SYK (spleen tyrosine kinase)

2016-03-01 Barnabas Nyesiga , Anette Gjörloff Wingren Affiliation

Department of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden. anette.gjorloff-wingren@mah.se

Identity

HGNC

SYK

LOCATION

9q22.2

IMAGE

LEGEND

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

LOCUSID

6850

ALIAS

p72-Syk

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

The spleen tyrosine kinase (SYK) gene encodes a member of the family of non-receptor type Tyr protein kinases (http://www.genecards.org/cgi-bin/carddisp.pl?gene=SYK). 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).

Transcription

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) (http://www.uniprot.org/uniprot/P43405): Isoform 1 (full-length); Isoform 2 (283-305 missing)

Mutations

Note

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).

Epigenetics

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

Implicated in

Entity name

t(5;9)(q33;q22)

Disease

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

Entity name

t(9;12)(q22;p12)

Disease

found in a case of myelodysplastic syndrome (Kuno et al. 2001).

Oncogenesis

ETV6-SYK is constituvely tyrosine phosphorylated

Entity name

Breast cancer

Note

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.

Entity name

Colon carcinoma

Note

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).

Entity name

Gastric cancer

Note

An inverse correlation between nuclear SYK and lymph node metastasis was observed in gastric cancer patients (Wang 2004).

Entity name

Ovarian cancer

Note

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.

Entity name

Lung cancer

Note

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).

Entity name

Chronic lymphocytic leukemia (CLL)

Note

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).

Entity name

Diffuse large B-cell lymphoma (DLBCL)

Note

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).

Entity name

Follicular lymphoma (FL)

Note

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).

Entity name

Mantle cell lymphoma (MCL)

Note

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).

Entity name

Marginal zone lymphoma (MZL)

Note

Ruiz-Ballesteros reported upregulation of SYK in splenic MZL, potentially due to downregulation of microRNAs predicted to modulate SYK gene transcription (Ruiz-Ballesteros 2005).

Entity name

B cell acute lymphocytic leukemia (B-ALL)

Note

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).

Entity name

Rheumatoid arthritis (RA)

