Affinage

BTK

Tyrosine-protein kinase BTK · UniProt Q06187

Round 2 corrected
Length
659 aa
Mass
76.3 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BTK is a cytoplasmic Tec-family tyrosine kinase that serves as a central signaling hub in B cell development, innate immunity, and inflammatory responses across multiple hematopoietic lineages. BTK is activated downstream of the B cell receptor (BCR), Toll-like receptors, Fc receptors, and Dectin-1 through a two-step mechanism: Src-family kinase (Lyn)-mediated transphosphorylation at Y551 in the activation loop—scaffolded by the adaptor BLNK—followed by autophosphorylation at Y223 in the SH3 domain, with membrane recruitment via PH domain binding to PIP3 or IP6-induced PH-TH dimerization required for activation (PMID:8629002, PMID:8630736, PMID:11226282, PMID:25699547). Activated BTK phosphorylates PLCγ2, BCAP, the TLR adaptor Mal, and MARCKS to regulate calcium flux, NF-κB signaling, PI3K-Akt activation, and NLRP3 inflammasome assembly, thereby controlling B cell maturation, macrophage polarization, NK cell cytotoxicity, microglial Fc receptor responses, and neutrophil oxidative burst during antifungal defense (PMID:11163197, PMID:16415872, PMID:26059659, PMID:22589540, PMID:34145876, PMID:38696257). Loss-of-function mutations in BTK cause X-linked agammaglobulinemia (XLA), while drug-resistant kinase-dead BTK mutants retain oncogenic scaffold functions by recruiting alternative kinases such as HCK, a vulnerability overcome by PROTAC-mediated BTK degradation (PMID:8380905, PMID:35639855, PMID:38301010).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1993 High

    Identification of BTK as the gene mutated in X-linked agammaglobulinemia established that a cytoplasmic tyrosine kinase is essential for human B cell development, framing the central biological question of how it transduces receptor signals.

    Evidence Positional cloning and mutation analysis in XLA families

    PMID:8380905 PMID:8425221

    Open questions at the time
    • Substrates and downstream signaling pathways unknown
    • Activation mechanism uncharacterized
    • Expression in non-B lineages not yet established
  2. 1994 High

    Demonstration that the BTK PH domain binds Gβγ subunits and PKC isoforms, together with broad hematopoietic expression profiling, revealed BTK as a multi-input signaling node extending beyond the BCR.

    Evidence GST-fusion pulldowns, co-immunoprecipitation, in vitro kinase assays, mutagenesis of PH domain tryptophan, Northern/Western blotting across cell lineages

    PMID:7522330 PMID:7972043 PMID:8283037

    Open questions at the time
    • PH domain lipid-binding specificity not yet resolved
    • Physiological relevance of G-protein coupling in B cells unclear
    • PKC phosphorylation sites on BTK not mapped
  3. 1995 High

    Genetic ablation of BTK PH or kinase domains in mice recapitulated the Xid phenotype—reduced B cells, B1 cell loss, IgM/IgG3 deficiency—providing definitive genetic proof that BTK kinase activity and membrane recruitment are both required for B lymphocyte development.

    Evidence Targeted gene disruption in ES cells with RAG2-deficient blastocyst complementation and immunological assays

    PMID:7552994

    Open questions at the time
    • Specific signaling events downstream of BTK in developing B cells undefined
    • Role of BTK in non-B hematopoietic cells not yet tested in vivo
  4. 1996 High

    Mapping the two-step activation mechanism—Y551 transphosphorylation by Src-family kinases followed by Y223 autophosphorylation in the SH3 domain—resolved how BTK is switched on and revealed that Y223 phosphorylation serves a negative regulatory role by modulating SH3-mediated interactions.

    Evidence In vitro kinase assays, phosphopeptide mapping, site-directed mutagenesis (Y551, Y223F), BCR crosslinking, fibroblast transformation assays

    PMID:8629002 PMID:8630736

    Open questions at the time
    • Identity of the scaffold bridging Src-family kinases to BTK unknown
    • Structural basis of autoinhibition unresolved
    • In vivo significance of Y223 phosphorylation not tested
  5. 2000 High

    Discovery that BTK (together with Syk) phosphorylates the adaptor BCAP to recruit PI3K and generate PIP3 placed BTK upstream of the PI3K-Akt axis within the BCR signaling cascade, and identification of BLNK as the scaffold enabling Syk-dependent BTK activation resolved how BTK is activated in a receptor-proximal complex.

