Affinage

SYK

Tyrosine-protein kinase SYK · UniProt P43405

Length
635 aa
Mass
72.1 kDa
Annotated
2026-04-28
100 papers in source corpus 44 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYK is a cytoplasmic non-receptor tyrosine kinase that serves as a central signal-transducing hub downstream of immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, integrin receptors, and C-type lectins, coupling receptor engagement to phagocytosis, cytoskeletal reorganization, inflammatory cytokine production, and lymphocyte development. Full-length crystal structures reveal an autoinhibited conformation relieved by ppITAM binding to the tandem SH2 domains, which primes SYK for LYN-mediated phosphorylation of linker tyrosines Tyr-348/352 and subsequent activation-loop autophosphorylation (PMID:23154170, PMID:30923129). Activated SYK phosphorylates BLNK to scaffold BTK activation, signals through PI3K–AKT–mTOR and CARD9–NF-κB axes, drives TREM2-dependent microglial plaque encasement, and is required for γδT17 cell development and complement-mediated phagocytosis (PMID:11226282, PMID:36306735, PMID:29202478, PMID:16449524). SYK protein levels are regulated by Cbl-mediated and TRIM31-mediated ubiquitination and USP10-dependent deubiquitination, and SYK functions as a tumor suppressor in breast epithelial cells by enforcing proper mitosis (PMID:34362877, PMID:31873727, PMID:10963601).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Establishing that SYK and ZAP-70 are functionally interchangeable at the BCR defined SYK as the canonical ITAM-proximal kinase in B cells, answering whether SH2-domain-containing kinases could substitute for one another at immunoreceptors.

    Evidence Reconstitution of Syk-deficient B cells with ZAP-70; direct binding assays to phosphorylated Igα/Igβ

    PMID:7538440

    Open questions at the time
    • Whether SYK and ZAP-70 differ in substrate selectivity was not resolved
    • Structural basis for functional equivalence was unknown
  2. 1996 High

    Demonstrating that clustered SYK kinase domains alone trigger phagocytosis and actin redistribution established that SYK catalytic activity is both necessary and sufficient for coupling immunoreceptor signals to the cytoskeleton.

    Evidence Chimeric receptor system in COS cells with kinase-dead point mutant; phagocytosis and actin assays

    PMID:8577722

    Open questions at the time
    • Downstream cytoskeletal effectors were not identified
    • Whether the SH2 domains modulate phagocytic efficiency in vivo was untested
  3. 2000 High

    Showing that SYK reintroduction suppresses breast cancer growth and metastasis while kinase-dead SYK promotes tumorigenesis revealed an unexpected tumor-suppressor function linked to mitotic fidelity, broadening SYK's role beyond immune cells.

    Evidence Gain- and loss-of-function in breast cancer xenografts with kinase-dead control; mitosis/cytokinesis analysis

    PMID:10963601

    Open questions at the time
    • The mitotic substrate(s) of SYK were not identified
    • Mechanism of SYK silencing in tumors was unknown
  4. 2001 High

    Identifying BLNK as the scaffold that couples SYK to BTK phosphorylation resolved how SYK propagates BCR signals to downstream effectors and explained why BLNK deficiency phenocopies SYK deficiency in B cells.

    Evidence Reconstitution system plus analysis of BLNK-deficient and Syk-deficient primary B cells

    PMID:11226282

    Open questions at the time
    • Whether additional scaffolds operate in parallel was unclear
    • Stoichiometry of the SYK–BLNK–BTK complex was not determined
  5. 2001 High

    Demonstrating phosphotyrosine-independent binding of SYK tandem SH2 domains to the integrin β3 cytoplasmic tail extended SYK signaling beyond classical ITAMs to integrins, explaining SYK's role in adhesion-dependent lamellipodia formation.

    Evidence Co-IP, β3-tail pulldown, β3-759X deletion mutant; adhesion and lamellipodia assays

    PMID:11719224

    Open questions at the time
    • Structural basis for phosphotyrosine-independent binding was not resolved
    • Whether this mode of activation occurs in vivo in platelets was not shown
  6. 2002 High

    Epistasis experiments in NK cells placed SYK upstream of PI3K in DAP12-mediated cytotoxicity and IL-2 survival signaling, defining the SYK→PI3K→Rac1→AKT axis as a core cascade in innate lymphocytes.

    Evidence Dominant-negative SYK, pharmacological inhibition, constitutively active PI3K/Rac1 rescue in NK cells

    PMID:11907067 PMID:12393431

    Open questions at the time
    • Direct phosphorylation of PI3K subunits by SYK was not demonstrated
    • Contribution of other kinases to PI3K activation was not excluded
  7. 2006 High

    Showing that SYK is required for complement receptor CR3-mediated phagocytosis and RhoA/Vav activation defined a second phagocytic receptor pathway dependent on SYK, paralleling the Fcγ receptor pathway.

    Evidence SYK siRNA and dominant-negative SYK in HL60 cells; CR3-dependent zymosan uptake and RhoA/Vav phosphorylation

    PMID:16449524

    Open questions at the time
    • Whether SYK directly phosphorylates Vav or acts through intermediates was unresolved
  8. 2008 High

    Demonstrating that Dectin-1/SYK cooperates with multiple TLRs for sustained NF-κB activation established SYK as an integrator of innate pattern-recognition signals beyond single-receptor pathways.

