SYK (spleen tyrosine kinase)
2016-03-01 Barnabas Nyesiga , Anette Gjörloff Wingren AffiliationDepartment of Biomedical Science, Health and Society, Malmö University, Malmö, Sweden. [email protected]
Identity
HGNC
LOCATION
9q22.2
IMAGE
LEGEND
Figure 1. Mapping of SYK gene on chromosome 9q22.2 (from GeneCards Syk gene).
LOCUSID
ALIAS
p72-Syk
FUSION GENES
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
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
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
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
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
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