    Evidence BCAP and BLNK gene disruption in DT40 cells, PIP3 measurement, Akt phosphorylation, co-immunoprecipitation, SH2 domain interaction analysis

    PMID:11163197 PMID:11226282

    Open questions at the time
    • Full spectrum of BTK substrates unknown
    • Quantitative contribution of BTK versus Syk to BCAP phosphorylation not determined
  6. 2003 High

    Demonstration that BTK directly binds TIR domains of multiple TLRs and the adaptors MyD88, Mal, and IRAK-1, and is required for TLR4-mediated NF-κB activation, established BTK as an innate immune signaling kinase beyond its BCR role.

    Evidence Co-immunoprecipitation, dominant-negative BTK, NF-κB reporter assays, kinase activity assays, pharmacological BTK inhibition

    PMID:12724322

    Open questions at the time
    • Structural basis of BTK-TIR interaction unknown
    • Role of BTK in TLR signaling in primary innate immune cells not fully dissected
  7. 2006 High

    Identification of Mal as a direct BTK substrate whose phosphorylation triggers SOCS-1-mediated ubiquitination and degradation revealed a negative-feedback loop limiting TLR2/TLR4 signaling, showing BTK can both activate and terminate innate immune pathways.

    Evidence Phosphorylation assays, ubiquitination assays, SOCS-1 genetic manipulation, NF-κB reporter assays

    PMID:16415872

    Open questions at the time
    • Sites of BTK-mediated Mal phosphorylation not fully mapped
    • Whether this feedback operates equivalently across all TLR-expressing cell types unknown
  8. 2012 High

    Establishing that BTK is required for TLR3-driven NK cell activation extended BTK's functional domain beyond B cells and macrophages into NK cell innate immunity.

    Evidence Btk knockout mice, adoptive transfer, in vivo BTK inhibitor, XLA patient NK cell assays

    PMID:22589540

    Open questions at the time
    • Direct BTK substrates in NK cells not identified
    • Whether BTK regulates other NK receptor pathways unknown
  9. 2013 High

    Recruitment of BTK to Dectin-1-dependent phagocytic cups in macrophages, where it colocalizes with PIP3 and drives DAG synthesis for PKCε recruitment, established BTK as an effector of antifungal phagocytic immunity.

    Evidence Live imaging, co-immunoprecipitation, BTK inhibitor, BTK-deficient macrophages, in vivo Candida infection model

    PMID:23825946

    Open questions at the time
    • Direct substrates at the phagocytic cup not identified
    • Relative contribution of BTK versus Syk to Dectin-1 signaling unclear
  10. 2014 High

    Discovery that ibrutinib resistance arises from the BTK C481S gatekeeper mutation or gain-of-function PLCγ2 mutations defined the first clinical resistance mechanisms and highlighted the pharmacological vulnerability of the covalent bond to Cys481.

    Evidence Whole-exome sequencing of CLL patients at baseline and relapse, functional analysis of C481S

    PMID:24869598

    Open questions at the time
    • Whether kinase-dead Cys481 mutants retain signaling function not yet explored
    • Resistance mechanisms beyond Cys481 and PLCγ2 undefined
  11. 2015 High

    Structural resolution of BTK autoinhibition—a compact conformation stabilized by PH-TH, SH2, and SH3 modules, relieved by IP6-induced PH-TH dimerization—provided the first atomic-level explanation of how membrane recruitment triggers kinase activation, complementing the biochemical activation model.

    Evidence X-ray crystallography, IP6 binding experiments, mutagenesis of PH-TH dimerization interface, in vitro kinase assays

    PMID:25699547

    Open questions at the time
    • Full-length BTK structure not solved
    • Dynamics of PH-TH dimerization on native membranes not captured
  12. 2015 High

    Demonstration that BTK physically interacts with ASC and NLRP3 and is required for inflammasome activation, caspase-1 cleavage, and IL-1β maturation broadened BTK's role to sterile inflammation and ischemic brain injury.

    Evidence Co-immunoprecipitation of BTK-ASC and BTK-NLRP3, Btk-deficient mice, ibrutinib treatment, mouse brain ischemia model

    PMID:26059659

    Open questions at the time
    • Whether BTK phosphorylates NLRP3 or ASC directly is unknown
    • Mechanism of BTK-NLRP3 interaction not structurally resolved
  13. 2019 High

    Systematic mutagenesis revealing that co-occurring gatekeeper (T474) and kinase-domain mutations produce a 10–15-fold gain in kinase activity with de novo transforming potential uncovered a mechanism by which autoinhibition can be catastrophically disrupted.