    Evidence Syk-deficient and MyD88-deficient macrophages; IκB degradation and NF-κB translocation assays

    PMID:18200499

    Open questions at the time
    • Molecular mechanism of TLR–SYK convergence on NF-κB was not identified
    • Whether CARD9 mediates all SYK-dependent NF-κB in this context was untested
  9. 2010 High

    Resolving the phosphorylation hierarchy — Lyn exclusively phosphorylates Tyr-346 while other sites are dual Lyn/autophosphorylation targets — and identifying C-terminal tyrosines (Tyr-623/624/625) as regulators of kinase activity and ITAM binding provided a detailed activation map of SYK.

    Evidence Selective kinase inhibitors, kinase-dead SYK, Lyn siRNA in mast cells; C-terminal tyrosine mutagenesis with reconstitution in Syk-deficient mast cells

    PMID:20554527 PMID:20828828

    Open questions at the time
    • The phosphatase(s) that dephosphorylate each specific site were not identified
    • Structural consequence of C-terminal tyrosine phosphorylation was not determined
  10. 2010 High

    Determining that CLEC-2 hemITAM dimers recruit SYK in a 2:1 stoichiometry established an alternative mode of SYK engagement distinct from the dual-ITAM model.

    Evidence SPR, peptide pulldown, tryptophan fluorescence, cross-linking, EM with CLEC-2 tail peptides

    PMID:20154219

    Open questions at the time
    • Whether hemITAM-bound SYK achieves equivalent catalytic output to ppITAM-bound SYK was unknown
  11. 2012 High

    The crystal structure of full-length autoinhibited SYK showed that ppITAM binding allosterically remodels the ATP-binding site, providing the first structural framework for the SYK activation mechanism.

    Evidence X-ray crystallography of full-length wild-type and Y348F/Y352F SYK with AMP-PNP; SPR, ITC, autophosphorylation assays

    PMID:23154170

    Open questions at the time
    • Structure of fully activated (linker-phosphorylated) SYK was not obtained
    • Dynamics of conformational change in membranes were not captured
  12. 2019 High

    Demonstrating that ppITAM binding alone is insufficient to fully activate monomeric SYK and that sequential LYN-mediated Tyr-352→Tyr-348 phosphorylation is required resolved a longstanding question about the obligatory role of Src-family kinase priming.

    Evidence In vitro kinase assay with monomeric untagged recombinant SYK; phosphoproteomics

    PMID:30923129

    Open questions at the time
    • Whether this two-step mechanism operates identically across all ITAM-bearing receptors was not tested
  13. 2020 Medium

    Identifying Cbl-mediated SYK degradation as a gatekeeper of germinal center B cell fate — attenuating BCR signal intensity to favor dark-zone recycling over plasma cell differentiation — connected SYK protein turnover to adaptive immune output.

    Evidence Mouse model defective in Cbl-mediated SYK degradation; Kras/ERK and PI3K/Foxo1 pathway analysis; GC B cell flow cytometry

    PMID:31873727

    Open questions at the time
    • Specific ubiquitin linkage type on SYK by Cbl was not defined
    • Whether USP10 counteracts Cbl in GC B cells was not tested
  14. 2021 High

    Discovery that TRIM31 catalyzes K27-linked polyubiquitination of SYK at Lys-375/517 to promote its membrane translocation and shield it from SHP-1 revealed a positive regulatory ubiquitination pathway distinct from Cbl-mediated degradative ubiquitination.

    Evidence Reconstituted ubiquitination assay, K375/517 mutagenesis, Trim31−/− mice, Candida infection model

    PMID:34362877

    Open questions at the time
    • Whether other E3 ligases also catalyze non-degradative SYK ubiquitination is unknown
    • Structural basis for K27-linked ubiquitin recognition by downstream effectors was not determined
  15. 2022 High

    Conditional SYK deletion in microglia ablated TREM2-dependent plaque encasement and the PI3K–AKT–mTOR axis required for the disease-associated microglia program, positioning SYK as an essential transducer in neurodegeneration-associated microglial activation.

    Evidence SYK conditional KO in microglia, TREM2R47H knock-in mice, anti-CLEC7A antibody rescue, Aβ plaque assays

    PMID:36257314 PMID:36306735

    Open questions at the time
    • Whether SYK inhibition is therapeutically beneficial or detrimental in Alzheimer's disease is unresolved
    • SYK substrates specific to microglia were not catalogued

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for full SYK activation in the membrane context (linker-phosphorylated, ITAM-bound), the complete inventory of direct SYK substrates across cell types, and whether SYK's tumor-suppressor and neuroinflammatory roles can be therapeutically separated remain open questions.
  • No structure of membrane-associated, fully activated SYK exists
  • Comprehensive substrate identification across cell types is lacking
  • Therapeutic window for SYK modulation in neurodegeneration versus immunity is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005768 endosome 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 6 R-HSA-109582 Hemostasis 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
BLNKBTKCBLCLEC1BLYNTREM2TRIM31USP10

