Tyrosine-protein kinase SYK

Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the SYK gene.

SYK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1A81, 1CSY, 1CSZ, 1XBA, 1XBB, 1XBC, 3BUW, 3EMG, 3FQE, 3FQH, 3FQS, 3SRV, 3TUB, 3TUC, 3TUD, 3VF8, 3VF9, 4DFL, 4DFN, 4F4P, 4FL1, 4FL2, 4FL3, 4FYN, 4FYO, 4FZ6, 4FZ7, 4GFG, 4I0R, 4I0S, 4I0T, 4PUZ, 4PV0, 4PX6, 4RX7, 4RX8, 4RX9, 5CXH, 5CXZ, 5CY3, 4XG6, 4XG2, 4XG3, 4XG8, 4XG7, 4YJR, 4YJP, 5C27, 4RSS, 4XG4, 5C26, 4YJV, 4YJO, 4WNM, 4YJT, 4YJU, 4YJS, 4XG9, 5GHV
Identifiers
Aliases	SYK, p72-Syk, spleen tyrosine kinase, spleen associated tyrosine kinase, IMD82
External IDs	OMIM: 600085; MGI: 99515; HomoloGene: 2390; GeneCards: SYK; OMA:SYK - orthologs
Gene location (Human) Chr. Chromosome 9 (human) Band 9q22.2 Start 90,801,787 bp End 90,898,549 bp
Gene location (Mouse) Chr. Chromosome 13 (mouse) Band 13 A5|13 27.41 cM Start 52,737,209 bp End 52,802,828 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte blood epithelium of nasopharynx bone marrow cells appendix trabecular bone lymph node spleen jejunal mucosa Top expressed in granulocyte spleen tibiofemoral joint blood mesenteric lymph nodes stroma of bone marrow Ileal epithelium ankle joint subcutaneous adipose tissue lumbar subsegment of spinal cord More reference expression data BioGPS More reference expression data
Gene ontology Molecular function kinase activity ATP binding protein kinase activity non-membrane spanning protein tyrosine kinase activity protein serine/threonine kinase activity transferase activity integrin binding protein binding protein tyrosine kinase activity protein kinase binding nucleotide binding phosphatase binding Toll-like receptor binding phosphotyrosine residue binding SH2 domain binding interleukin-15 receptor binding Cellular component cytoplasm cytosol membrane extrinsic component of cytoplasmic side of plasma membrane nucleus early phagosome B cell receptor complex plasma membrane T cell receptor complex protein-containing complex Biological process leukocyte cell-cell adhesion adaptive immune response positive regulation of receptor internalization neutrophil activation involved in immune response platelet activation Fc-epsilon receptor signaling pathway protein phosphorylation cell surface receptor signaling pathway regulation of DNA-binding transcription factor activity serotonin secretion angiogenesis animal organ morphogenesis positive regulation of cell adhesion mediated by integrin cell population proliferation regulation of platelet aggregation B cell receptor signaling pathway positive regulation of calcium-mediated signaling blood vessel morphogenesis Fc-gamma receptor signaling pathway involved in phagocytosis transmembrane receptor protein tyrosine kinase signaling pathway regulation of tumor necrosis factor-mediated signaling pathway serotonin secretion by platelet cellular response to low-density lipoprotein particle stimulus stimulatory C-type lectin receptor signaling pathway lymph vessel development neutrophil chemotaxis macrophage activation involved in immune response defense response to bacterium positive regulation of alpha-beta T cell proliferation regulation of ERK1 and ERK2 cascade positive regulation of peptidyl-tyrosine phosphorylation protein autophosphorylation leukotriene biosynthetic process viral process positive regulation of alpha-beta T cell differentiation cellular response to molecule of fungal origin regulation of neutrophil degranulation phosphorylation immune system process positive regulation of B cell differentiation beta selection leukocyte activation involved in immune response peptidyl-tyrosine autophosphorylation integrin-mediated signaling pathway regulation of superoxide anion generation enzyme linked receptor protein signaling pathway intracellular signal transduction receptor internalization positive regulation of bone resorption positive regulation of mast cell degranulation regulation of arachidonic acid secretion peptidyl-serine phosphorylation peptidyl-tyrosine phosphorylation regulation of phagocytosis regulation of platelet activation positive regulation of gamma-delta T cell differentiation positive regulation of type I interferon production inflammatory response innate immune response collagen-activated tyrosine kinase receptor signaling pathway positive regulation of peptidyl-tyrosine autophosphorylation protein import into nucleus positive regulation of interleukin-4 production interleukin-2-mediated signaling pathway interleukin-3-mediated signaling pathway positive regulation of cold-induced thermogenesis positive regulation of protein-containing complex assembly positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6850 20963 Ensembl ENSG00000165025 ENSMUSG00000021457 UniProt P43405 P48025 RefSeq (mRNA) NM_001135052 NM_001174167 NM_001174168 NM_003177 NM_001198977 NM_011518 RefSeq (protein) NP_001128524 NP_001167638 NP_001167639 NP_003168 NP_001185906 NP_035648 Location (UCSC) Chr 9: 90.8 – 90.9 Mb Chr 13: 52.74 – 52.8 Mb PubMed search
Wikidata
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Function

SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor tyrosine kinases share a characteristic dual SH2 domain separated by a linker domain. However, activation of SYK relies less on phosphorylation by Src family kinases than ZAP70. SYK and ZAP70 share a common evolutionary origin and split from a common ancestor in the jawed vertebrates.