    Evidence Systematic BTK mutagenesis screen, in vitro transformation assays, in vivo xenografts, computational structural analysis

    PMID:31217352

    Open questions at the time
    • Frequency of these compound mutations in patients not determined
    • Structural basis of synergistic autoinhibition loss not fully resolved
  14. 2022 High

    Discovery that kinase-dead BTK C481F/C481Y mutants sustain BCR signaling by recruiting HCK via Y551-SH2 interactions revealed a kinase-independent scaffold function, fundamentally redefining the drug target from enzymatic activity to protein presence.

    Evidence In vitro kinase assays confirming kinase-dead status, co-immunoprecipitation of BTK-HCK, phosphorylation and clonogenic assays

    PMID:35639855

    Open questions at the time
    • Full repertoire of kinases recruited by scaffold BTK unknown
    • Whether scaffold function operates in non-B cell contexts unexplored
  15. 2024 High

    PROTAC-mediated degradation of mutant BTK proteoforms (NX-2127) achieved >80% BTK depletion in CLL patients and blocked BCR signaling irrespective of kinase activity, providing clinical proof-of-concept that degradation overcomes scaffold-mediated resistance; separately, neutrophil-specific Btk deletion established BTK as essential for NADPH oxidase-dependent antifungal defense via p40phox and RAC2 activation.

    Evidence PROTAC degradation assays and clinical trial data; conditional Btk KO mice, human XLA neutrophils, in vivo aspergillosis model

    PMID:38301010 PMID:38696257

    Open questions at the time
    • Long-term clinical efficacy of BTK degraders unknown
    • Mechanism by which BTK activates p40phox and RAC2 not fully dissected
    • Impact of BTK degradation on NLRP3 inflammasome versus inhibition not compared

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length BTK structure in its native membrane context, the complete substrate repertoire in each innate immune cell type, and the structural basis of BTK's scaffold interactions with HCK and NLRP3 remain unresolved.
  • No full-length BTK structure on membranes
  • Complete substrate inventory in macrophages, neutrophils, and microglia lacking
  • Structural mechanism of kinase-independent scaffold signaling unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 10 R-HSA-162582 Signal Transduction 8 R-HSA-1643685 Disease 5 R-HSA-5357801 Programmed Cell Death 2
Partners
BLNKHCKLYNMYD88NLRP3PLCG2PYCARDTIRAP
Complex memberships
NLRP3 inflammasome