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Syk binds directly to the integrin β3 cytoplasmic tail through its tandem SH2 domains in a phosphotyrosine-independent manner, and this interaction is required for Syk activation and lamellipodia formation upon cell adhesion to fibrinogen; deletion of the four C-terminal residues of β3 abolished Syk binding, activation, and lamellipodia formation without affecting FAK phosphorylation. Co-immunoprecipitation, pulldown with β3 cytoplasmic tail, cell adhesion assay with mutant integrin (β3-759X), kinase activity assay Current biology : CB High 11719224
1996 Clustered Syk kinase domains are sufficient to autonomously trigger phagocytosis and filamentous actin redistribution in COS cells; a catalytic-domain point mutation abolishes this activity, and the kinase domain alone is sufficient for cytoskeletal coupling. Chimeric transmembrane receptor expression in COS cells, phagocytosis assay, actin redistribution assay, catalytic-dead point mutant Proceedings of the National Academy of Sciences of the United States of America High 8577722
2001 BLNK mediates Syk-dependent Btk activation: Syk phosphorylates Btk on Tyr-551 via BLNK as a scaffold, requiring the Btk-SH2 domain interaction with BLNK; BCR-induced Btk phosphorylation and activation are significantly reduced in both BLNK-deficient and Syk-deficient B cells. Reconstitution cell system co-expression, in vitro phosphorylation assay, BLNK-deficient and Syk-deficient B cell analysis Proceedings of the National Academy of Sciences of the United States of America High 11226282
2010 CLEC-2 activates Syk through receptor dimerization: the single YxxL hemITAM in the CLEC-2 cytosolic tail, when phosphorylated, recruits Syk tandem SH2 domains in a 2:1 (CLEC-2:Syk) stoichiometry; CLEC-2 exists as a dimer in resting platelets and forms larger complexes upon activation. Peptide pulldown, surface plasmon resonance, quantitative Western blot, tryptophan fluorescence, competition experiments, cross-linking, electron microscopy Blood High 20154219
2012 Crystal structures of full-length Syk (wild type and Y348F/Y352F mutant) in complex with AMP-PNP reveal an autoinhibited conformation; pITAM binding to the tSH2 domain stimulates in vitro autophosphorylation and confers conformational changes at the ATP-binding site of the kinase domain, consistent with allosteric activation. X-ray crystallography of full-length Syk, surface plasmon resonance, isothermal titration calorimetry, in vitro autophosphorylation assay, mutagenesis (Y348F/Y352F) Journal of molecular biology High 23154170
2019 SYK activation requires both ppITAM binding (which primes SYK) and LYN-mediated phosphorylation of Tyr-352 then Tyr-348 in the SH2-kinase linker, which then facilitates activation-loop phosphorylation and full SYK activation; ppITAM alone is insufficient to fully activate monomeric untagged SYK. In vitro kinase assay with unphosphorylated and phosphorylated recombinant SYK (monomeric and obligatory-dimeric forms), immunoblot, phosphoproteomics The Journal of biological chemistry High 30923129
2010 Syk tyrosine 346 in FcεRI signaling is exclusively phosphorylated by Src family kinases (predominantly Lyn), while tyrosines 317, 342, 519, and 520 are phosphorylated by both Syk auto/trans-phosphorylation and Src family kinases; Lyn knockdown impairs phosphorylation of Syk substrates SLP-76 and LAT but paradoxically sensitizes cells to degranulation by enhancing distal ERK activation. Selective kinase inhibitors, kinase-dead Syk, Lyn siRNA knockdown, site-specific phospho-antibodies in RBL-2H3 and bone marrow-derived mast cells Molecular immunology High 20828828
2010 C-terminal tyrosines Tyr-623, Tyr-624, and Tyr-625 of Syk regulate its kinase activity and ITAM binding: mutation of these residues increases basal autophosphorylation and reduces kinase activity toward exogenous substrates, decreases ITAM binding, and impairs FcεRI-induced degranulation, NFAT, NFκB, and MAP kinase activation; Tyr-625 has the dominant role. Site-directed mutagenesis, in vitro kinase assay, ITAM binding assay, degranulation assay, signaling readouts in Syk-deficient mast cells reconstituted with wild-type or mutant Syk The Journal of biological chemistry High 20554527
1995 ZAP-70 and Syk are functionally homologous: ZAP-70 expression in Syk-deficient B cells reconstitutes BCR function, requiring intact SH2 and catalytic domains; both kinases bind directly to phosphorylated Igα and Igβ subunits with comparable affinities. Reconstitution of Syk-deficient B cells with ZAP-70, direct binding assay to phosphorylated BCR subunits, domain-deletion mutants Immunity High 7538440
2006 Syk is required for pathogen engulfment in complement-mediated phagocytosis (via CR3): Syk becomes tyrosine-phosphorylated and accumulates around nascent phagosomes during C3bi-opsonized zymosan uptake; Syk-siRNA or dominant-negative Syk impairs engulfment, actin accumulation/depolymerization around phagosomes, and RhoA activation/Vav tyrosine phosphorylation. siRNA knockdown, dominant-negative Syk expression, fluorescence quenching phagocytosis assay, immunofluorescence, tyrosine phosphorylation assay in HL60 cells Blood High 16449524
