Affinage

BLK

Tyrosine-protein kinase Blk · UniProt P51451

Length
505 aa
Mass
57.7 kDa
Annotated
2026-04-28
95 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BLK is a B-lymphoid Src-family non-receptor tyrosine kinase that transduces signals from the B-cell receptor and pre-BCR, phosphorylating Igβ ITAMs and activating Syk to regulate B-cell development, activation thresholds, and immunoglobulin gene rearrangement (PMID:14662906, PMID:8709147, PMID:25926555). Its expression is transcriptionally controlled by PAX5/BSAP, RUNX1/AML1, NF-κB, and NERF-2/ELF-2, which synergistically regulate the BLK promoter during B-cell differentiation, while activated BLK protein is turned over via E6AP-mediated ubiquitin-proteasome degradation (PMID:8195169, PMID:10455134, PMID:10449731). Beyond canonical BCR signaling—where BLK cooperates with BANK1 and PLCγ2 to modulate B-cell activation and suppress IRF5/type-I IFN pathways relevant to lupus (PMID:23555801, PMID:31101814)—BLK phosphorylates IRF3-Y107 to promote antiviral innate immunity and phosphorylates TOLLIP-Y76/86/152 to facilitate TLR/IL-1R signaling (PMID:37871014, PMID:38078859). BLK also functions as a tumor suppressor in CML leukemic stem cells through a Pax5–BLK–p27 axis, acts downstream of Gα13 to phosphorylate p190RhoGAP and inhibit RhoA-driven invasion, and enhances insulin synthesis in pancreatic β-cells by upregulating Pdx1 and Nkx6.1 (PMID:22797726, PMID:25025568, PMID:19667185).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1990 High

    Identification of BLK as a B-lymphoid-specific Src-family tyrosine kinase established the existence of a lineage-restricted kinase that could mediate B-cell-specific signaling events.

    Evidence cDNA cloning and in vitro kinase assay in bacterial expression system

    PMID:2404338

    Open questions at the time
    • No substrates or signaling pathway identified
    • In vivo function unknown
  2. 1993 High

    Demonstrating that BLK kinase activity is required for anti-IgM-induced growth arrest and apoptosis in B-cell lymphoma, and that its SH2 domain binds distinct BCR-stimulated phosphoproteins, linked BLK functionally to BCR signaling.

    Evidence Antisense knockdown with growth/apoptosis readout; SH2 domain pulldowns from B-cell lysates with phosphoamino acid analysis

    PMID:7690139 PMID:8226767

    Open questions at the time
    • Direct substrates not yet identified
    • Relationship to other Src kinases in BCR signaling unclear
  3. 1996 High

    Determination of BLK's substrate consensus motif (I/L-Y-D/E-X-L) matching Igα/Igβ ITAMs identified the likely physiological substrates linking BLK to BCR complex phosphorylation.

    Evidence Phage display peptide library selection with in vitro phosphorylation

    PMID:8709147

    Open questions at the time
    • Direct phosphorylation of Igβ ITAMs not yet shown in cells
    • Relative contribution versus Lyn unknown
  4. 1998 High

    Mapping the transcriptional control of BLK by PAX5/BSAP, NF-κB p50/p65, and later AML1/RUNX1 and NERF-2 explained how BLK expression is restricted to B-lymphoid cells and modulated during differentiation, including downregulation in plasma cells.

    Evidence EMSA, supershift, mutagenesis, reporter assays across multiple studies; synergistic activation by AML1+BSAP (>50-fold)

    PMID:10455134 PMID:14970218 PMID:8195169 PMID:9660839

    Open questions at the time
    • Epigenetic regulation not addressed
    • In vivo promoter occupancy dynamics during B-cell differentiation not mapped
  5. 1998 High

    Constitutively active Blk(Y495F) transgenic mice developed B-lymphoid and thymic tumors, revealing that uncontrolled BLK signaling is oncogenic during lymphoid development and establishing the need for tight regulation of BLK activity.