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 BTK was identified as the gene defective in X-linked agammaglobulinemia (XLA); it encodes a cytoplasmic protein-tyrosine kinase expressed in B cells and belonging to the Src family of proto-oncogenes. Positional cloning, mutation analysis in XLA families, expression studies Nature High 8380905 8425221
1994 The pleckstrin homology (PH) domain of BTK directly interacts with protein kinase C (PKC) isoforms (alpha, beta I, beta II, epsilon, zeta) in mast cells; PKC phosphorylates BTK and down-regulates its enzymatic activity. GST-fusion pulldown with mast cell lysates, co-immunoprecipitation from intact cells, in vitro kinase assay, PKC depletion/inhibition experiments Proceedings of the National Academy of Sciences of the United States of America High 7522330
1994 The PH domain of BTK binds the beta-gamma dimer of heterotrimeric G proteins in vitro and in vivo; a conserved tryptophan in subdomain 6 of the PH domain is critical for this interaction, linking BTK to G-protein-coupled signaling. In vitro binding assay, in vivo competition assay, site-directed mutagenesis of PH domain tryptophan Proceedings of the National Academy of Sciences of the United States of America High 7972043
1994 BTK mRNA and protein are expressed broadly in hematopoietic lineages (B cells, monocytes, mast cells, myeloid cells) but are selectively down-regulated in T lymphocytes and plasma cells. Northern blotting, immunoprecipitation, Western blotting, PCR-based analysis across diverse cell lines and primary cells Journal of immunology High 8283037
1995 Genetic ablation of BTK's PH or kinase domain in mice causes reduced conventional B cell numbers, severe B1 cell deficiency, serum IgM/IgG3 deficiency, and defective responses to thymus-independent type II antigens, recapitulating the Xid phenotype and proving BTK is required for B lymphocyte development and activation. Targeted gene disruption in ES cells (deletion of PH or kinase domain), RAG2-deficient blastocyst complementation, germline introduction; in vitro and in vivo immunological assays Immunity High 7552994
1996 BTK is activated by SRC family kinases through transphosphorylation at tyrosine 551 (Y551) in the kinase activation loop; this leads to BTK autophosphorylation at a second site and membrane association of the activated kinase. The same two sites are phosphorylated upon BCR cross-linking. In vitro kinase assay, phosphopeptide mapping, site-directed mutagenesis, cell-based BCR crosslinking with phosphorylation analysis Science High 8629002
1996 The major BTK autophosphorylation site is Y223 within the SH3 domain; mutation of Y223 to F blocks autophosphorylation and potentiates the transforming activity of the gain-of-function Btk* (E41K) mutant, indicating that autophosphorylation at Y223 negatively regulates SH3-mediated signaling. Phosphopeptide mapping, site-directed mutagenesis (Y223F), fibroblast transformation assay, co-expression with Src kinase Immunity High 8630736
1998 BTK promotes radiation-induced apoptosis (pro-apoptotic via down-regulation of STAT3 anti-apoptotic activity) but inhibits Fas-activated apoptosis by associating with the death receptor Fas and impairing its interaction with FADD, thereby preventing assembly of the death-inducing signaling complex (DISC). Co-immunoprecipitation (BTK-Fas interaction), functional apoptosis assays, STAT3 activity measurements Biochemical pharmacology Medium 9751072
2000 BCAP (B cell adaptor for PI3K) is tyrosine-phosphorylated by both Syk and BTK downstream of BCR engagement; phosphorylated BCAP binds the p85 subunit of PI3K and recruits PI3K to lipid rafts (GEMs), mediating PIP3 generation and Akt activation. BCAP gene disruption in DT40 cells, co-immunoprecipitation, PIP3 measurement, Akt phosphorylation assay, subcellular fractionation Immunity High 11163197
2001 BLNK (B cell linker protein) mediates Syk-dependent BTK activation: BLNK allows Syk to phosphorylate BTK at Y551 through a BLNK–BTK SH2 domain interaction, thereby enhancing BTK activity. BCR-induced BTK phosphorylation and activation are significantly reduced in BLNK-deficient B cells. Reconstitution cell system with co-expression experiments, BCR-induced phosphorylation assays in BLNK-deficient and Syk-deficient B cells, SH2-domain interaction analysis Proceedings of the National Academy of Sciences of the United States of America High 11226282
2002 Endogenous BTK and Akt interact with each other in B cells, and this interaction is inducible by H2O2 stimulation; BTK and Akt co-localize in the perinuclear region and membrane ruffles, and BTK is involved in PI3K-dependent Akt phosphorylation following oxidative stress. Co-immunoprecipitation from DT40 and Nalm6 B cells, confocal co-localization in COS-7 cells, PI3K inhibition experiments, phosphorylation assays Biochemical and biophysical research communications Medium 12054657