2012 Jedi-1 and MEGF10 signal engulfment of apoptotic neurons through Syk: Syk interacts with the ITAMs of both receptors; ITAM phosphorylation by Src family kinases enhances Syk interaction and activation; ITAM tyrosine mutation or Syk inhibition blocks phagocytosis of microspheres and apoptotic neurons in glial precursor cocultures. Co-immunoprecipitation, ITAM tyrosine mutagenesis, pharmacologic Syk inhibition (BAY 61-3606), Syk siRNA knockdown in mouse embryonic glial precursors, engulfment assay The Journal of neuroscience : the official journal of the Society for Neuroscience High 22993420
2014 Retroviral retention induces phosphorylation of conserved tyrosines in tetherin cytoplasmic tail dimers, recruiting Syk; Syk is required for downstream NF-κB activation; tetherin signaling is coupled to cortical actin via RICH2 (ARHGAP44), and a naturally occurring tetherin polymorphism with reduced RICH2 binding shows decreased tetherin phosphorylation and NF-κB activation. Co-immunoprecipitation, phosphorylation assays, NF-κB reporter assay, tetherin polymorphism analysis, retroviral particle retention assay Cell host & microbe High 25211072
2021 TRIM31 E3 ligase catalyzes K27-linked polyubiquitination of SYK at Lys-375 and Lys-517, promoting SYK plasma membrane translocation and binding to C-type lectin receptors, and preventing interaction with the phosphatase SHP-1; Trim31-deficient macrophages and dendritic cells show dampened SYK-mediated signaling and impaired cytokine responses to Candida albicans. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K375/K517), subcellular fractionation, Trim31-/- mouse model, in vitro infection assay Signal transduction and targeted therapy High 34362877
2020 USP10 is a major deubiquitinase required for SYK protein stabilization; USP10 inhibition induces SYK degradation via the proteasome and kills cells driven by active SYK or oncogenic FLT3. USP10 inhibitor treatment, SYK protein stability assays, cell viability assays, co-immunoprecipitation British journal of cancer Medium 32015510
2004 IgE/FcεRI stimulation of basophils leads to c-Cbl phosphorylation, c-Cbl association with Syk, Syk ubiquitylation, and proteasome-dependent Syk degradation over hours; proteasome inhibition with lactacystin A results in accumulation of high-molecular-weight ubiquitylated Syk species. Immunoprecipitation, immunoblotting, proteasome inhibition (lactacystin A), primary human basophils The Journal of allergy and clinical immunology Medium 15577829
2020 Cbl-mediated Syk degradation in germinal center B cells attenuates BCR signaling intensity by mitigating Kras/Erk and PI3K/Foxo1 pathways, restraining plasma cell formation and promoting light-zone-to-dark-zone transition. Mouse model defective in Cbl-mediated Syk degradation, gene expression analysis, flow cytometry, signaling pathway analysis The Journal of experimental medicine Medium 31873727
2006 Syk shuttles between nuclear and cytoplasmic compartments via an unconventional shuttling sequence at the junction of the catalytic domain and linker B region; BCR engagement causes nuclear exclusion of Syk through protein kinase C activation and new protein synthesis; nuclear exclusion promotes stress-induced caspase-3 activation. Deletion mutant analysis, subcellular fractionation, live-cell imaging, pharmacological inhibitors (PKC), caspase-3 activation assays Molecular and cellular biology Medium 16611990
2005 Syk colocalizes and copurifies with the centrosomal marker γ-tubulin, exhibits catalytic activity within centrosomes, requires intact kinase activity for centrosomal localization, and is degraded via ubiquitinylation/proteasome during mitosis; unrestrained Syk overexpression causes multipolar spindles, supernumerary centrosomes, and mitotic catastrophe. Colocalization by immunofluorescence, centrosome purification/copurification, in vitro kinase assay, DsRed-Syk overexpression, live-cell imaging Cancer research Medium 16322234
2002 In NK cells, Syk acts upstream of PI3K in the DAP12-mediated cytotoxicity pathway: tumor cell ligation induces DAP12 tyrosine phosphorylation and DAP12-Syk association; kinase-deficient Syk or Syk inhibitor blocks PI3K, Rac1, PAK1, MEK, and ERK activation as well as perforin movement and NK cytotoxicity; constitutively active PI3K rescues all downstream events in Syk-impaired cells. Dominant-negative Syk expression, pharmacological inhibition (piceatannol), constitutively active PI3K rescue, co-immunoprecipitation, kinase activity assays, cytotoxicity assays Journal of immunology (Baltimore, Md. : 1950) High 11907067
2002 In NK cells, IL-2 activates a Syk → PI3K → Rac1 → Akt survival cascade: kinase-deficient Syk or Syk inhibitor markedly suppresses IL-2-stimulated PI3K and Akt activation; constitutively active PI3K reverses Syk-impaired Akt activation; dominant-negative Rac1 blocks PI3K-induced Akt activation, while constitutively active Rac1 rescues Akt even in PI3K-impaired cells. Dominant-negative Syk, piceatannol inhibition, constitutively active/dominant-negative PI3K and Rac1 constructs, Akt phosphorylation assay, cell viability assay Blood High 12393431
1997 Pyk2 tyrosine phosphorylation and activation following FcεRI aggregation is downstream of Syk: loss of Syk activity abolishes FcεRI-induced Pyk2 phosphorylation; in contrast, G-protein-coupled receptor-induced Pyk2 phosphorylation is Syk-independent. FcεRI aggregation assay, Syk-deficient cell analysis, Pyk2 kinase activity assay, pharmacological dissection The Journal of biological chemistry Medium 9405454
