Affinage

SYK

Tyrosine-protein kinase SYK · UniProt P43405

Length
635 aa
Mass
72.1 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYK is a cytoplasmic non-receptor tyrosine kinase that couples immunoreceptor and adhesion-receptor engagement to downstream activation of the actin cytoskeleton and the PI3K-AKT-mTOR, Ras/ERK, NF-κB, and NFAT signaling pathways (PMID:7477353, PMID:12881490, PMID:11907067). It is recruited to and activated by its tandem SH2 domains engaging dual-phosphorylated ITAMs in receptor signaling chains (e.g., the BCR Igα/β chains), with full activation requiring ppITAM-mediated priming followed by LYN-catalyzed phosphorylation of the SH2-kinase linker tyrosines Tyr-348/Tyr-352 and activation-loop phosphorylation (PMID:7477353, PMID:30923129); it can also be engaged in a phosphotyrosine-independent manner through the integrin β3 cytoplasmic tail and through dimerization of single-YxxL receptors such as CLEC-2 (PMID:11719224, PMID:20154219). Its clustered kinase domain is sufficient to autonomously drive phagocytosis and F-actin remodeling, and SYK directs actin dynamics, RhoA, and Vav during complement-mediated engulfment (PMID:8577722, PMID:16449524). Active SYK propagates signaling by phosphorylating and partnering with substrates including the adaptor BLNK/SLP-65, which forms a positive-feedback complex and relays signal to Btk, PKCβI to recruit Grb2/Sos for Ras/ERK activation, α-tubulin, and nucleolin to stabilize Bcl-xL mRNA and resist apoptosis (PMID:11226282, PMID:18369315, PMID:12881490, PMID:10862713, PMID:25092868). SYK abundance and localization are tightly controlled by Cbl-mediated proteasomal degradation, TRIM31-catalyzed K27-linked polyubiquitination promoting membrane translocation, and USP10-mediated deubiquitinative stabilization (PMID:34362877, PMID:32015510, PMID:31873727). At the organismal level SYK is essential for B-cell development and vascular integrity, NK cytotoxicity, fungal/Dectin-1 immunity, γδT17 differentiation, and microglial encasement of amyloid plaques, and its dysregulation contributes to FLT3-ITD AML and to tau/Aβ pathology through mTOR and GSK-3β control (PMID:7477353, PMID:18200499, PMID:11907067, PMID:24525236, PMID:29202478, PMID:36306735, PMID:31324720).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1995 High

    Established that SYK is the obligate ITAM-coupled kinase linking immunoreceptors to lymphocyte development and that it is required for vascular integrity in vivo.

    Evidence Knockout mice plus biochemical ITAM-binding studies and pre-B cell development analysis

    PMID:7477353

    Open questions at the time
    • Did not define the activation-loop/linker phosphorylation steps required for catalytic activation
    • Did not resolve which receptor partners account for the hemorrhagic phenotype
  2. 1996 High

    Showed that the SYK kinase domain itself, when clustered, is sufficient to trigger phagocytosis and actin remodeling, defining a catalytic, kinase-dependent coupling to the cytoskeleton.

    Evidence Chimeric transmembrane SYK constructs with catalytic point mutant in COS cells, phagocytosis and actin assays

    PMID:8577722

    Open questions at the time
    • Did not identify the cytoskeletal substrates downstream of the kinase domain
    • Used a non-hematopoietic reconstitution system
  3. 2001 Medium

    Defined non-canonical, phosphotyrosine-independent recruitment of SYK to the integrin β3 tail and identified direct receptor partners (EpoR) and adaptors (CrkL/WASP) that diversify SYK signaling beyond classical ITAMs.

    Evidence Co-IP, far-Western/SH2 domain mapping, deletion mutagenesis, adhesion and cytoskeletal fractionation assays

    PMID:11313252 PMID:11719224 PMID:9852052

    Open questions at the time
    • Structural basis of phosphotyrosine-independent β3 binding not resolved
    • Single-lab binding studies for several partners
  4. 2001 High

    Resolved how SYK transmits BCR signal to Btk, showing BLNK/SLP-65 acts as both substrate and bridging adaptor for Btk Tyr-551 phosphorylation.