2003 BTK binds directly to the Toll/IL-1 receptor (TIR) domains of TLR4, TLR6, TLR8, and TLR9, as well as to the TLR adaptor proteins MyD88, Mal, and IRAK-1 (but not TRAF-6); BTK is activated (tyrosine-phosphorylated) by LPS/TLR4 stimulation and is required for TLR4-mediated NF-κB activation. Co-immunoprecipitation, dominant-negative BTK expression, NF-κB reporter assay, kinase activity assay, BTK-specific inhibitor (LFM-A13) experiments The Journal of biological chemistry High 12724322
2006 BTK phosphorylates the TLR adaptor protein Mal, which then interacts with SOCS-1, leading to Mal polyubiquitination and degradation. This negative-feedback mechanism limits TLR2/TLR4-dependent NF-κB activation. Co-immunoprecipitation, phosphorylation assays, ubiquitination assays, genetic KO and overexpression of SOCS-1, NF-κB reporter assays Nature immunology High 16415872
2009 Activation loop phosphorylation at Y551 by Src-family kinase Lyn is required for BTK kinase domain activity: the isolated kinase domain is largely inactive without Y551 phosphorylation; in vitro phosphorylation restores full activity comparable to full-length BTK. BTK also requires a second Mg2+ ion for activity. In vitro kinase reconstitution using Lyn-mediated phosphorylation of isolated BTK kinase domain, mass spectrometry phosphorylation mapping, kinetic analysis, divalent metal dependence studies Biochemistry High 19206206
2012 BTK is required for NK cell activation via the TLR3 pathway; Btk-/- murine NK cells show decreased IFN-γ, perforin, and granzyme-B expression and reduced cytotoxicity; BTK promotes TLR3-triggered NK cell activation mainly by activating the NF-κB pathway. BTK-deficient (XLA) human NK cells also show reduced TLR3-triggered activation. Btk knockout mouse studies, adoptive transfer experiments, in vivo BTK inhibitor administration, XLA patient NK cell functional assays, cytokine and surface marker measurements The Journal of biological chemistry High 22589540
2013 BTK and Vav1 are recruited to phagocytic cups during Dectin-1-mediated phagocytosis of Candida albicans in macrophages; BTK co-localizes with PI(3,4,5)P3 and F-actin at the cup; BTK contributes to DAG synthesis and subsequent PKCε recruitment at the phagocytic cup; BTK- or Vav1-deficient macrophages show impaired phagocytosis and mice are more susceptible to systemic C. albicans infection. Co-immunoprecipitation (Dectin-1 interactors), fluorescence microscopy/live imaging, selective BTK inhibitor, BTK- and Vav1-deficient mouse macrophages (peritoneal and bone-marrow-derived), in vivo infection model PLoS pathogens High 23825946
2014 Ibrutinib (PCI-32765) irreversibly inhibits BTK by covalently modifying Cys481; resistance in CLL arises from a C481S mutation at this site (making BTK only reversibly inhibited) or from gain-of-function mutations in downstream PLCγ2 (R665W, L845F) that produce autonomous BCR activity. Whole-exome sequencing at baseline and relapse, functional analysis of C481S mutation, Ion Torrent targeted sequencing The New England journal of medicine High 24869598
2015 BTK is an essential component of the NLRP3 inflammasome: BTK physically interacts with both ASC and NLRP3; pharmacological or genetic inhibition of BTK severely impairs NLRP3 inflammasome activation, caspase-1 cleavage, and IL-1β secretion. In a mouse brain ischemia model, ibrutinib suppresses infarct volume and neurological damage by inhibiting inflammasome-mediated IL-1β maturation in infiltrating macrophages and neutrophils. Co-immunoprecipitation (BTK-ASC and BTK-NLRP3), pharmacological BTK inhibition (ibrutinib), genetic BTK-deficient mice, mouse brain ischemia/reperfusion model, caspase-1 and IL-1β assays Nature communications High 26059659
2015 BTK drives macrophage polarization toward a TH2 phenotype in pancreatic ductal adenocarcinoma (PDAC) via a B cell–macrophage cross-talk involving FcRγ+ tumor-associated macrophages and PI3Kγ-dependent BTK activation; BTK inhibition with ibrutinib reprograms macrophages toward TH1 and restores CD8+ T-cell cytotoxicity against PDAC. BTK inhibitor (ibrutinib) in PDAC mouse models, PI3Kγ inhibition, macrophage phenotyping, T-cell functional assays, tumor growth measurements Cancer discovery High 26715645
2015 Autoinhibited BTK adopts a compact inactive conformation (analogous to c-Src and c-Abl) stabilized by the PH-TH module together with SH2 and SH3 domains; inositol hexakisphosphate (IP6) activates BTK by inducing transient PH-TH dimerization that promotes transphosphorylation of kinase domains. PIP3-containing membranes also activate BTK by a related mechanism. X-ray crystallography of BTK domains, biochemical activity assays, IP6 binding experiments, mutagenesis of PH-TH interface eLife High 25699547
2016 BTK phosphorylates p53 in response to DNA damage, creating a positive feedback loop that increases p53 protein levels and enhances transactivation of p53 target genes; BTK induction leads to enhanced p53-dependent senescence and apoptosis, while BTK inhibition reduces both responses. BTK inhibition and overexpression in cell lines, DNA damage assays, p53 phosphorylation analysis, senescence assays, apoptosis assays Cancer research Medium 27630139
