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FLASH GENE
Symbol SYK contributors: mct/npt - updated : 03-03-2016
HGNC name spleen tyrosine kinase
HGNC id 11491
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • an N-terminal pair of Src homology 2 (SH2)2 domains
  • an inter-SH2 linker
  • an SH2-domain-kinase linker
  • and a C-terminal kinase domain
  • multiple sites of phosphorylation which both regulate activity and serve as docking motifs for other proteins
    • mono polymer complex
    HOMOLOGY
    interspecies ortholog to rattus Syk (92.5pc)
    ortholog to murine Syk (93pc)
    Homologene
    FAMILY
  • protein kinase superfamily
  • Tyr protein kinase family
  • SYK/ZAP-70 subfamily
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    text intracellular signaling cascade
    basic FUNCTION
  • tyrosine kinase that functions immediately downstream of antigen receptors in immune cells including B lymphocytes, mast cells, and macrophages
  • coupling activated immunoreceptors to downstream signaling events
  • mediates LPS-induced tyrosine phosphorylation of BCAP in a manner similar to BCR signaling
  • coupling the B cell antigen receptor (BCR) to the mobilization of calcium ion either through a phosphoinositide 3-kinase-dependent pathway, when not phosphorylated on tyrosines of the linker region, or through a phospholipase C-gamma-dependent pathway, when phosphorylated on Tyr-342 and Tyr-346
  • potential modulator of cell growth
  • regulating blood and vascular separation (through hematopoietic signaling pathway)
  • involved in signal transduction in a variety of cell types
  • acting as a positive effector of BCR-stimulated responses
  • having a crucial role in adaptive immune receptor signalling
  • also mediates other, unexpectedly diverse biological functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development
  • required for FCER1A signalling in mast cells and FCGR signalling in neutrophils and macrophages
  • dual-specificity kinase that self-regulates the signal output from the B-cell antigen receptor
  • requirement for SYK in migration and polarization of naive recirculating B cells by interaction with SWAP70
  • CLEC1B acts as a SYK-coupled C-type lectin receptors (CLR) able to modulate TLR signaling and inflammatory responses
  • with CLEC1B, are essential for development in the megakaryocytic/platelet lineage
  • plays a key role in TLR4-mediated macrophage responses to host-generated ligands, with subsequent activation of an AP-1 transcription program
  • SYK plays an indispensable role in nuclear localization of native IKZF1
  • ZAP70 inhibits SYK-mediated osteoclast function
  • regulator of immune cell function, plays an increasingly recognized role in tumorigenesis as a promoter of cell survival in both hematological and nonhematological malignancies
  • differential requirements of ZAP70 and SYK during thymic development, peripheral homeostasis as well as effector functions of CD4 and CD8 T cells (PMUID: 26187144)
    • CELLULAR PROCESS cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS development
    text organ morphogenesis
    PATHWAY
    metabolism
    signaling signal transduction
  • integrin-mediated signaling pathway
  • pathway of SYK regulation by PRKCB in human platelets
  • SYK/SHC1 pathway that regulates the plasma membrane levels of CFTR channels, contributing to a better understanding of how CFTR-mediated chloride secretion is regulated
  • SIGLEC15-TYROBP-SYK-signaling cascade plays a critical role in functional osteoclast formation
    • a component
  • T cell receptor complex
  • key component of a signaling network of proteins
  • ITK-SYK exists in the active conformation state and is therefore capable of signaling without SRC family kinases or stimulation of the T cell receptor
    • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
    • protein
  • activating BTK (BLNK dependent), phosphorylating BLNK
  • LCP2(interaction required to regulate separation of blood and lymphatic vascular networks)
  • can bind a variety of differently spaced ITAM motifs within the cell
  • CBL and SLA when it is phosphorylated (interaction with SLA may link it to CBL, leading to its destruction)
  • phosphorylated NFAM1
  • TYROBP and TREM2, with SYK are required for the cytokine-induced formation of giant cells