    Evidence Reconstitution cell system plus BLNK- and SYK-deficient B cells

    PMID:11226282

    Open questions at the time
    • Did not establish stoichiometry of the SYK/BLNK/Btk assembly
  5. 2003 High

    Identified a direct substrate-to-pathway link by which SYK phosphorylates PKCβI/α to recruit Grb2/Sos and activate Ras/ERK in mast cells.

    Evidence In vitro kinase assay, phosphosite mutagenesis, SH2-binding and Ras/ERK readouts

    PMID:12881490

    Open questions at the time
    • Dependence on prior PKC serine autophosphorylation leaves ordering of the kinase cascade incompletely mapped
  6. 2006 High

    Demonstrated SYK requirement in complement (CR3)-mediated phagocytosis, linking it to RhoA and Vav-driven actin dynamics at the phagosome.

    Evidence siRNA and dominant-negative SYK, immunofluorescence, RhoA activation assays

    PMID:16449524

    Open questions at the time
    • Did not define the direct SYK substrate controlling actin depolymerization
  7. 2008 High

    Placed SYK at the node integrating C-type lectin (Dectin-1) and TLR/MyD88 signals for optimal innate cytokine responses.

    Evidence SYK- and MyD88-deficient macrophages with cytokine and NF-κB readouts

    PMID:18200499

    Open questions at the time
    • Molecular point of SYK–MyD88 pathway convergence not defined
  8. 2008 High

    Revealed a positive-feedback loop in which SLP-65 binds an autophosphorylated SYK tyrosine to amplify and sustain BCR-driven ERK/NF-κB/NFAT and Ca2+ signaling.

    Evidence Reciprocal Co-IP, mutant mice, calcium flux and pathway analysis

    PMID:18369315

    Open questions at the time
    • Akt arm shown to be SLP-65-independent but the alternate route not mapped
  9. 2010 Medium

    Clarified activation mechanisms for non-ITAM receptors, showing CLEC-2 activates SYK via 2:1 cross-linking and that SYK can open BCR dimers by inside-out signaling to amplify receptor signaling.

    Evidence Biophysical stoichiometry (SPR, cross-linking, EM) and nanoscale proximity ligation assays

    PMID:20154219 PMID:24963139

    Open questions at the time
    • Inside-out conformational mechanism shown by a single method/lab
    • How dimer cross-linking is regulated in vivo unresolved
  10. 2010 High

    Mapped intramolecular regulatory determinants, identifying C-terminal Tyr-623/624/625 that tune SYK kinase activity and ITAM binding.

    Evidence Site-directed mutagenesis with in vitro kinase, ITAM-binding, and degranulation assays in SYK-deficient mast cells

    PMID:20554527

    Open questions at the time
    • Structural mechanism by which these tyrosines couple to the active site not resolved
  11. 2019 High

    Reconstituted the two-step activation logic of SYK: ppITAM priming enables rapid LYN-mediated linker phosphorylation (Tyr-352 then Tyr-348) and activation-loop phosphorylation for full activity.

    Evidence In vitro kinase assays with monomeric vs obligate-dimeric purified SYK plus phosphoproteomics

    PMID:30923129

    Open questions at the time
    • Kinetics of in-cell coordination between LYN and ITAM engagement not fully captured
  12. 2021 Medium

    Defined ubiquitin-based control of SYK localization and stability: TRIM31 K27-linked polyubiquitination drives membrane translocation and CLR binding while blocking SHP-1, complementing Cbl-mediated degradation and USP10-mediated stabilization.

    Evidence Site-specific ubiquitination mutagenesis, membrane fractionation, TRIM31-/- mice; Cbl-degradation-defective mice; USP10 inhibitor studies

    PMID:31873727 PMID:32015510 PMID:34362877

    Open questions at the time
    • USP10–SYK relationship inferred from inhibitor studies without direct DUB-substrate reconstitution
    • Interplay between competing ubiquitin marks not integrated
  13. 2017 High

    Showed SYK is non-redundantly required (ZAP70 cannot substitute) for γδTCR-driven PI3K/Akt signaling and γδT17 development.

    Evidence Conditional SYK, RhoH, and PI3K-mutant mice with thymic development and skin inflammation readouts

    PMID:29202478

    Open questions at the time
    • Molecular basis for SYK-vs-ZAP70 functional non-equivalence not defined
  14. 2021 High

    Established that aberrant ZAP70 competes with SYK at the BCR signalosome to redirect signaling from NFAT-driven negative selection to tonic PI3K survival signaling, promoting malignant/autoreactive clone persistence.