2001 CrkL acts as an adapter linking Wiskott-Aldrich syndrome protein (WASP) and Syk: CrkL binds WASP through its SH3 domain and co-precipitates kinase-active Syk; both SH2 and SH3 domains of CrkL are involved in Syk binding; WASP, CrkL, Syk, and Hic-5 are incorporated into the platelet cytoskeleton after aggregation. Anti-CrkL immunoprecipitation, GST-fusion pulldown, in vitro kinase assay, platelet aggregation cytoskeletal fractionation Blood Medium 11313252
2008 Dectin-1 signaling through Syk is required for collaborative cytokine production with TLR2, TLR4, TLR5, TLR7, and TLR9 in macrophages; deficiency of either Syk or the TLR adaptor MyD88 abolishes collaborative responses; Syk/TLR collaboration results in sustained IκB degradation and enhanced NFκB nuclear translocation. Syk-deficient macrophages, MyD88-deficient macrophages, NFκB nuclear translocation assay, IκB degradation assay, cytokine measurement European journal of immunology High 18200499
2000 Syk suppresses malignant growth and metastasis in breast cancer cells: reintroduction of wild-type Syk into Syk-negative breast cancer cells inhibited tumor growth and metastasis in athymic mice, while overexpression of kinase-deficient Syk in Syk-positive cells increased tumor incidence; tumor suppression by Syk is associated with aberrant mitosis and cytokinesis. Syk cDNA transfection, kinase-deficient Syk overexpression, in vivo xenograft mouse model, microscopic analysis of mitosis/cytokinesis Nature High 10963601
2005 Syk kinase activity is required for endothelial cell proliferation and migration; adenoviral expression of Syk dominant-negative mutants severely impaired proliferation and migration of human umbilical vein endothelial cells; Syk kinase activity is closely linked to ERK activation in this context. Adenovirus-mediated dominant-negative Syk expression, cell proliferation assay, migration assay, ERK phosphorylation assay Biochemical and biophysical research communications Medium 11485328
2008 In airway epithelial cells, Syk associates with clathrin and is recruited to the plasma membrane upon HRV16-ICAM-1 binding, then redistributes to endosomal structures during internalization; kinase-inactive Syk(K396R) blocks HRV endocytosis; Syk is required for HRV-induced PI3K/Akt activation. Confocal microscopy, co-immunoprecipitation, kinase-dead mutant (K396R), Syk siRNA knockdown, Akt phosphorylation assay Journal of immunology (Baltimore, Md. : 1950) Medium 18178826
2015 Syk is recruited to stress granules through a phosphotyrosine-dependent mechanism and via interaction with Grb7; Syk recruitment promotes autophagosome formation and clearance of stress granules from cells, enhancing cell survival after stress. Proteomic analysis of Syk-binding partners, co-immunoprecipitation, stress granule induction assays, autophagosome formation assay, Grb7 interaction studies The Journal of biological chemistry Medium 26429917
2017 In γδT cells, Syk (but not ZAP-70) is essential for γδTCR signal transduction and development of IL-17-producing γδT17 cells; Syk activates the PI3K/Akt pathway upon γδTCR stimulation; mice deficient in PI3K signaling show complete loss of γδT17; RhoH (an adaptor that recruits Syk) is required for γδT17-dependent skin inflammation. Syk conditional knockout mice, ZAP-70 rescue experiments, PI3K-deficient mice, RhoH-deficient mice, γδTCR stimulation assays The Journal of clinical investigation High 29202478
2021 STAT1 is activated by Syk downstream of RIG-I/MAVS signaling at early stages of influenza A virus infection, independently of cytokines and JAKs; Syk deletion attenuates STAT1 Tyr-701 phosphorylation and ISG expression in vitro and in vivo; STAT1-Y701F knockin mice also show suppressed antiviral responses. Syk deletion (conditional KO), STAT1-Y701F knockin mice, STAT1 phosphorylation assay, ISG expression analysis, IAV infection model Cell reports High 33472080
2022 TREM2-DAP12 receptor complex transmits signals through SYK; SYK-deficient microglia cannot encase Aβ plaques; SYK deficiency impairs the PI3K-AKT-GSK-3β-mTOR pathway required for disease-associated microglia (DAM) profile; a parallel SYK-independent DAP10-dependent pathway supports microglial proliferation and prodromal DAM; antibody-mediated activation of CLEC7A (which directly activates SYK) rescues microglial activation in TREM2R47H mice. SYK conditional KO in microglia, TREM2R47H knock-in mice, PI3K/AKT pathway analysis, Aβ plaque encasement assay, anti-CLEC7A antibody treatment Cell High 36257314 36306735
2011 CLEC-2 and Syk in the megakaryocyte/platelet lineage are required for normal brain vascular and lymphatic development; conditional deletion of Syk or CLEC-2 specifically in megakaryocytes/platelets recapitulates the vascular/lymphatic defects; platelets (but not platelet releasate) directly modulate lymphatic endothelial cell migration and intercellular adhesion through CLEC-2 and Syk. Conditional KO mice (hematopoietic lineage-specific and megakaryocyte/platelet-specific), lymphatic endothelial cell migration/adhesion assays in vitro Blood High 22186994