    Evidence Transgenic mouse model with gain-of-function Blk mutant; tumor phenotyping by flow cytometry

    PMID:9636152

    Open questions at the time
    • Downstream oncogenic effectors not identified
    • Whether kinase-dead rescue prevents tumorigenesis not tested
  6. 1999 High

    Discovery that activated BLK is degraded via E6AP-mediated ubiquitin-proteasome proteolysis provided the mechanism for limiting BLK kinase activity, explaining how BLK turnover is coupled to its activation state.

    Evidence Co-immunoprecipitation of E6AP with Src-family kinases, ubiquitination assay, proteasome inhibitor experiments

    PMID:10449731

    Open questions at the time
    • Specific ubiquitination sites on BLK not mapped
    • Whether E6AP loss affects B-cell phenotype through BLK stabilization not tested
  7. 2000 High

    The absence of a B-cell developmental phenotype in Blk knockout mice demonstrated functional redundancy among Src-family kinases, but left open the question of BLK's non-redundant roles.

    Evidence Gene targeting/knockout mouse with comprehensive B-cell subset and humoral immunity analysis

    PMID:10648608

    Open questions at the time
    • Compound knockouts with Lyn/Fyn not tested
    • Marginal zone B-cell subset not specifically examined
  8. 2003 High

    Active BLK was shown to substitute for pre-BCR signaling in vivo—driving Igβ/Syk phosphorylation, B-cell maturation past the pro-B stage, and immunoglobulin gene rearrangement—establishing BLK as a critical kinase linking the pre-BCR to developmental checkpoints.

    Evidence Transgenic active Blk expression in pre-BCR-deficient mice with flow cytometry and phosphorylation analysis

    PMID:14662906

    Open questions at the time
    • Whether endogenous BLK (not constitutively active) is the dominant pre-BCR kinase remains unclear
    • Signaling intermediates between Syk activation and gene rearrangement not defined
  9. 2009 High

    Discovery of BLK expression and function in pancreatic β-cells, where it enhances insulin synthesis/secretion by upregulating Pdx1 and Nkx6.1, expanded BLK's biological roles beyond the immune system and linked the Ala71Thr variant to impaired β-cell function.

    Evidence BLK expression in beta cell lines, glucose-stimulated insulin secretion assay, Pdx1/Nkx6.1 reporter assay, mutagenesis

    PMID:19667185

    Open questions at the time
    • Direct kinase substrates in β-cells not identified
    • Mechanism linking BLK kinase activity to Pdx1/Nkx6.1 transcription unknown
  10. 2012 High

    BLK was identified as a tumor suppressor in CML leukemic stem cells, operating through a Pax5–BLK–p27 axis that is silenced by BCR-ABL/c-Myc, providing a mechanism for leukemic stem cell self-renewal and a rationale for reactivating BLK in CML therapy.

    Evidence Retroviral expression, shRNA knockdown in CML mouse model, genetic epistasis, human CML stem cell assays

    PMID:22797726

    Open questions at the time
    • How BLK upregulates p27 mechanistically not defined
    • Whether BLK reactivation is therapeutically feasible not addressed
  11. 2013 High

    Elucidation of the BLK–BANK1–PLCγ2 signaling module downstream of the BCR revealed how BLK kinase activity promotes BANK1–PLCγ2 complex assembly, and how disease-associated variants in BLK and BANK1 disrupt this pathway.

    Evidence Yeast two-hybrid, co-immunoprecipitation, mutational analysis of BANK1 tyrosine/proline residues

    PMID:21978998 PMID:23555801 PMID:26821283

    Open questions at the time
    • Whether BANK1 is a direct BLK substrate not proven by in vitro kinase assay
    • Downstream consequences of PLCγ2 activation specificity via this module not resolved
  12. 2014 High

    Identification of BLK as a Gα13 effector that phosphorylates p190RhoGAP to inactivate RhoA revealed a non-BCR signaling axis controlling cell invasion, broadening BLK's mechanistic repertoire beyond lymphocyte biology.

    Evidence RNAi knockdown, co-immunoprecipitation, RhoA activation assay, invasion assay

    PMID:25025568

    Open questions at the time
    • Physiological context for Gα13–BLK axis in B cells not established
    • Whether this pathway operates in vivo not tested
  13. 2016 High

    CRISPR-Cas9 validation that both BLK and BTK are functional ibrutinib targets in pre-BCR+ B-ALL established BLK as a therapeutic target in acute lymphoblastic leukemia, with inhibition deactivating PI3K/Akt signaling.