    Evidence Conditional ZAP70 expression and B-ALL/B-CLL mouse models with NFAT-vs-PI3K pathway analysis

    PMID:33878293

    Open questions at the time
    • Biochemical basis of differential pathway output between the two kinases not resolved
  15. 2022 High

    Defined SYK as the signaling hub for disease-associated microglia, required for PI3K-AKT-GSK-3β-mTOR anabolic support and Aβ plaque encasement, with the AD-risk TREM2 R47H variant failing to engage it.

    Evidence Microglial conditional SYK knockout in 5xFAD mice, DAM profiling, DAP10 epistasis, TREM2 R47H knock-in

    PMID:36306735

    Open questions at the time
    • How SYK selectively enables DAM anabolic state vs DAP10-driven proliferation mechanistically unresolved
  16. 2023 Medium

    Identified a small-molecule/metabolite control point: itaconate alkylates SYK Cys593 to inhibit its kinase activity and dampen inflammation.

    Evidence Biochemical alkylation, kinase activity assay, Cys593 mutation, in vivo macrophage inhibition

    PMID:37897551

    Open questions at the time
    • Single lab with limited mutagenesis detail
    • Structural consequence of Cys593 alkylation on the active site not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SYK's distinct signaling outputs (cytoskeletal, survival/mTOR, NF-κB/NFAT) are selected by receptor context, ubiquitin marks, and subcellular localization remains unresolved.
  • No unified model linking activation mode to downstream pathway choice
  • Functional consequences of centrosomal/nuclear SYK pools incompletely defined
  • Structural basis of competing ubiquitin and phosphorylation marks unintegrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 4 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-109582 Hemostasis 2 R-HSA-9612973 Autophagy 2
Partners
BLNKBTKCLEC-2CRKLDAP12GRB7LYNTRIM31
Complex memberships
BCR signalosomeplatelet cytoskeleton (WASP/CrkL/Hic-5)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Syk tandem SH2 domains bind dual phosphotyrosine sites in ITAM motifs of receptor signaling chains (e.g., immunoglobulin α and β chains of the BCR), leading to Syk activation. Homozygous syk-/- mice showed severe hemorrhaging and perinatal lethality, and syk mutation impaired pre-B cell differentiation by disrupting pre-BCR signaling. Gene targeting (knockout mouse), biochemical binding studies, lymphocyte development analysis Nature High 7477353
2001 Syk is recruited and activated by direct binding to the integrin β3 cytoplasmic tail through its tandem SH2 domains in a phosphotyrosine-independent manner. Deletion of four C-terminal residues of the β3 tail decreased Syk binding and disrupted its physical association with integrin αIIbβ3, and cells expressing this mutant failed to show Syk activation or lamellipodia formation upon fibrinogen adhesion. Co-immunoprecipitation, pulldown assays, deletion mutagenesis, cell adhesion assays Current biology : CB High 11719224
2001 BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on tyrosine 551, enhancing Btk activity. This depends on interaction of Btk and BLNK via the Btk-SH2 domain. BCR-induced Btk phosphorylation and activation are significantly reduced in both BLNK-deficient and Syk-deficient B cells. Reconstitution cell system, phosphorylation assays, genetic deficiency models (BLNK-/- and Syk-/- B cells) Proceedings of the National Academy of Sciences of the United States of America High 11226282
1996 Clustered Syk kinase domains are sufficient to autonomously trigger phagocytosis and filamentous actin redistribution in COS cells when expressed as chimeric transmembrane proteins. A point mutation in the Syk catalytic domain abolishes this response, and the kinase domain alone is sufficient for cytoskeletal coupling. Chimeric transmembrane protein expression, catalytic domain point mutagenesis, phagocytosis assay, actin redistribution assay Proceedings of the National Academy of Sciences of the United States of America High 8577722
2008 SLP-65 is not only a Syk substrate but also a direct binding partner and activator of Syk. The SH2 domain of SLP-65 binds to an autophosphorylated tyrosine of Syk, creating a positive feedback loop. B cells unable to form the Syk/SLP-65 complex are defective in BCR-induced ERK, NF-κB, and NFAT (but not Akt) activation, are blocked in B-cell development, and show impaired sustained Ca2+ responses. Co-immunoprecipitation, B cell development analysis in mutant mice, calcium flux assays, signaling pathway analysis The EMBO journal High 18369315