2000 CCR5 signaling through MIP-1β activates Syk, which associates with RAFTK (Pyk2); RAFTK acts upstream of Syk (dominant-negative RAFTK suppresses Syk activation; overexpressed RAFTK enhances Syk activity); SHP1 and SHP2 are also activated and associate with Syk and Grb2. Co-immunoprecipitation, dominant-negative RAFTK expression, kinase activity assays, phosphatase inhibitor experiments The Journal of biological chemistry Medium 10747947
2005 The tyrosine kinase Syk regulates TPL2 (Cot) activation downstream of TNF-α: Syk inhibition or Syk deficiency blocks Tpl2-dependent ERK activation; Syk acts downstream of RIP1 and TRAF2 in the TNFR1 pathway but Tpl2 cannot be activated by RIP1/TRAF2 alone without Syk. Genetic Syk deficiency, pharmacological Syk inhibition, overexpression epistasis (RIP1, TRAF2), kinase activity assays The Journal of biological chemistry Medium 16291755
2014 Pharmacological inhibition or siRNA knockdown of Syk reduces Aβ production and increases Aβ clearance across the blood-brain barrier; Syk inhibition induces increased phosphorylation of GSK-3β Ser-9 (inhibitory) via PKA activation, reducing GSK-3β-dependent Tau phosphorylation. Syk pharmacological inhibitors, siRNA knockdown, in vivo transgenic mouse models (Aβ overexpression and Tau P301S), GSK-3β Ser-9 phosphorylation assay, PKA activity measurement The Journal of biological chemistry Medium 25331948
2019 SYK inhibition increases autophagic Tau degradation without affecting Tau production; SYK acts upstream of the mTOR pathway, and SYK inhibition/knockdown decreases mTOR pathway activation and increases autophagy flux; chronic SYK inhibition in a tauopathy mouse model reduces Tau accumulation, neuroinflammation, neuronal/synaptic loss, and reverses defective autophagy. SYK pharmacological inhibition, shRNA knockdown, mTOR pathway analysis, autophagy flux assay, tauopathy mouse model The Journal of biological chemistry Medium 31324720
2011 Alternative splicing of SYK regulates mitosis and cell survival; modulating SYK splicing pattern impairs cell-cycle progression and anchorage-independent growth in cancer cells; EGF exposure promotes the pro-survival SYK isoform associated with cancer tissues. Splicing modulation by antisense oligonucleotides/splicing factors, cell growth/viability/apoptosis assays, anchorage-independent growth assay Nature structural & molecular biology Medium 21552259
2021 In B cells, SYK mediates negative selection of autoreactive and premalignant clones; when ZAP-70 is aberrantly expressed in B cells, it competes with SYK at the BCR signalosome, redirecting SYK from NFAT-dependent negative selection to tonic PI3K signaling and promoting survival; conditional Zap70 expression accelerates B cell malignancy and compromises negative selection. Conditional Zap70 knock-in mice, SYK genetic deletion, BCR signaling assays (NFAT vs PI3K), B-ALL and B-CLL mouse models Molecular cell High 33878293
2022 Amyloid-β activates the NLRP3 inflammasome in microglia by activating Syk and inhibiting AMPK; inhibited AMPK causes metabolic dysregulation, mitochondrial fragmentation, and ROS formation leading to NLRP3 activation; Syk thus acts upstream of the AMPK-NLRP3 axis. Syk inhibition, AMPK pathway analysis, ROS measurement, NLRP3 inflammasome activation assay, mitochondrial morphology analysis Aging cell Medium 35474599
2013 Syk activation induces Blimp-1 expression in B cells, which suppresses Bcl-2 and limits B cell expansion; constitutive Syk activity (via TEL-Syk fusion) drives plasma cell differentiation rather than transformation; combined Syk activation with Bcl-2 transgene leads to plasma cell expansion. Inducible TEL-Syk knock-in mouse model, Bcl-2 transgene, flow cytometry, gene expression analysis Oncogene Medium 23955076
2010 Syk is involved in CD40 signaling and is synergistically activated by BCR/CD40 co-stimulation; CD40 alone activates BLNK, Btk, and Vav-2 downstream of Syk, and enhances BCR-induced complex formation of Vav-2, Btk, BLNK, and PLCγ2, leading to ERK, p38, Akt, and NFκB activation. Co-immunoprecipitation, kinase activity assay, B cell stimulation with anti-CD40 and anti-IgM, Syk inhibitor Immunobiology Medium 21074890
2024 PCSK9 binds to CAP1 (adenylyl cyclase-associated protein 1) on macrophages, and this interaction activates Syk and PKCδ as key mediators of inflammation; serum PCSK9 levels positively correlate with Syk, PKCδ, and p65 phosphorylation in human PBMCs; CAP1-Fc fusion protein mitigates PCSK9-mediated SYK signaling. Co-immunoprecipitation, CAP1 knockdown, kinase phosphorylation assays, LDL receptor KO mouse model, human PBMC correlation studies Nature communications Medium 38555386
2015 CD59 crosslinking on erythrocytes induces Syk-dependent phosphorylation of Band 3 and echinocyte morphology; Syk is required for FasL release; FasL-dependent RIP1 phosphorylation combined with membrane pore formation executes necroptosis through RIP3. CD59 crosslinking, Syk inhibition, Band 3 phosphorylation assay, FasL measurement, RIP1/RIP3 phosphorylation assay, morphological analysis Cell death & disease Medium 26018734
2016 CEACAM3 engagement by Moraxella catarrhalis UspA1 induces NF-κB activation via Syk and the CARD9 pathway in granulocytes; this signaling is dependent on phosphorylation of the CEACAM3 ITAM-like motif and triggers degranulation, ROS production, and chemokine secretion. Syk inhibitor, siRNA, luciferase NF-κB reporter, chromatin immunoprecipitation, CEACAM3 ITAM phosphorylation assay, granulocyte infection model Cellular microbiology Medium 27038042