    Evidence CRISPR-Cas9 gene editing of BTK and BLK individually, drug sensitivity assays, mouse xenograft model

    PMID:28031181

    Open questions at the time
    • Relative contribution of BLK vs BTK inhibition to clinical ibrutinib efficacy unknown
    • BLK-specific inhibitors not available
  14. 2019 High

    Rare SLE-associated BLK variants were shown to impair suppression of IRF5 and type-I IFN, with BLK and BANK1 functioning together to restrain this pathway, establishing a direct mechanistic link between BLK loss-of-function and lupus pathogenesis.

    Evidence Functional assay of rare variants in human B cell lines, lupus-prone mouse model, co-immunoprecipitation

    PMID:31101814

    Open questions at the time
    • How BLK kinase activity suppresses IRF5 mechanistically not defined
    • Whether this pathway is B-cell-intrinsic or involves other cell types not resolved
  15. 2023 High

    BLK was established as a direct kinase for IRF3 (at Y107) in antiviral innate immunity and for TOLLIP (at Y76/86/152) in TLR/IL-1R signaling, revealing BLK as a broadly active innate immune signaling kinase beyond its classical BCR role.

    Evidence In vitro kinase assays with site-directed mutagenesis, co-immunoprecipitation of receptor complexes, BLK knockout mice with viral/IL-1β challenge

    PMID:37871014 PMID:38078859

    Open questions at the time
    • Cell types responsible for BLK-mediated innate immunity in vivo not defined
    • Whether BLK phosphorylation of IRF3 and TOLLIP occurs in the same or different cell contexts unclear
  16. 2025 Medium

    FAK was identified as an upstream activator that forms a complex with BLK to drive endoplasmic reticulum stress and fibrosis in endometrial stromal cells, extending BLK function to a non-immune fibrotic disease context.

    Evidence Co-immunoprecipitation of FAK-BLK, siRNA knockdown, in vivo Blk knockdown in intrauterine adhesion mouse model