2010 CLEC-2 activates Syk through dimerization: the single YxxL-containing CLEC-2 cytoplasmic tail, when phosphorylated, activates Syk by cross-linking through Syk tandem SH2 domains at a 2:1 (CLEC-2:Syk) stoichiometry. CLEC-2 exists as a dimer in resting platelets and forms larger complexes upon activation. Peptide pull-down, surface plasmon resonance, quantitative Western blotting, tryptophan fluorescence, cross-linking, electron microscopy Blood High 20154219
2019 Syk activation requires ppITAM binding to prime SYK for rapid LYN-mediated phosphorylation of Tyr-352, then Tyr-348 of the SH2-kinase linker, which facilitates activation loop phosphorylation and full SYK activation. ppITAM peptide alone strongly activates dimerized (GST-tagged) SYK but poorly activates monomeric unphosphorylated SYK; LYN alone activates monomeric SYK more than ppITAM does, and both together achieve rapid full activation. In vitro kinase assays with purified proteins (monomeric vs. obligatory dimeric SYK), immunoblot, phosphoproteomics (mass spectrometry), site-specific phosphorylation kinetics The Journal of biological chemistry High 30923129
2006 Syk is required for pathogen engulfment in complement-mediated phagocytosis. Syk becomes tyrosine-phosphorylated and accumulates around nascent phagosomes upon C3bi-opsonized zymosan binding to CR3. Syk-siRNA or dominant-negative Syk impairs phagocytic engulfment. Syk regulates actin dynamics (accumulation and depolymerization) and RhoA activation with tyrosine phosphorylation of Vav during this process. siRNA knockdown, dominant-negative expression, phagocytosis quenching assay, immunofluorescence, RhoA activation assay Blood High 16449524
2008 Syk kinase is required for Dectin-1/Syk pathway collaboration with TLR/MyD88 pathways to induce optimal cytokine responses. Deficiency of Syk abolishes collaborative TNF, MIP-1α, and MIP-2 production and sustained IκB degradation/NF-κB nuclear translocation induced by co-stimulation of Dectin-1 with TLR2, 4, 5, 7, or 9. Syk-deficient macrophages, MyD88-deficient macrophages, cytokine measurement (ELISA), NF-κB nuclear translocation, IκB degradation assay European journal of immunology High 18200499
2003 Syk phosphorylates PKCβI at Tyr-662 and PKCα at Tyr-658 in the membrane compartment of FcεRI-stimulated mast cells, dependent on prior PKC autophosphorylation of adjacent serine residues. These phosphorylations generate a binding site for the Grb-2 SH2 domain, recruiting Grb-2/Sos to the plasma membrane to activate the Ras/ERK pathway. In vitro kinase assay, mutagenesis of phosphorylation sites, SH2 domain binding assay, Ras/ERK activation assay in mast cells Proceedings of the National Academy of Sciences of the United States of America High 12881490
2000 Syk phosphorylates α-tubulin on tyrosine both in vitro and in intact B-lymphocytes. Following BCR engagement or pervanadate treatment, α-tubulin within the polymerized microtubule network is phosphorylated in a Syk-dependent manner. At low pervanadate concentrations, centrosomes show preferential tyrosine phosphorylation. Tyrosine-phosphorylated tubulin assembles into microtubules in vitro. In vitro kinase assay, immunofluorescence, Western blotting with anti-phosphotyrosine antibodies, Syk-deficient cell comparison Journal of cell science Medium 10862713
2005 Syk colocalizes with and copurifies with centrosomal component γ-tubulin, exhibits catalytic activity within centrosomes, and its centrosomal localization depends on intact kinase activity. Centrosomal Syk is degraded via ubiquitination and proteasomal degradation during mitosis. Unrestrained Syk overexpression causes multipolar mitotic spindles, supernumerary centrosomes, and cell death resembling mitotic catastrophe. Co-purification/colocalization with γ-tubulin, fluorescent protein chimera expression (DsRed-Syk), kinase-dead mutant analysis, mitotic analysis Cancer research Medium 16322234
2006 Syk shuttles between nucleus and cytoplasm via an unconventional shuttling sequence near the junction of the catalytic domain and the linker B region. BCR engagement causes nuclear exclusion of Syk via protein kinase C activation and new protein synthesis. Nuclear Syk restricts stress-induced caspase 3 activation, while nuclear exclusion potentiates it. Deletion mutant analysis, subcellular fractionation, caspase 3 activation assay, PKC inhibition Molecular and cellular biology Medium 16611990
1997 Pyk2 tyrosine phosphorylation and activation following FcεRI aggregation in mast cells is downstream of Syk, not Src-family kinases. FcεRI-induced Pyk2 activation was dependent on Syk, whereas Pyk2 activation by G-protein-coupled receptors was Syk-independent. Genetic epistasis using Syk-deficient cells, pharmacological inhibition, immunoprecipitation/kinase assay The Journal of biological chemistry Medium 9405454
