Target General Infomation
Target ID
T37952
Former ID
TTDI02237
Target Name
mRNA of SYK
Gene Name
SYK
Synonyms
Spleen tyrosine kinase (mRNA); Tyrosine-protein kinase SYK (mRNA); p72-Syk (mRNA); SYK
Target Type
Discontinued
Disease Asthma [ICD10: J45]
Function
Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine- phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T- cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that isrequired for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.
BioChemical Class
Target of siRNA drug
UniProt ID
EC Number
EC 2.7.10.2
Sequence
MASSGMADSANHLPFFFGNITREEAEDYLVQGGMSDGLYLLRQSRNYLGGFALSVAHGRK
AHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQGVQPKTGPF
EDLKENLIREYVKQTWNLQGQALEQAIISQKPQLEKLIATTAHEKMPWFHGKISREESEQ
IVLIGSKTNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIPEGKKFDTLWQL
VEHYSYKADGLLRVLTVPCQKIGTQGNVNFGGRPQLPGSHPATWSAGGIISRIKSYSFPK
PGHRKSSPAQGNRQESTVSFNPYEPELAPWAADKGPQREALPMDTEVYESPYADPEEIRP
KEVYLDRKLLTLEDKELGSGNFGTVKKGYYQMKKVVKTVAVKILKNEANDPALKDELLAE
ANVMQQLDNPYIVRMIGICEAESWMLVMEMAELGPLNKYLQQNRHVKDKNIIELVHQVSM
GMKYLEESNFVHRDLAARNVLLVTQHYAKISDFGLSKALRADENYYKAQTHGKWPVKWYA
PECINYYKFSSKSDVWSFGVLMWEAFSYGQKPYRGMKGSEVTAMLEKGERMGCPAGCPRE
MYDLMNLCWTYDVENRPGFAAVELRLRNYYYDVVN
Drugs and Mode of Action
Drug(s) Syk kinase silencer Drug Info Discontinued in Phase 2 Asthma [548313]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway NF-kappa B signaling pathway
PI3K-Akt signaling pathway
Osteoclast differentiation
Platelet activation
Natural killer cell mediated cytotoxicity
B cell receptor signaling pathway
Fc epsilon RI signaling pathway
Fc gamma R-mediated phagocytosis
Tuberculosis
Epstein-Barr virus infection
Viral carcinogenesis
PANTHER Pathway B cell activation
Pathway Interaction Database Fc-epsilon receptor I signaling in mast cells
BCR signaling pathway
GMCSF-mediated signaling events
Atypical NF-kappaB pathway
Osteopontin-mediated events
FAS (CD95) signaling pathway
Thromboxane A2 receptor signaling
IL2-mediated signaling events
Class I PI3K signaling events
Alpha-synuclein signaling
PathWhiz Pathway Fc Epsilon Receptor I Signaling in Mast Cells
Reactome GPVI-mediated activation cascade
FCGR activation
Regulation of actin dynamics for phagocytic cup formation
Role of phospholipids in phagocytosis
DAP12 signaling
Fc epsilon receptor (FCERI) signaling
Role of LAT2/NTAL/LAB on calcium mobilization
FCERI mediated MAPK activation
FCERI mediated Ca+2 mobilization
Integrin alphaIIb beta3 signaling
Interleukin-2 signaling
CLEC7A (Dectin-1) signaling
Dectin-2 family
Regulation of signaling by CBL
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
WikiPathways IL-2 Signaling Pathway
IL-3 Signaling Pathway
Fc epsilon receptor (FCERI) signaling
Signaling by the B Cell Receptor (BCR)
Interleukin-2 signaling
Fcgamma receptor (FCGR) dependent phagocytosis
DAP12 interactions
B Cell Receptor Signaling Pathway
RANKL/RANK Signaling Pathway
Integrin alphaIIb beta3 signaling
GPVI-mediated activation cascade
Regulation of toll-like receptor signaling pathway
IL-5 Signaling Pathway
References
Ref 548313Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024464)
Ref 544130Clinical Status of Duplex RNA. Bioorg Med Chem Lett. 2010 June 1; 20(11): 3203-3207.

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