    PMID:41174819

    Open questions at the time
    • Direct FAK phosphorylation sites on BLK not mapped
    • Single study; independent replication needed
    • Whether BLK–ER stress axis operates in other fibrotic tissues not examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for BLK's substrate selectivity versus other Src-family kinases; the identity of BLK's direct substrates linking it to Pdx1/Nkx6.1 in β-cells and to p27 in CML stem cells; and whether BLK-specific inhibitors can be developed for therapeutic applications.
  • No crystal structure of BLK
  • No BLK-specific small-molecule inhibitor characterized
  • In vivo compound Src-family kinase knockouts needed to define non-redundant BLK functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2
Partners
BANK1CLDN6E6APFAKGNA13IRF3PLCG2TOLLIP
Complex memberships
BANK1-BLK-PLCγ2 moduleIL-1R1/IL1RAcP-BLK complexpre-BCR signaling complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 BLK (B lymphoid kinase) encodes a 55 kDa Src-family protein tyrosine kinase specifically expressed in B lymphoid cells; the protein exhibits tyrosine kinase activity when expressed in bacterial cells. cDNA cloning, in vitro kinase activity assay in bacterial expression system Science High 2404338
1992 BLK gene expression is regulated during B-cell development: blk RNA is expressed in pro-B, pre-B, and mature B cells but is absent from plasma cell lines; this developmental-stage specificity is regulated at least in part by changes in transcription rate. Nuclear run-on transcription assay, primer extension, S1 nuclease protection, immunolocalization The Journal of Biological Chemistry High 1537861
1993 BLK tyrosine kinase activity is required for anti-IgM-mediated growth inhibition and apoptosis in B-cell lymphoma; antisense oligonucleotides to blk prevent anti-mu-chain-mediated growth arrest and apoptosis without affecting TGF-β-mediated arrest. Antisense oligonucleotide knockdown, cell growth inhibition assay, in vitro kinase assay Proceedings of the National Academy of Sciences of the United States of America High 7690139
1993 The SH2 domains of BLK, Lyn, and Fyn(T) bind distinct sets of phosphoproteins from B lymphocytes in a phosphotyrosine-dependent manner; BLK SH2 domain preferentially binds phosphoproteins of 90, 130, and 150 kDa whose tyrosine phosphorylation increases after antigen receptor cross-linking. SH2 domain pulldown assay from B-cell lysates, phosphoamino acid analysis, chimeric SH2 domain binding assays The Journal of Biological Chemistry High 8226767
1994 The BLK promoter is specifically bound by the B-cell-specific activator protein BSAP (PAX5), which acts as a positive transcriptional regulator of BLK expression in B-lymphoid cells. Gel mobility shift assay, competition with known BSAP sites, anti-BSAP antibody supershift, transient transfection reporter assay The Journal of Biological Chemistry High 8195169
1994 Proteins binding to BLK and Fyn SH2 domains are constitutively tyrosine-phosphorylated in unstimulated pre-B cells, but only appear upon antigen-receptor ligation in mature B cells, suggesting distinct constitutive signaling through the pre-BCR. SH2 domain pulldown from pre-B and B cell lysates (unstimulated and anti-IgM stimulated) Proceedings of the National Academy of Sciences of the United States of America Medium 7514299
1996 BLK preferentially phosphorylates peptide substrates with the consensus I/L-Y-D/E-X-L, resembling ITAM motifs found in Igα and Igβ components of the B-cell receptor; BLK requires hydrophobic residue (I/L) at position −1 and negatively charged residue at position +1 relative to the phosphorylated tyrosine. Phage display peptide library selection after in vitro phosphorylation, substrate sequence enrichment analysis Journal of Molecular Biology High 8709147
1998 Activated BLK expression in early B and T lymphoid progenitors induces malignant transformation: constitutively active Blk(Y495F) transgenic mice develop B lymphoid tumors with pro-B/pre-B phenotype and clonal thymic lymphomas, indicating BLK controls proliferation during lymphocyte development. Transgenic mouse model with constitutively active Blk(Y495F) mutant; tumor phenotyping by flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 9636152
1998 CD72 ligation on B cells activates Lyn and BLK (but not Syk) tyrosine kinases, while also activating BTK; BTK can substitute for Syk in inducing PLC-γ2 tyrosine phosphorylation and calcium mobilization in CD72-stimulated B cells. In vitro kinase assay on immunoprecipitated BLK and Lyn from CD72-ligated B cells; comparison with BCR signaling Journal of Immunology Medium 9531290
1999 Activated BLK is preferentially degraded by the ubiquitin-proteasome pathway; its ubiquitination is mediated by E6AP (an E3 ubiquitin protein ligase), establishing ubiquitin-mediated proteolysis as a regulatory mechanism for BLK activity. Co-immunoprecipitation of E6AP with Src-family kinases, ubiquitination assay, proteasome inhibitor experiments Proceedings of the National Academy of Sciences of the United States of America High 10449731
1999 AML1 (RUNX1) binds specifically to a site in the BLK promoter through its runt DNA-binding domain and physically interacts with the paired DNA-binding domain of BSAP; AML1 and BSAP synergistically activate BLK promoter transcription by more than 50-fold. Gel mobility shift assay, in vitro binding/pulldown, transient transfection reporter assay The Journal of Biological Chemistry High 10455134