2002 In NK92 cells, Syk acts upstream of PI3K and signals through PI3K→Rac1→PAK1→MEK→ERK cascade for NK cytotoxicity. DAP12 tyrosine phosphorylation recruits and activates Syk upon tumor cell ligation. Kinase-deficient Syk or piceatannol blocked PI3K, Rac1, PAK1, MEK, ERK activation, perforin movement, and cytotoxicity. Constitutively active PI3K rescued downstream events in Syk-impaired NK cells. Dominant-negative/kinase-dead Syk, pharmacological inhibition (piceatannol), co-immunoprecipitation, constitutively active PI3K epistasis, cytotoxicity assay Journal of immunology (Baltimore, Md. : 1950) Medium 11907067
2014 Syk directly binds to and transactivates FLT3 in AML. Highly activated SYK is predominantly found in FLT3-ITD-positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. SYK overexpression promotes resistance to FLT3-ITD-targeted therapy. Kinase activity profiling, co-immunoprecipitation (direct binding), in vivo FLT3-ITD mouse model, shRNA knockdown Cancer cell Medium 24525236
2010 In B cell activation, Syk opens BCR dimers by an inside-out signaling mechanism that amplifies BCR signaling, as demonstrated by high-resolution proximity ligation assay monitoring BCR conformation at 10-20 nm resolution. Proximity ligation assay (PLA) at nanoscale resolution, B cell activation assays eLife Medium 24963139
2001 Syk directly binds to the erythropoietin receptor (EpoR) through its tandem SH2 domains following Epo stimulation, with both N- and C-terminal SH2 domains contributing (C-terminal predominantly). This interaction only occurs after Epo activation (EpoR phosphorylation on tyrosine). Syk kinase activity is increased upon EpoR binding. Co-immunoprecipitation, far Western blotting with recombinant SH2 domain constructs, kinase activity assay The Journal of biological chemistry Medium 9852052
2005 Syk is required for TPL2 (Tpl2/Cot) activation downstream of TNF-α signaling. TNF-α-induced ERK activation through TPL2 depends on Syk tyrosine kinase activity. RIP1 and TRAF2 are required for TPL2-ERK engagement but are insufficient without Syk. Genetic epistasis (Syk-deficient cells), biochemical evidence (Co-IP), overexpression studies The Journal of biological chemistry Medium 16291755
2021 TRIM31 E3 ligase interacts with SYK and catalyzes K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination promotes SYK plasma membrane translocation, binding to C-type lectin receptors, and prevents SHP-1 phosphatase interaction. TRIM31 deficiency in BMDCs and BMDMs dampens SYK-mediated signaling against C. albicans. Co-immunoprecipitation, ubiquitination assay (K27-linkage specific), mutagenesis (Lys375/517), membrane fractionation, TRIM31-/- mice Signal transduction and targeted therapy High 34362877
2020 USP10 is a major deubiquitinase required for stabilization of SYK. Inhibition of USP10 leads to proteasome-mediated degradation of SYK. USP10 inhibition causes death of cells driven by active SYK or oncogenic FLT3 and potentiates anti-leukemic effects of FLT3 inhibition. USP10 inhibitor treatment, SYK protein level analysis, co-targeting experiments in AML cells British journal of cancer Medium 32015510
2020 Cbl-mediated Syk degradation restrains plasma cell formation in germinal centers and promotes B cell light zone to dark zone transition. This degradation machinery attenuates BCR signaling by mitigating Kras/Erk and PI3K/Foxo1 pathways and restricting expression of plasma cell transcription factors in GC B cells. Mouse model defective in Cbl-mediated Syk degradation, signaling pathway analysis, transcription factor expression, flow cytometry The Journal of experimental medicine Medium 31873727
2014 Syk binds to nucleolin and phosphorylates it on tyrosine, enhancing nucleolin's ability to bind Bcl-xL mRNA and stabilize it, thereby protecting cells from apoptosis induced by oxidative or genotoxic stress. Co-immunoprecipitation, in vitro kinase assay, mRNA stability assay, RNA interference (nucleolin knockdown), apoptosis assay Molecular and cellular biology Medium 25092868
2015 Syk is recruited to stress granules in a phosphorylation-dependent manner. Grb7 is a Syk-binding protein involved in recruiting Syk to stress granules. Syk recruitment promotes autophagosome formation and clearance of stress granules, enhancing cell survival after stress. Stress granule formation assay, Co-immunoprecipitation (Syk-Grb7), autophagosome formation assay, Syk inhibition/knockdown The Journal of biological chemistry Medium 26429917