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The SYK tyrosine kinase: a crucial player in diverse biological functions. Nature reviews. Immunology 1091 20467426
2022 TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways. Cell 356 36306735
2000 Tyrosine kinase SYK: essential functions for immunoreceptor signalling. Immunology today 324 10689303
2008 Syk kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors. European journal of immunology 303 18200499
2000 The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature 277 10963601
2022 SYK coordinates neuroprotective microglial responses in neurodegenerative disease. Cell 226 36257314
2010 The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cellular signalling 200 20206686
2014 Getting Syk: spleen tyrosine kinase as a therapeutic target. Trends in pharmacological sciences 194 24975478
2011 The role of Syk/CARD9 coupled C-type lectins in antifungal immunity. European journal of immunology 178 21267996
2005 Src and Syk kinases: key regulators of phagocytic cell activation. Trends in immunology 173 15797511
2014 Functional roles of Syk in macrophage-mediated inflammatory responses. Mediators of inflammation 148 25045209
2004 Targeting Syk as a treatment for allergic and autoimmune disorders. Expert opinion on investigational drugs 138 15212616
2001 Activation of Syk protein tyrosine kinase through interaction with integrin beta cytoplasmic domains. Current biology : CB 131 11719224
2012 The SYK side of TLR4: signalling mechanisms in response to LPS and minimally oxidized LDL. British journal of pharmacology 126 22776094
2010 CLEC-2 activates Syk through dimerization. Blood 115 20154219
2008 Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas. Leukemia 114 18401419
2011 CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development. Blood 113 22186994
2014 Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer. Biochimica et biophysica acta 112 25447675
2001 BLNK mediates Syk-dependent Btk activation. Proceedings of the National Academy of Sciences of the United States of America 112 11226282
2020 Dectin-1/Syk signaling triggers neuroinflammation after ischemic stroke in mice. Journal of neuroinflammation 106 31926564
1996 Clustered syk tyrosine kinase domains trigger phagocytosis. Proceedings of the National Academy of Sciences of the United States of America 97 8577722
2011 Alternative splicing of SYK regulates mitosis and cell survival. Nature structural & molecular biology 95 21552259
2006 The Syk tyrosine kinase: a new negative regulator in tumor growth and progression. Cancer letters 95 16442709
2002 Syk regulation of phosphoinositide 3-kinase-dependent NK cell function. Journal of immunology (Baltimore, Md. : 1950) 93 11907067
2018 Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis. Hepatology (Baltimore, Md.) 85 29537660
1995 Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase. Immunity 84 7538440
2010 The Syk kinase SmTK4 of Schistosoma mansoni is involved in the regulation of spermatogenesis and oogenesis. PLoS pathogens 80 20169182
2012 Jedi-1 and MEGF10 signal engulfment of apoptotic neurons through the tyrosine kinase Syk. The Journal of neuroscience : the official journal of the Society for Neuroscience 76 22993420
2009 Autoinhibition and adapter function of Syk. Immunological reviews 76 19909371
2008 Syk associates with clathrin and mediates phosphatidylinositol 3-kinase activation during human rhinovirus internalization. Journal of immunology (Baltimore, Md. : 1950) 73 18178826
2022 Gefitinib and fostamatinib target EGFR and SYK to attenuate silicosis: a multi-omics study with drug exploration. Signal transduction and targeted therapy 72 35551173
2012 Structural and biophysical characterization of the Syk activation switch. Journal of molecular biology 71 23154170
2006 Protein-tyrosine kinase Syk is required for pathogen engulfment in complement-mediated phagocytosis. Blood 71 16449524
2004 Progressive loss of Syk and abnormal proliferation in breast cancer cells. Cancer research 70 15492255
2000 Beta-chemokine receptor CCR5 signals through SHP1, SHP2, and Syk. The Journal of biological chemistry 69 10747947
2009 Protein tyrosine kinase, syk: a key player in phagocytic cells. Journal of biochemistry 66 19124456
2022 Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib. Platelets 65 36331249
2022 Amyloid-β activates NLRP3 inflammasomes by affecting microglial immunometabolism through the Syk-AMPK pathway. Aging cell 63 35474599
2004 Loss of syk kinase during IgE-mediated stimulation of human basophils. The Journal of allergy and clinical immunology 63 15577829
2018 Dectin-1-Syk-CARD9 Signaling Pathway in TB Immunity. Frontiers in immunology 62 29487599
2014 The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation. The Journal of biological chemistry 59 25331948
2014 SYK is a candidate kinase target for the treatment of advanced prostate cancer. Cancer research 59 25388286
2001 Spleen tyrosine kinase (Syk) deficiency in childhood pro-B cell acute lymphoblastic leukemia. Oncogene 58 11494125
2005 The Syk tyrosine kinase localizes to the centrosomes and negatively affects mitotic progression. Cancer research 56 16322234
2010 Therapeutic targeting of Syk in autoimmune diabetes. Journal of immunology (Baltimore, Md. : 1950) 55 20601600
2006 Nucleocytoplasmic trafficking of the Syk protein tyrosine kinase. Molecular and cellular biology 55 16611990
2002 Regulation of Akt-dependent cell survival by Syk and Rac. Blood 55 12393431
2005 Spleen tyrosine kinase (Syk) as a novel target for allergic asthma and rhinitis. Expert opinion on therapeutic targets 52 16185147
2001 A critical role for Syk in endothelial cell proliferation and migration. Biochemical and biophysical research communications 52 11485328
2014 Retroviral retention activates a Syk-dependent HemITAM in human tetherin. Cell host & microbe 51 25211072
2017 γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program. The Journal of clinical investigation 47 29202478