2018 The BTK C481S mutation drives ibrutinib resistance via reactivation of BTK–PLCγ2–ERK1/2 signaling; ibrutinib-treated BTKCys481Ser cells release pro-survival cytokines IL-6 and IL-10 through an ERK1/2-dependent mechanism, and these cytokines protect BTK-wild-type MYD88-mutated cells from ibrutinib via a paracrine mechanism. Engineered BTKCys481Ser-expressing cell lines, ERK1/2 inhibitor experiments, Transwell co-culture system, IL-6/IL-10 blocking antibodies, serum cytokine analysis in WM patients Blood High 29496671
2019 Noncovalent BTK inhibitors reveal that the gatekeeper residue T474 and kinase domain residues (L512M, E513G, F517L, L547P) are critical for BTK activity; co-occurrence of gatekeeper and kinase domain mutations in cis produces 10-15-fold gain of BTK kinase activity and de novo transforming potential, disrupting an intramolecular autoinhibitory mechanism. Systematic BTK mutagenesis screen, in vitro transformation assays, in vivo xenograft models, computational structural analysis JCI insight High 31217352
2021 BTK is a required signaling node downstream of Fc receptors in microglia: MOG autoantibody-induced microglial proliferation is amplified in BtkE41K constitutively-active knock-in mice and blunted by a CNS-penetrant BTK inhibitor; this establishes BTK as mediating FcR-driven microglial responses in the CNS. In vivo MOG antibody injection model, FcγR knockout mice, BtkE41K knock-in mice, CNS-penetrant BTK inhibitor treatment, microglial proliferation and gene expression assays Brain High 34145876
2021 In ABC-DLBCL, primary resistance to BTK inhibitor ibrutinib is epigenetic: the transcription factor TCF4 drives a phenotypic shift in which RAC2 substitutes for BTK to activate PLCγ2 and sustain NF-κB signaling; elevated RAC2–PLCγ2 interaction was also observed in CLL cells from patients with persistent disease on BTK inhibitors. Ibrutinib resistance modeling in DLBCL cells, transcriptomic and epigenetic profiling, RNAi/genetic perturbation, biochemical interaction assays, patient CLL cell analysis Blood cancer discovery Medium 34778802
2021 MARCKS is a BTK substrate in CLL cells: BCR stimulation induces MARCKS phosphorylation that is reduced by BTK inhibitors; MARCKS sequesters PIP2 and affects BCR clustering; genetic loss of MARCKS increases AKT signaling and migratory capacity of CLL cells. Phosphoproteomic analysis under ibrutinib treatment, MARCKS genetic knockdown, AKT signaling assays, migration assays, clinical correlation with acalabrutinib treatment Blood Medium 33735912
2022 Kinase-dead BTK mutants C481F and C481Y maintain BCR signaling by physically recruiting hematopoietic cell kinase (HCK): Src family kinases phosphorylate mutant BTK at Y551, which engages HCK's SH2 domain, disrupts HCK's autoinhibition, and activates HCK to phosphorylate PLCγ2, sustaining NF-κB signaling and clonogenic proliferation independently of BTK kinase activity. In vitro kinase assays confirming kinase-dead status, structural modeling, co-immunoprecipitation (BTK-HCK), phosphorylation assays, BCR signaling pathway analysis, clonogenic assay Science signaling High 35639855
2023 Pirtobrutinib (a noncovalent BTK inhibitor) stabilizes BTK in a closed, inactive conformation through an extensive interaction network in the ATP-binding region that does not contact C481; it prevents Y551 phosphorylation in the activation loop and inhibits both wild-type and C481-mutant BTK with similar potencies. Differential scanning fluorimetry, enzymatic inhibition assays, cell-based phosphorylation assays, in vivo xenograft models, kinome selectivity profiling Blood High 36796019
2024 Some drug-resistant BTK mutants (including kinase-impaired forms) sustain BCR signaling through novel protein-protein interactions that scaffold downstream effectors independently of BTK kinase activity; NX-2127, a BTK/IKZF1/3 degrader, can bind and proteasomally degrade each mutant BTK proteoform, achieving >80% BTK degradation in CLL patients and potent BCR signaling blockade. Characterization of acquired resistance mutations, in vitro enzymatic activity assays, protein-protein interaction studies, PROTAC-mediated degradation assays, clinical treatment with NX-2127 Science High 38301010
2024 BTK drives antifungal immunity in neutrophils: upon fungal exposure, BTK is activated in human neutrophils via TLR2, Dectin-1, and FcγR signaling, triggering the oxidative burst; BTK inhibition selectively blocks Aspergillus hyphal damage and primary granule release by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation; neutrophil-specific Btk deletion in mice enhances aspergillosis susceptibility. Human neutrophil activation assays, BTK inhibitor treatment, XLA patient neutrophil studies, neutrophil-specific Btk conditional KO mice, p40phox and RAC2 activation assays, in vivo aspergillosis model, GM-CSF rescue experiments The Journal of clinical investigation High 38696257