Note

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.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
15507431	2004	A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase.	Atwell S et al
19290920	2009	The structure, regulation, and function of ZAP-70.	Au-Yeung BB et al
15797511	2005	Src and Syk kinases: key regulators of phagocytic cell activation.	Berton G et al
15923611	2005	Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases.	Brdicka T et al
1423621	1992	ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.	Chan AC et al
8176201	1994	Differential 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
18048647	2008	ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemia.	Chen L et al
7477353	1995	Syk tyrosine kinase required for mouse viability and B-cell development.	Cheng AM et al
22025527	2011	SYK inhibition and response prediction in diffuse large B-cell lymphoma.	Cheng S et al
10963601	2000	The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells.	Coopman PJ et al
7518561	1994	Activation of p56lck by p72syk through physical association and N-terminal tyrosine phosphorylation.	Couture C et al
9314552	1997	A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages.	Crowley MT et al
17512407	2007	Structural basis for the inhibition of tyrosine kinase activity of ZAP-70.	Deindl S et al
18465772	2008	Redundant role for Zap70 in B cell development and activation.	Fallah-Arani F et al
18045459	2007	Spleen tyrosine kinase Syk is critical for sustained leukocyte adhesion during inflammation in vivo.	Frommhold D et al
9698567	1998	Structural 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
19306898	2009	Syk and pTyr'd: Signaling through the B cell antigen receptor.	Geahlen RL et al
19521399	2009	Signalling through C-type lectin receptors: shaping immune responses.	Geijtenbeek TB et al
7659156	1995	Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor.	Hatada MH et al
16872848	2006	Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy.	Hirahashi J et al
1569106	1992	Association of the 72-kDa protein-tyrosine kinase PTK72 with the B cell antigen receptor.	Hutchcroft JE et al
16835385	2006	Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells.	Irish JM et al
2331984	1990	Purification and characterization of a cytosolic protein-tyrosine kinase from porcine spleen.	Kobayashi T et al
8334702	1993	T cell activation by clustered tyrosine kinases.	Kolanus W et al
7538440	1995	Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase.	Kong GH et al
25447675	2015	Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer.	Krisenko MO et al
8082894	1994	Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans.	Ku G et al
18369315	2008	The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development.	Kulathu Y et al
11159536	2001	Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12).	Kuno Y et al
7513017	1994	Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling.	Kurosaki T et al
8163536	1994	Molecular cloning of human Syk. A B cell protein-tyrosine kinase associated with the surface immunoglobulin M-B cell receptor complex.	Law CL et al
8475064	1993	CD22 associates with the human surface IgM-B-cell antigen receptor complex.	Leprince C et al
16912221	2006	Syk-dependent mTOR activation in follicular lymphoma cells.	Leseux L et al
11160190	2001	Visualization 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
17669674	2008	Syk inhibitors as treatment for allergic rhinitis.	Masuda ES et al
16339999	2006	Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation.	Matsubara S et al
20467426	2010	The SYK tyrosine kinase: a crucial player in diverse biological functions.	Mócsai A et al
8168854	1994	Molecular cloning of the human homologue to the pig protein-tyrosine kinase syk.	Müller B et al
8590001	1995	Solution structure of the C-terminal SH2 domain of the human tyrosine kinase Syk complexed with a phosphotyrosine pentapeptide.	Narula SS et al
23861534	2013	Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis.	Nijjar JS et al
10691030	1999	Identification 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
21211067	2010	Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases.	Pamuk ON et al
11493682	2001	Ubiquitination and degradation of Syk and ZAP-70 protein tyrosine kinases in human NK cells upon CD16 engagement.	Paolini R et al
24828076	2014	Therapeutic potential of spleen tyrosine kinase inhibition for treating high-risk precursor B cell acute lymphoblastic leukemia.	Perova T et al
20225218	2010	Novel 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
21552259	2011	Alternative splicing of SYK regulates mitosis and cell survival.	Prinos P et al
16409295	2006	Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma.	Rinaldi A et al
15914563	2005	Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis.	Ruiz-Ballesteros E et al
11250739	2001	Syk: a new player in the field of breast cancer.	Stewart ZA et al
16341044	2006	Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma.	Streubel B et al
1874735	1991	Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis.	Taniguchi T et al
16754322	2006	Complement-mediated phagocytosis--the role of Syk.	Tohyama Y et al
11412303	2001	Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling.	Toyabe S et al
18818202	2008	Molecular mechanism of the Syk activation switch.	Tsang E et al
10731700	2000	Purification 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
7477352	1995	Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk.	Turner M et al
10689303	2000	Tyrosine kinase SYK: essential functions for immunoreceptor signalling.	Turner M et al
12907655	2003	Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer.	Wang L et al
15188513	2004	Hypermethylation of Syk gene in promoter region associated with oncogenesis and metastasis of gastric carcinoma.	Wang S et al
15212616	2004	Targeting Syk as a treatment for allergic and autoimmune disorders.	Wong BR et al
11676469	2001	Syk expression and novel function in a wide variety of tissues.	Yanagi S et al
11454707	2001	Hypermethylation leads to silencing of the SYK gene in human breast cancer.	Yuan Y et al
10931839	2000	Phosphorylation 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
16611990	2006	Nucleocytoplasmic trafficking of the Syk protein tyrosine kinase.	Zhou F et al

Other Information

Locus ID:

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

Variants:

dbSNP: 6850
ClinVar: 6850
TCGA: ENSG00000165025
COSMIC: SYK

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000165025	ENST00000375746	P43405
ENSG00000165025	ENST00000375746	A0A024R244
ENSG00000165025	ENST00000375747	P43405
ENSG00000165025	ENST00000375747	A0A024R273
ENSG00000165025	ENST00000375751	P43405
ENSG00000165025	ENST00000375751	A0A024R273
ENSG00000165025	ENST00000375754	P43405
ENSG00000165025	ENST00000375754	A0A024R244