2015 Syk Is Recruited to Stress Granules and Promotes Their Clearance through Autophagy. The Journal of biological chemistry 47 26429917
2011 The Syk kinase as a therapeutic target in leukemia and lymphoma. Expert opinion on investigational drugs 47 21438742
1997 Activation of protein-tyrosine kinase Pyk2 is downstream of Syk in FcepsilonRI signaling. The Journal of biological chemistry 47 9405454
2021 Critical role of Syk-dependent STAT1 activation in innate antiviral immunity. Cell reports 46 33472080
2009 Therapeutic prospect of Syk inhibitors. Expert opinion on therapeutic patents 46 19670961
2018 SYK inhibition blocks proliferation and migration of glioma cells and modifies the tumor microenvironment. Neuro-oncology 41 29401256
2013 Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling. PloS one 41 24013589
2018 SYK inhibitor entospletinib prevents ocular and skin GVHD in mice. JCI insight 40 30282825
2005 Effector-induced Syk-mediated phosphorylation in human erythrocytes. Biochimica et biophysica acta 40 16085052
2001 CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk. Blood 40 11313252
2024 PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor. Nature communications 39 38555386
2006 Complement-mediated phagocytosis--the role of Syk. IUBMB life 39 16754322
2019 A reevaluation of the spleen tyrosine kinase (SYK) activation mechanism. The Journal of biological chemistry 38 30923129
2004 Hypermethylation of Syk gene in promoter region associated with oncogenesis and metastasis of gastric carcinoma. World journal of gastroenterology 38 15188513
2017 SYK expression in monomorphic epitheliotropic intestinal T-cell lymphoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 36 29052597
2020 Identification of SYK inhibitor, R406 as a novel senolytic agent. Aging 34 32379705
2020 Macrophage Syk-PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk-PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression. Molecular cancer therapeutics 33 31974273
2010 Syk mediates BCR- and CD40-signaling integration during B cell activation. Immunobiology 33 21074890
1995 Syk mutation in Jurkat E6-derived clones results in lack of p72syk expression. The Journal of biological chemistry 33 7592872
2022 Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases. Expert opinion on investigational drugs 32 35130124
2019 Spleen tyrosine kinase (SYK) blocks autophagic Tau degradation in vitro and in vivo. The Journal of biological chemistry 32 31324720
2010 Syk and Lyn mediate distinct Syk phosphorylation events in FcɛRI-signal transduction: implications for regulation of IgE-mediated degranulation. Molecular immunology 32 20828828
2019 Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia. Cancer discovery 31 31771968
2021 Diverse innate stimuli activate basophils through pathways involving Syk and IκB kinases. Proceedings of the National Academy of Sciences of the United States of America 29 33727419
2018 Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia. Expert opinion on investigational drugs 29 29611449
2014 SYK allelic loss and the role of Syk-regulated genes in breast cancer survival. PloS one 29 24523870
2021 Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer. Molecular cell 28 33878293
2021 TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity. Signal transduction and targeted therapy 28 34362877
2020 Inhibition of the deubiquitinase USP10 induces degradation of SYK. British journal of cancer 28 32015510
2016 Moraxella catarrhalis induces CEACAM3-Syk-CARD9-dependent activation of human granulocytes. Cellular microbiology 28 27038042
2019 Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis. Oncogene 27 30742098
2011 Phosphorylated Syk expression is enhanced in Nasu-Hakola disease brains. Neuropathology : official journal of the Japanese Society of Neuropathology 26 21981270
2007 Involvement of Syk protein tyrosine kinase in LPS-induced responses in macrophages. Journal of endotoxin research 26 17621553
2015 A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response. Pharmacological research 25 26051661
2010 Tyrosines in the carboxyl terminus regulate Syk kinase activity and function. The Journal of biological chemistry 25 20554527
2015 CD59 signaling and membrane pores drive Syk-dependent erythrocyte necroptosis. Cell death & disease 24 26018734
2022 SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies. Cellular signalling 22 35398488
2004 Protein tyrosine kinase Syk modulates EGFR signalling in human mammary epithelial cells. Cellular signalling 22 15337524
2021 CCL4-mediated targeting of spleen tyrosine kinase (Syk) inhibitor using nanoparticles alleviates inflammatory bowel disease. Clinical and translational medicine 21 33634985
2015 Inhibition of AMPK through Lyn-Syk-Akt enhances FcεRI signal pathways for allergic response. Journal of molecular medicine (Berlin, Germany) 21 26373430
2015 Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice. Arthritis research & therapy 21 26653844
2020 Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers. The Journal of experimental medicine 20 31873727
2017 Oxindole-based SYK and JAK3 dual inhibitors for rheumatoid arthritis: designing, synthesis and biological evaluation. Future medicinal chemistry 20 28722479
2015 Spleen tyrosine kinase (Syk) inhibitor fostamatinib limits tissue damage and fibrosis in a bleomycin-induced scleroderma mouse model. Clinical and experimental rheumatology 20 26148346
2013 Inducible expression of hyperactive Syk in B cells activates Blimp-1-dependent terminal differentiation. Oncogene 20 23955076
2005 The tyrosine kinase Syk regulates TPL2 activation signals. The Journal of biological chemistry 20 16291755
2017 Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation. Cancer research 19 28202529
2010 SYK kinase signaling and the NLRP3 inflammasome in antifungal immunity. Journal of molecular medicine (Berlin, Germany) 19 20401456
2004 The spleen tyrosine kinase (Syk) in human disease, implications for design of tyrosine kinase inhibitor based therapy. Current pharmaceutical design 18 15180536