Syk

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
External IDs	OMIM: 600085 MGI: 99515 HomoloGene: 2390 GeneCards: SYK
Genetically Related Diseases
type 2 diabetes mellitus, multiple sclerosis, vascular dementia[1]
Gene ontology Molecular function • kinase activity • ATP binding • protein kinase activity • signal transducer, downstream of receptor, with protein tyrosine 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 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 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 sequence-specific DNA binding transcription factor activity • serotonin secretion • angiogenesis • animal organ morphogenesis • positive regulation of cell adhesion mediated by integrin • cell proliferation • regulation of platelet aggregation • B cell receptor signaling pathway • positive regulation of calcium-mediated signaling • blood vessel morphogenesis • activation of JUN kinase activity • Fc-gamma receptor signaling pathway involved in phagocytosis • transmembrane receptor protein tyrosine kinase signaling pathway • positive regulation of cytokine secretion • 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 • positive regulation of interleukin-3 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 • transcription factor import into nucleus • positive regulation of granulocyte macrophage colony-stimulating factor biosynthetic process • activation of MAPK activity • 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 Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
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_001128524.1 NP_001167638.1 NP_001167639.1 NP_003168.2	NP_001185906.1 NP_035648.2
Location (UCSC)	Chr 9: 90.8 – 90.9 Mb	Chr 13: 52.58 – 52.65 Mb
PubMed search	[2]	[3]
Wikidata

Spleen tyrosine kinase, also known as Syk, is an enzyme which in humans is encoded by the SYK gene.^[4][5][6]

Function

SYK, along with Zap-70, is a member of the Syk family of tyrosine kinases. These non-receptor cytoplasmic tyrosine kinases share a characteristic dual SH2 domain separated by a linker domain.^[7]

While Syk and Zap-70 are primarily expressed in hematopoietic tissues, there is expression of Syk in a variety of tissues. Within B and T cells respectively, Syk and Zap-70 transmit signals from the B-Cell receptor and T-Cell receptor.^[7] 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.^[8]

Clinical significance

Abnormal function of Syk has been implicated in several instances of hematopoeitic malignancies including translocations involving Itk and Tel. Constitutive Syk activity can transform B cells.^[7] 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.^[9] This has been demonstrated by the orally active inhibitor fostamatinib (R788) in the treatment of rheumatoid arthritis.^[10] The 6-month double-blind, placebo-controlled trial investigated clinical responses in 457 patients with rheumatoid arthritis who were not sufficiently responsive to methotrexate. The drug indeed caused a dose-dependent improvement in disease severity. The drug was however associated with an increase in the frequency in diarrhea, upper respiratory tract infections, neutropenia. Moreover, R788 increased blood pressure and a concomitant increase in treatment with antihypertensive drugs. The drug is investigational and at present the final position within the broad set of antirheumatic drugs and its long-term safety are unknown.

SYK inhibition is also been studied in Alzheimer's disease. it is believed that suppressing this protein may reduce all the 3 pathologies namely amyloid beta, tau and neuroinflamation. A drug called Nilvadipine is currently in phase 3 trials for the treatment of Alzheimer's disease.

Syk inhibition has also been proposed as a therapy for both lymphoma and chronic lymphocytic leukemia.<^[7] 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. Newer Syk inhibitors have entered the clinic and are also in clinical development (GS-9973).^[9] now named entospletinib.^[11][12]

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.^[13]

Interactions

Syk has been shown to interact with:

• Cbl gene^[14][15][16]
• CRKL,^[17]
• FCGR2A,^[18][19]
• FYN,^[20][21]
• Grb2,^[22][23]
• Lck,^[24]
• LYN,^[25]
• PTK2,^[26]
• PTPN6,^[22][27] and
• VAV1.^[14][28][29]

References

Further reading

External links

• Syk kinase at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery
1a81: CRYSTAL STRUCTURE OF THE TANDEM SH2 DOMAIN OF THE SYK KINASE BOUND TO A DUALLY TYROSINE-PHOSPHORYLATED ITAM  1csy: SYK TYROSINE KINASE C-TERMINAL SH2 DOMAIN COMPLEXED WITH A PHOSPHOPEPTIDEFROM THE GAMMA CHAIN OF THE HIGH AFFINITY IMMUNOGLOBIN G RECEPTOR, NMR  1csz: SYK TYROSINE KINASE C-TERMINAL SH2 DOMAIN COMPLEXED WITH A PHOSPHOPEPTIDEFROM THE GAMMA CHAIN OF THE HIGH AFFINITY IMMUNOGLOBIN G RECEPTOR, NMR  1xba: Crystal structure of apo syk tyrosine kinase domain  1xbb: Crystal structure of the syk tyrosine kinase domain with Gleevec  1xbc: Crystal structure of the syk tyrosine kinase domain with Staurosporin