2010 Conserved C-terminal tyrosines Tyr-623, Tyr-624, and Tyr-625 of Syk regulate its kinase activity and ITAM binding. Mutation of all three to Phe results in increased autophosphorylation in resting cells, reduced binding to phosphorylated ITAM, reduced kinase activity toward exogenous substrate, and decreased FcεRI-induced degranulation and downstream signaling. Tyr-624 and especially Tyr-625 have major roles. Site-directed mutagenesis, in vitro kinase assay, ITAM binding assay, degranulation assay, downstream signaling analysis in Syk-deficient mast cells The Journal of biological chemistry High 20554527
2017 Syk is essential for γδTCR signal transduction and development of IL-17-producing γδT (γδT17) cells in the mouse thymus. Syk induces PI3K/Akt pathway activation upon γδTCR stimulation. ZAP70 cannot functionally substitute for Syk in γδT17 development. RhoH (adaptor that recruits Syk) deficiency ameliorates γδT17-dependent skin inflammation. Genetic mouse models (Syk conditional KO, RhoH KO, PI3K signaling-deficient mice), thymic development analysis, cytokine analysis The Journal of clinical investigation High 29202478
2022 SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impairs the PI3K-AKT-GSK-3β-mTOR pathway, incapacitating anabolic support required for disease-associated microglia (DAM) profile. However, SYK-deficient microglia can still proliferate and advance to an Apoe-expressing prodromal DAM stage via the DAP10 adapter pathway. The human TREM2R47H variant associated with high AD risk fails to activate SYK. Conditional SYK knockout in microglia, 5xFAD mouse model, Aβ plaque encasement assay, PI3K-AKT pathway analysis, DAM transcriptional profiling, TREM2R47H knock-in mice Cell High 36306735
2019 SYK inhibition blocks autophagic Tau degradation by acting upstream of the mTOR pathway. Pharmacological inhibition or knockdown of SYK decreases mTOR pathway activation and increases autophagic Tau degradation. In a tauopathy mouse model, chronic SYK inhibition reduced Tau accumulation, neuroinflammation, neuronal and synaptic loss, and reversed defective autophagy. SYK pharmacological inhibition, shRNA knockdown, mTOR pathway analysis, autophagic flux measurement, tauopathy mouse model The Journal of biological chemistry Medium 31324720
2014 SYK inhibition decreases Aβ production and increases Aβ clearance across the blood-brain barrier. SYK inhibition induces increased phosphorylation of inhibitory Ser-9 of GSK-3β by activating protein kinase A, providing a mechanism for reduction of Tau phosphorylation at GSK3β-dependent epitopes. Pharmacological SYK inhibition, SYK siRNA knockdown, transgenic mouse models (Aβ overexpression, P301S Tau), BBB clearance assay, GSK-3β Ser-9 phosphorylation assay The Journal of biological chemistry Medium 25331948
2021 When ZAP70 is aberrantly expressed in B cells, it competes with SYK at the BCR signalosome and redirects SYK from NFAT-dependent negative selection signaling to tonic PI3K signaling, promoting B cell survival and impairing elimination of autoreactive/premalignant clones. Conditional ZAP70 expression in B cells, genetic mouse models (B-ALL, B-CLL), BCR signaling pathway analysis (NFAT vs PI3K), negative selection assay, autoantibody measurement Molecular cell High 33878293
2013 SYK regulates mTOR and its upstream activator AKT in AML. Both small-molecule SYK inhibition and SYK-directed shRNA suppressed mTOR and downstream signaling effectors, as well as AKT. SYK inhibition showed heterogeneous effects on MAPK pathway (downregulating MEK/ERK in some cell lines, paradoxical increase in RAS-mutated AML). Small-molecule SYK inhibition, shRNA knockdown, phospho-protein analysis (mTOR, AKT, MEK, ERK), AML cell viability assay Leukemia Medium 23535559
2001 CrkL binds to Syk through its SH2 and SH3 domains and co-precipitates kinase-active Syk. CrkL serves as a molecular adapter between WASP and Syk, with both SH2 and SH3 domains of CrkL involved in Syk binding. WASP, CrkL, Syk, and Hic-5 incorporate into platelet cytoskeleton after platelet aggregation. Co-immunoprecipitation, GST-fusion domain pulldown, in vitro kinase assay, platelet cytoskeleton fractionation Blood Medium 11313252
2023 Itaconate directly inhibits SYK kinase through alkylation at the Cys593 site, suppressing inflammation. Biochemical alkylation assay, SYK kinase activity assay, site-specific mutation (Cys593), pharmacological inhibition in macrophages and in vivo Cellular and molecular life sciences : CMLS Medium 37897551