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science (New York, N.Y.) 1601 25636800
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2013 Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. The New England journal of medicine 1345 23782157
1993 The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1242 8380905
1993 Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1134 8425221
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. The New England journal of medicine 1055 24869598
2005 The DNA sequence of the human X chromosome. Nature 816 15772651
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 662 21422473
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1995 Defective B cell development and function in Btk-deficient mice. Immunity 600 7552994
1994 Prolactin induces phosphorylation of Tyr694 of Stat5 (MGF), a prerequisite for DNA binding and induction of transcription. The EMBO journal 542 7925280
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2006 Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nature immunology 444 16415872
2014 Targeting Bruton's tyrosine kinase in B cell malignancies. Nature reviews. Cancer 438 24658273
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. Cancer discovery 410 26715645
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2009 Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunological reviews 398 19290921
1996 Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science (New York, N.Y.) 391 8629002
2015 Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nature communications 365 26059659
1994 The pleckstrin homology domain of Bruton tyrosine kinase interacts with protein kinase C. Proceedings of the National Academy of Sciences of the United States of America 312 7522330
2018 Targeting the C481S Ibrutinib-Resistance Mutation in Bruton's Tyrosine Kinase Using PROTAC-Mediated Degradation. Biochemistry 302 29851337
1996 Regulation of Btk function by a major autophosphorylation site within the SH3 domain. Immunity 261 8630736
2003 Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. The Journal of biological chemistry 250 12724322
2019 Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. The New England journal of medicine 246 31075187
1994 Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. Journal of immunology (Baltimore, Md. : 1950) 241 8283037
1994 Binding of beta gamma subunits of heterotrimeric G proteins to the PH domain of Bruton tyrosine kinase. Proceedings of the National Academy of Sciences of the United States of America 240 7972043
2000 BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity 225 11163197
2021 Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. Frontiers in cell and developmental biology 204 33777941
2016 Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. Journal of hematology & oncology 190 26957112
2013 Ibrutinib and novel BTK inhibitors in clinical development. Journal of hematology & oncology 187 23958373
2023 Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. The New England journal of medicine 173 37407001
1998 Btk function in B cell development and response. Seminars in immunology 154 9695187
2018 The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation. Cancer discovery 140 30093506
2018 The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review. European journal of medicinal chemistry 139 29631132
2014 miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways. International journal of oncology 118 24603851
2022 Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia. The New England journal of medicine 112 35417637
2001 BLNK mediates Syk-dependent Btk activation. Proceedings of the National Academy of Sciences of the United States of America 112 11226282
2024 Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science (New York, N.Y.) 111 38301010
2016 BTK Signaling in B Cell Differentiation and Autoimmunity. Current topics in microbiology and immunology 110 26341110
2023 Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor. Blood 108 36796019
2021 Bruton's Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures. Frontiers in immunology 106 34803999
2017 Bruton's tyrosine kinase (BTK) as a promising target in solid tumors. Cancer treatment reviews 105 28641100
1995 The Btk subfamily of cytoplasmic tyrosine kinases: structure, regulation and function. Seminars in immunology 95 8520028
2015 Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate. eLife 89 25699547
2014 Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Current hematologic malignancy reports 83 24357428
2022 Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance. Blood advances 79 35901282
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2021 BTK Inhibitors in Chronic Lymphocytic Leukemia: Biological Activity and Immune Effects. Frontiers in immunology 76 34276674
2013 Bruton's Tyrosine Kinase (BTK) and Vav1 contribute to Dectin1-dependent phagocytosis of Candida albicans in macrophages. PLoS pathogens 74 23825946
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2023 BTK signaling-a crucial link in the pathophysiology of chronic spontaneous urticaria. The Journal of allergy and clinical immunology 54 38141832
2021 Overcoming Acquired Epigenetic Resistance to BTK Inhibitors. Blood cancer discovery 53 34778802
2021 Emerging small-molecule inhibitors of the Bruton's tyrosine kinase (BTK): Current development. European journal of medicinal chemistry 52 33740548