While Syk and ZAP70 are primarily expressed in hematopoietic tissues, a variety of tissues express Syk. Within B and T cells, respectively, Syk and ZAP70 transmit signals from the B-cell receptor and T-cell receptor. Syk plays a similar role in transmitting signals from a variety of cell surface receptors including CD74, Fc receptor, and integrins.

Function during development

Mice that lack Syk completely (Syk^−/−, Syk-knockout) die during embryonic development around midgestation. They show severe defects in the development of the lymphatic system. Normally, the lymphatic system and the blood system are strictly separated from each other. However, in Syk deficient mice the lymphatics and the blood vessels form abnormal shunts, leading to leakage of blood into the lymphatic system. The reason for this phenotype was identified by a genetic fate mapping approach, showing that Syk is expressed in myeloid cells which orchestrate the proper separation of lymphatics and blood system during embryogenesis and beyond. Thus, Syk is an essential regulator of the lymphatic system development in mice.

Clinical significance

Abnormal function of Syk has been implicated in several instances of hematopoietic malignancies including translocations involving Itk and Tel. Constitutive Syk activity can transform B cells. Several transforming viruses contain "Immunoreceptor Tyrosine Activation Motifs" (ITAMs) which lead to activation of Syk including Epstein–Barr virus, bovine leukemia virus, and mouse mammary tumor virus.

SYK inhibition

Given the central role of SYK in transmission of activating signals within B-cells, a suppression of this tyrosine kinase might aid in the treatment of B cell malignancies and autoimmune diseases.

Syk inhibition has been proposed as a therapy for both lymphoma and chronic lymphocytic leukemia. Syk inhibitors are in clinical development, including cerdulatinib and entospletinib. Other inhibitors of B-cell receptor (BCR) signaling including ibrutinib (PCI-32765) which inhibits BTK, and idelalisib (PI3K inhibitor - CAL-101 / GS-1101) showed activity in the diseases as well.

The orally active SYK inhibitor fostamatinib (R788) in the treatment of immune thrombocytopenia.

The Syk inhibitor nilvadipine has been shown to regulate amyloid-β production and Tau phosphorylation and hence has been proposed as a treatment for Alzheimer's disease and has entered phase III clinical trials.

Epithelial malignancies

The role of Syk in epithelial malignancies is controversial. Several authors have suggested that abnormal Syk function facilitates transformation in Nasopharyngeal carcinoma and head and neck cancer while other authors have suggested a tumor suppressor role in breast and gastric cancer.

Without Syk, the protein it makes, and genetic disruption in a panel of 55 genes thought also to be controlled by Syk, breast ductal carcinoma in situ (breast DCIS, which can become invasive), it is believed that the cancer has a markedly increased tendency to invade and metastasize.

Interactions

Syk has been shown to interact with:

• Cbl gene
• CRKL,
• FCGR2A,
• FYN,
• Grb2,
• Lck,
• LYN,
• PTK2,
• PTPN6, and
• VAV1.

Further reading

• Turner M, Schweighoffer E, Colucci F, Di Santo JP, Tybulewicz VL (March 2000). "Tyrosine kinase SYK: essential functions for immunoreceptor signalling". Immunology Today. 21 (3): 148–54. doi:10.1016/S0167-5699(99)01574-1. PMID 10689303.
• Fruman DA, Satterthwaite AB, Witte ON (July 2000). "Xid-like phenotypes: a B cell signalosome takes shape". Immunity. 13 (1): 1–3. doi:10.1016/S1074-7613(00)00002-9. PMID 10933389.
• Yanagi S, Inatome R, Takano T, Yamamura H (November 2001). "Syk expression and novel function in a wide variety of tissues". Biochemical and Biophysical Research Communications. 288 (3): 495–8. doi:10.1006/bbrc.2001.5788. PMID 11676469.
• Tohyama Y, Yamamura H (2006). "Complement-mediated phagocytosis--the role of Syk". IUBMB Life. 58 (5–6): 304–8. doi:10.1080/15216540600746377. PMID 16754322. S2CID 41684033.
• Schymeinsky J, Mócsai A, Walzog B (August 2007). "Neutrophil activation via beta2 integrins (CD11/CD18): molecular mechanisms and clinical implications". Thrombosis and Haemostasis. 98 (2): 262–73. doi:10.1160/th07-02-0156. PMID 17721605. S2CID 41094726.

External links

• Syk+kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P43405 (Tyrosine-protein kinase SYK) at the PDBe-KB.