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 1108 20467426
1995 Syk tyrosine kinase required for mouse viability and B-cell development. Nature 536 7477353
2022 TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways. Cell 381 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
2009 Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity 249 19913447
2001 Structure and function of Syk protein-tyrosine kinase. Journal of biochemistry 241 11481033
2022 SYK coordinates neuroprotective microglial responses in neurodegenerative disease. Cell 236 36257314
2019 Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke. Cell death & disease 219 31324751
2010 The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cellular signalling 202 20206686
2014 Getting Syk: spleen tyrosine kinase as a therapeutic target. Trends in pharmacological sciences 197 24975478
2005 Src and Syk kinases: key regulators of phagocytic cell activation. Trends in immunology 173 15797511
2001 Syk expression and novel function in a wide variety of tissues. Biochemical and biophysical research communications 151 11676469
2014 Functional roles of Syk in macrophage-mediated inflammatory responses. Mediators of inflammation 149 25045209
2017 Syk inhibitors in clinical development for hematological malignancies. Journal of hematology & oncology 140 28754125
2009 Syk and pTyr'd: Signaling through the B cell antigen receptor. Biochimica et biophysica acta 139 19306898
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
2011 Syk-coupled C-type lectins in immunity. Trends in immunology 128 21334257
2014 SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer cell 127 24525236
2012 The SYK side of TLR4: signalling mechanisms in response to LPS and minimally oxidized LDL. British journal of pharmacology 127 22776094
2002 Protein tyrosine kinase Syk in mast cell signaling. Molecular immunology 119 12217388
2014 B cell activation involves nanoscale receptor reorganizations and inside-out signaling by Syk. eLife 118 24963139
2010 CLEC-2 activates Syk through dimerization. Blood 116 20154219
2008 Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas. Leukemia 115 18401419
2001 BLNK mediates Syk-dependent Btk activation. Proceedings of the National Academy of Sciences of the United States of America 115 11226282
2014 Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer. Biochimica et biophysica acta 114 25447675
2011 CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development. Blood 113 22186994
2020 Dectin-1/Syk signaling triggers neuroinflammation after ischemic stroke in mice. Journal of neuroinflammation 111 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
2000 Role of Syk in B-cell development and antigen-receptor signaling. Proceedings of the National Academy of Sciences of the United States of America 92 10677523
2018 Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis. Hepatology (Baltimore, Md.) 86 29537660
2009 Autoinhibition and adapter function of Syk. Immunological reviews 77 19909371
2022 Gefitinib and fostamatinib target EGFR and SYK to attenuate silicosis: a multi-omics study with drug exploration. Signal transduction and targeted therapy 74 35551173
2006 Protein-tyrosine kinase Syk is required for pathogen engulfment in complement-mediated phagocytosis. Blood 72 16449524
2016 Targeting Syk in Autoimmune Rheumatic Diseases. Frontiers in immunology 70 27014261
2008 The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development. The EMBO journal 69 18369315
2022 Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib. Platelets 68 36331249
2009 Protein tyrosine kinase, syk: a key player in phagocytic cells. Journal of biochemistry 67 19124456
2018 Dectin-1-Syk-CARD9 Signaling Pathway in TB Immunity. Frontiers in immunology 63 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
2003 A Ras activation pathway dependent on Syk phosphorylation of protein kinase C. Proceedings of the National Academy of Sciences of the United States of America 59 12881490
2007 Syk inhibitors as treatment for allergic rhinitis. Pulmonary pharmacology & therapeutics 58 17669674
2005 The Syk tyrosine kinase localizes to the centrosomes and negatively affects mitotic progression. Cancer research 57 16322234
2001 Syk expression in endothelial cells and their morphologic defects in embryonic Syk-deficient mice. Blood 57 11675365