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Natural killer cell mediated cytotoxicity	KEGG	ko04650
B cell receptor signaling pathway	KEGG	ko04662
Fc epsilon RI signaling pathway	KEGG	ko04664
Natural killer cell mediated cytotoxicity	KEGG	hsa04650
B cell receptor signaling pathway	KEGG	hsa04662
Fc epsilon RI signaling pathway	KEGG	hsa04664
Fc gamma R-mediated phagocytosis	KEGG	ko04666
Fc gamma R-mediated phagocytosis	KEGG	hsa04666
Osteoclast differentiation	KEGG	ko04380
Osteoclast differentiation	KEGG	hsa04380
Tuberculosis	KEGG	ko05152
Tuberculosis	KEGG	hsa05152
Epstein-Barr virus infection	KEGG	hsa05169
Epstein-Barr virus infection	KEGG	ko05169
NF-kappa B signaling pathway	KEGG	hsa04064
NF-kappa B signaling pathway	KEGG	ko04064
Viral carcinogenesis	KEGG	hsa05203
Viral carcinogenesis	KEGG	ko05203
PI3K-Akt signaling pathway	KEGG	hsa04151
PI3K-Akt signaling pathway	KEGG	ko04151
Platelet activation	KEGG	hsa04611
Immune System	REACTOME	R-HSA-168256
Adaptive Immune System	REACTOME	R-HSA-1280218
Signaling by the B Cell Receptor (BCR)	REACTOME	R-HSA-983705
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	REACTOME	R-HSA-983695
Innate Immune System	REACTOME	R-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosis	REACTOME	R-HSA-2029480
FCGR activation	REACTOME	R-HSA-2029481
Regulation of actin dynamics for phagocytic cup formation	REACTOME	R-HSA-2029482
Role of phospholipids in phagocytosis	REACTOME	R-HSA-2029485
DAP12 interactions	REACTOME	R-HSA-2172127
DAP12 signaling	REACTOME	R-HSA-2424491
Fc epsilon receptor (FCERI) signaling	REACTOME	R-HSA-2454202
FCERI mediated MAPK activation	REACTOME	R-HSA-2871796
FCERI mediated Ca+2 mobilization	REACTOME	R-HSA-2871809
Role of LAT2/NTAL/LAB on calcium mobilization	REACTOME	R-HSA-2730905
C-type lectin receptors (CLRs)	REACTOME	R-HSA-5621481
CLEC7A (Dectin-1) signaling	REACTOME	R-HSA-5607764
Dectin-2 family	REACTOME	R-HSA-5621480
Cytokine Signaling in Immune system	REACTOME	R-HSA-1280215
Signaling by Interleukins	REACTOME	R-HSA-449147
Interleukin-2 signaling	REACTOME	R-HSA-451927
Interleukin-3, 5 and GM-CSF signaling	REACTOME	R-HSA-512988
Regulation of signaling by CBL	REACTOME	R-HSA-912631
Hemostasis	REACTOME	R-HSA-109582
Platelet activation, signaling and aggregation	REACTOME	R-HSA-76002
GPVI-mediated activation cascade	REACTOME	R-HSA-114604
Platelet Aggregation (Plug Formation)	REACTOME	R-HSA-76009
Integrin alphaIIb beta3 signaling	REACTOME	R-HSA-354192
Signal Transduction	REACTOME	R-HSA-162582
Phospholipase D signaling pathway	KEGG	ko04072
Phospholipase D signaling pathway	KEGG	hsa04072

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37522746	2024	Mast cells are upregulated in hidradenitis suppurativa tissue, associated with epithelialized tunnels and normalized by spleen tyrosine kinase antagonism.	0
37792549	2024	Spleen tyrosine kinase facilitates the progression of papillary thyroid cancer regulated by the hsa_circ_0006417/miR-377-3p axis.	0
38522019	2024	DNA hypomethylation of Syk induces oxidative stress and apoptosis via the PKCβ/P66shc signaling pathway in diabetic kidney disease.	0
38594692	2024	SIRPB1 regulates inflammatory factor expression in the glioma microenvironment via SYK: functional and bioinformatics insights.	0
38636338	2024	Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.	0
37522746	2024	Mast cells are upregulated in hidradenitis suppurativa tissue, associated with epithelialized tunnels and normalized by spleen tyrosine kinase antagonism.	0
37792549	2024	Spleen tyrosine kinase facilitates the progression of papillary thyroid cancer regulated by the hsa_circ_0006417/miR-377-3p axis.	0
38522019	2024	DNA hypomethylation of Syk induces oxidative stress and apoptosis via the PKCβ/P66shc signaling pathway in diabetic kidney disease.	0
38594692	2024	SIRPB1 regulates inflammatory factor expression in the glioma microenvironment via SYK: functional and bioinformatics insights.	0
38636338	2024	Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.	0
36428281	2023	Syk Activation in Circulating and Tissue Innate Immune Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.	4
36598976	2023	Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19.	4
36857592	2023	Bacterial DNA promoting inflammation via the Sgk1/Nedd4L/Syk pathway in mast cells contributes to antihistamine-nonresponsive CSU.	1
36889573	2023	Epigenetic upregulation of spleen tyrosine kinase in cancer cells through p53-dependent downregulation of DNA methyltransferase.	0
37175486	2023	Differential Regulation of GPVI-Induced Btk and Syk Activation by PKC, PKA and PP2A in Human Platelets.	0

Citation

Barnabas Nyesiga ; Anette Gjörloff Wingren

SYK (spleen tyrosine kinase)

Atlas Genet Cytogenet Oncol Haematol. 2016-03-01

Online version: http://atlasgeneticsoncology.org/gene/394/syk-(spleen-tyrosine-kinase)

Historical Card

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

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