-912631
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Platelet Aggregation (Plug Formation)REACTOMER-HSA-76009
Integrin alphaIIb beta3 signalingREACTOMER-HSA-354192
Signal TransductionREACTOMER-HSA-162582
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
159562832005Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production.167
191226532009Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk.154
203688002010Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase.116
180066962008SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma.111
127116062003Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase.110
171458632006Epigenetic silencing of novel tumor suppressors in malignant melanoma.71
198005742009Proteomic and genetic approaches identify Syk as an AML target.69
195499112009Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia.67
123877352002ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1.64
190928492009Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells.64


Barnabas Nyesiga ; Anette Gjörloff Wingren

SYK (spleen tyrosine kinase)

Atlas Genet Cytogenet Oncol Haematol. 2016-03-01

Online version:

Historical Card

2002-02-01 SYK (spleen tyrosine kinase) by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France