2000 Syk-dependent phosphorylation of microtubules in activated B-lymphocytes. Journal of cell science 57 10862713
2006 Nucleocytoplasmic trafficking of the Syk protein tyrosine kinase. Molecular and cellular biology 55 16611990
2005 Spleen tyrosine kinase (Syk) as a novel target for allergic asthma and rhinitis. Expert opinion on therapeutic targets 52 16185147
2010 Regulation of Syk kinase and FcRbeta expression in human basophils during treatment with omalizumab. The Journal of allergy and clinical immunology 50 20236696
2013 SYK regulates mTOR signaling in AML. Leukemia 49 23535559
2017 γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program. The Journal of clinical investigation 48 29202478
2015 Syk Is Recruited to Stress Granules and Promotes Their Clearance through Autophagy. The Journal of biological chemistry 48 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
2009 Therapeutic prospect of Syk inhibitors. Expert opinion on therapeutic patents 46 19670961
2024 PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor. Nature communications 45 38555386
2018 SYK inhibition blocks proliferation and migration of glioma cells and modifies the tumor microenvironment. Neuro-oncology 42 29401256
2018 SYK inhibitor entospletinib prevents ocular and skin GVHD in mice. JCI insight 41 30282825
2016 Cholesterol crystals activate Syk and PI3 kinase in human macrophages and dendritic cells. Atherosclerosis 41 27356299
2013 Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling. PloS one 41 24013589
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
2019 A reevaluation of the spleen tyrosine kinase (SYK) activation mechanism. The Journal of biological chemistry 39 30923129
2006 Complement-mediated phagocytosis--the role of Syk. IUBMB life 39 16754322
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 Macrophage Syk-PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk-PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression. Molecular cancer therapeutics 35 31974273
2011 TEC family kinases in health and disease--loss-of-function of BTK and ITK and the gain-of-function fusions ITK-SYK and BTK-SYK. The FEBS journal 35 21518255
2020 Identification of SYK inhibitor, R406 as a novel senolytic agent. Aging 34 32379705
2000 Syk: a new player in the field of breast cancer. Breast cancer research : BCR 34 11250739
2019 Spleen tyrosine kinase (SYK) blocks autophagic Tau degradation in vitro and in vivo. The Journal of biological chemistry 33 31324720
2019 Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia. Cancer discovery 33 31771968
2017 Syk and Src-targeted anti-inflammatory activity of aripiprazole, an atypical antipsychotic. Biochemical pharmacology 33 29241811
2010 Syk mediates BCR- and CD40-signaling integration during B cell activation. Immunobiology 33 21074890
2022 Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases. Expert opinion on investigational drugs 32 35130124
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 31 33727419
2020 Inhibition of the deubiquitinase USP10 induces degradation of SYK. British journal of cancer 30 32015510
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
2019 Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis. Oncogene 28 30742098
2011 Phosphorylated Syk expression is enhanced in Nasu-Hakola disease brains. Neuropathology : official journal of the Japanese Society of Neuropathology 26 21981270
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
1998 Physical and functional interaction between p72(syk) and erythropoietin receptor. The Journal of biological chemistry 24 9852052
2022 SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies. Cellular signalling 23 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 Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice. Arthritis research & therapy 21 26653844
2023 Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis. Cellular and molecular life sciences : CMLS 20 37897551
2020 Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers. The Journal of experimental medicine 20 31873727
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
2014 Syk interacts with and phosphorylates nucleolin to stabilize Bcl-x(L) mRNA and promote cell survival. Molecular and cellular biology 20 25092868
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

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