2021 Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors. Frontiers in immunology 51 34349760
2021 Low-dose Btk inhibitors selectively block platelet activation by CLEC-2. Haematologica 50 31949019
2019 Bruton's tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018). Expert opinion on therapeutic patents 50 30888232
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2021 MOG autoantibodies trigger a tightly-controlled FcR and BTK-driven microglia proliferative response. Brain : a journal of neurology 49 34145876
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2014 Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model. The Journal of clinical investigation 38 25105368
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2021 Discovery of novel BTK PROTACs for B-Cell lymphomas. European journal of medicinal chemistry 36 34509879
2022 Discovery of a potent BTK and IKZF1/3 triple degrader through reversible covalent BTK PROTAC development. Current research in chemical biology 33 36712232
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2002 XLA patients with BTK splice-site mutations produce low levels of wild-type BTK transcripts. Journal of clinical immunology 31 12405164
2021 COVID-19 and X-linked agammaglobulinemia (XLA) - insights from a monogenic antibody deficiency. Current opinion in allergy and clinical immunology 29 34596095
2024 BTK drives neutrophil activation for sterilizing antifungal immunity. The Journal of clinical investigation 28 38696257
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2010 TLR signaling and effector functions are intact in XLA neutrophils. Clinical immunology (Orlando, Fla.) 28 20634142
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2024 BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair. Acta neuropathologica 27 38656399
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2022 Cardiotoxicity of BTK inhibitors: ibrutinib and beyond. Expert review of hematology 27 35437106
2019 Noncovalent inhibitors reveal BTK gatekeeper and auto-inhibitory residues that control its transforming activity. JCI insight 27 31217352
2019 Effects of BTK signalling in pathogenic microorganism infections. Journal of cellular and molecular medicine 27 31397086
2008 Phylogeny of Tec family kinases identification of a premetazoan origin of Btk, Bmx, Itk, Tec, Txk, and the Btk regulator SH3BP5. Advances in genetics 27 19161832
2024 Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms. International journal of molecular sciences 25 38542207
2019 Long Non-Coding RNA HOTAIR Modulates KLF12 to Regulate Gastric Cancer Progression via PI3K/ATK Signaling Pathway by Sponging miR-618. OncoTargets and therapy 25 31819516
2020 BTK/ITK dual inhibitors: Modulating immunopathology and lymphopenia for COVID-19 therapy. Journal of leukocyte biology 24 32640487
2023 Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL). Genes 23 38137005
2022 Relapsed/Refractory Mantle Cell Lymphoma: Beyond BTK Inhibitors. Journal of personalized medicine 23 35330376
2019 Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption. Bone reports 23 30956999
2018 TCF19 enhances cell proliferation in hepatocellular carcinoma by activating the ATK/FOXO1 signaling pathway. Neoplasma 23 30509085
2024 Comparative CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis. Drugs in R&D 22 38965189
2021 Follicular Lymphoma-associated BTK Mutations are Inactivating Resulting in Augmented AKT Activation. Clinical cancer research : an official journal of the American Association for Cancer Research 22 33419778
2024 How I use genomics and BTK inhibitors in the treatment of Waldenström macroglobulinemia. Blood 21 38211337
2022 BTK inhibitors impair humoral and cellular responses to recombinant zoster vaccine in CLL. Blood advances 21 35157769
2021 MARCKS affects cell motility and response to BTK inhibitors in CLL. Blood 20 33735912
2021 Targeting Solid Tumors With BTK Inhibitors. Frontiers in cell and developmental biology 20 33937249
2024 Bruton's tyrosine kinase (BTK) inhibitors for the treatment of primary central nervous system lymphoma (PCNSL): current progress and latest advances. Leukemia & lymphoma 19 38597202
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2022 BRUIN MCL-321: phase III study of pirtobrutinib versus investigator choice of BTK inhibitor in BTK inhibitor naive mantle cell lymphoma. Future oncology (London, England) 18 36377973
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2020 ROR2 knockdown suppresses breast cancer growth through PI3K/ATK signaling. Aging 18 32614787
2019 Design and synthesis of boron-containing diphenylpyrimidines as potent BTK and JAK3 dual inhibitors. Bioorganic & medicinal chemistry 18 31843459
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1995 Inflorescence-specific expression of AtK-1, a novel Arabidopsis thaliana homologue of shaggy/glycogen synthase kinase-3. Plant molecular biology 18 7865793
2024 New Means and Challenges in the Targeting of BTK. Clinical cancer research : an official journal of the American Association for Cancer Research 17 38578606
2021 Huiyang Shengji decoction promotes wound healing in diabetic mice by activating the EGFR/PI3K/ATK pathway. Chinese medicine 17 34727961
2020 Bruton's Tyrosine Kinase (BTK) Inhibitor (Ibrutinib)-Suppressed Migration and Invasion of Prostate Cancer. OncoTargets and therapy 16 32494164