  • overexpression of TRAIP sensitizes cells to TNF-induced apoptosis, an effect that can be reversed by the coexpression of SYK
  • association of SYK to IL4R is of biological significance and IL4R is a new candidate to be added to the few cytokine receptor components which associate with SYK
  • interaction between SYK and the ubiquitin-specific protease 25 (USP25)
  • CLEC1B activates platelets through SRC and SYK tyrosine kinases, leading to tyrosine phosphorylation of downstream adapter proteins and effector enzymes, including PLCG2
  • interacting with UBASH3B in platelets (able to associate with SYK and dephosphorylate it)
  • BCAR1 is a physiological substrate of SYK
  • KAT2A binds to the 5prime proximal regions of SYK and BTK genes, suggesting that gene expressions of SYK and BTK are regulated by KAT2A
  • stimulates likely angiogenesis via transactivation of the EGF receptor, which promotes the phosphorylation of FLT1 and activation of SYK independent of VEGFA expression
  • new role for THBS1 and CD36 in the activation of the KDR signaling pathway that requires SYK
  • regulation of CFTR by SYK, a recognized controller of inflammation
  • CLEC1B signals through a pathway that is critically dependent on the tyrosine kinase SYK
  • SELPLG/ERM-binding sequence plays a critical role in recruiting leukocytes on selectins and in activating the MAPK pathway
  • SELPLG/ERM-binding sequence is involved in ERK phosphorylation but is dispensable for SYK activation
  • SYK is a partner and posttranslational regulator of IKZF1
  • LCP2 is critical for ITK-SYK activation and is particularly required for the ITK-SYK-dependent phosphorylation of SYK activation loop tyrosines
  • role for PRKCB as a negative regulator of SYK tyrosine phosphorylation downstream of GP6
  • binds robustly to nucleolin and phosphorylates it on tyrosine, enhancing its ability to bind the BCL2L1 mRNA
  • SYK negatively regulates TLR4-mediated production of IFNB1 and IL10 and promotes inflammatory responses in dendritic cells through divergent regulation of downstream PI3K-AKT1 and NFKB1 signaling pathways
  • UBASH3B suppresses activation of SYK through the GP6 platelet receptor for collagen by dephosphorylating Tyr(P)346, a regulatory site of SYK
  • BCNP1 promotes BCR signaling by modulating the phosphorylation of BLNK, SYK, and PLCG2
    • cell & other
  • Epstein-Barr virus LMP2A
  • leukocyte adhesion
    • REGULATION
    activated by a mechanism of switch-like activation (explain how SYK is both rapidly activated after receptor binding but also sustains activity over time to facilitate longer term changes in gene expression)
    by C-type lectins and integrins
    inhibited by dephosphorylation of phospho-Tyr58 (likely promote the down-regulation of SYk activation and suppression of mast cell responses)
    Other differential phosphorylation of Syk can determine the pathway by which BCR is coupled to the regulation of intracellular calcium ion
    ubiquitinated by CBLB after BCR activation promoting proteasomal degradation
    phosphorylation on Tyr-323 creates a binding site for c-Cbl, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling
    phosphorylation on Tyr-348 and Tyr-352 enhances the phosphorylation and activation of phospholipase C-gamma and the early phase of calcium ion mobilization via a phosphoinositide 3-kinase-independent pathway
    kinase activity is equivalently increased by phosphorylation, ITAM binding, or both stimuli together
    autophosphorylated
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral        
    absent in invasive breast carcinoma
    tumoral       gain of function
    in 44p100 primary diffuse large B-cell lymphoma tissues (
    constitutional        
    loss of Syk kinase-mediated integrin signaling impairs leukocyte activation, leading to reduced host defense responses
    Susceptibility
    Variant & Polymorphism
    Candidate gene
  • may act as potential therapeutic target for the treatment of breast cancer
  • SYK inhibition could be beneficial for treatment of disorders including rheumatoid arthritis, allergic rhinitis, and asthma
    • Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhemopathy 
    SYK kinase inhibition is suggested as a powerful tool for the therapy of different pathologies
    cancerhemopathy 
    SYK inhibition as a potentially useful therapy for diffuse large B-cell lymphoma
    ANIMAL & CELL MODELS