1998 NF-κB/p50 homodimer interacts with a sequence overlapping the PAX5 binding site on the BLK promoter in LPS-activated B cells and plasma cells; p50 homodimers and p50/p65 heterodimers have opposing effects on BLK transcription, providing a mechanism for differential regulation during B-cell development. Electrophoretic mobility shift assay (EMSA), site-specific mutagenesis, CAT reporter transfection, PAX5 overexpression The Journal of Biological Chemistry High 9660839
2000 BLK is dispensable for B-cell development, in vitro activation, and humoral immune responses to T-cell-dependent and -independent antigens in mice; Blk knockout mice show no B-cell phenotype, consistent with functional redundancy among Src family kinases. Gene targeting/knockout mouse model, B-cell subset analysis, in vitro activation assays, immunization experiments Molecular and Cellular Biology High 10648608
2003 Activated BLK mimics pre-BCR signaling: expression of an active Blk mutant in B progenitors causes proliferation, supports maturation beyond the pro-B stage in pre-BCR-deficient mice, suppresses VH-to-DJH rearrangement, relieves selection for productive heavy-chain rearrangement, stimulates kappa rearrangement, and induces tyrosine phosphorylation of Igβ and Syk. Transgenic active Blk expression in pre-BCR-deficient mice; flow cytometry for B-cell subsets; tyrosine phosphorylation analysis The Journal of Experimental Medicine High 14662906
2004 NERF-2 (ELF-2 isoform) physically interacts with AML1 via a basic region upstream of the Ets domain to cooperatively activate the BLK promoter; the inhibitory isoform NERF-1a interacts with AML1 via the same domain to repress AML1-mediated BLK transcription. In vitro binding assay, co-immunoprecipitation, transient transfection reporter assay, domain mapping The Journal of Biological Chemistry High 14970218
2009 BLK is expressed in pancreatic beta cells where it enhances insulin synthesis and secretion in response to glucose by up-regulating transcription factors Pdx1 and Nkx6.1; the Ala71Thr mutation greatly attenuates these functions. BLK expression in beta cell lines, glucose-stimulated insulin secretion assay, Pdx1/Nkx6.1 reporter assay, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 19667185
2011 BLK and BANK1 physically interact (co-immunoprecipitate) in Daudi cells and primary naive B cells; this interaction is enhanced upon BCR stimulation with anti-IgM antibodies. Co-immunoprecipitation, confocal microscopy co-localization Annals of the Rheumatic Diseases Medium 21978998
2011 BLK haploinsufficiency and deficiency impair the generation of marginal zone (MZ) B cells; MZ B cells from Blk-mutant mice are hyper-responsive to BCR stimulation both in vitro and in vivo, revealing a role for BLK in MZ B-cell development and activation threshold. Blk heterozygous and knockout mouse analysis, flow cytometry for B-cell subsets, in vitro BCR stimulation assays Immunology and Cell Biology High 21894171
2012 BCR-ABL downregulates BLK through c-Myc in CML leukemic stem cells; BLK functions as a tumor suppressor in leukemic stem cells through a pathway involving upstream regulator Pax5 and downstream effector p27, suppressing LSC function without affecting normal hematopoietic stem cells. Retroviral gene expression, shRNA knockdown in CML mouse model, genetic epistasis (Pax5-BLK-p27), human CML stem cell proliferation assay Nature Genetics High 22797726
2012 The SLE-associated Ala71Thr substitution in BLK decreases protein half-life; NFκB p50 and p65 bind to an associated 1.2 kb haplotype segment in the BLK promoter region, with the risk haplotype showing reduced BLK mRNA levels. Protein stability assay with cycloheximide and western blot, ChIP-qPCR for NF-κB binding, transfection of BLK constructs in HEK293 cells Annals of the Rheumatic Diseases High 22696686
2013 BANK1 and BLK act through phospholipase C gamma 2 (PLCγ2) in B-cell signaling: PLCγ2 interacts with BANK1 (identified by Y2H), and BLK kinase activity enhances BANK1-PLCγ2 binding; interaction is suppressed upon BLK depletion and requires specific tyrosine and proline residues on BANK1. Yeast two-hybrid, co-immunoprecipitation, mutational analysis of BANK1 tyrosine/proline residues, BCR stimulation PloS one High 23555801
2014 BLK acts downstream of activated Gα13 to phosphorylate p190RhoGAP, causing RhoA inactivation and deficient cell invasion in response to CXCL12; BLK binds Gα13, and BLK-mediated p190RhoGAP phosphorylation upon Gα13 activation correlates with weakening of Gα13-BLK association and increased BLK-p190RhoGAP assembly. RNAi knockdown, protein overexpression, co-immunoprecipitation, RhoA activation assay, invasion assay Cellular Signalling High 25025568
2015 BLK risk haplotype (associated with reduced BLK expression) leads to lower basal BCR signaling but hyperactivatable B cells: enhanced CD86 up-regulation after BCR crosslinking, greater T cell stimulatory capacity, and increased isotype-switched memory B cells. Primary human B cells from RA patients/healthy donors stratified by BLK haplotype, flow cytometry, BCR crosslinking assays, cell culture Arthritis & Rheumatology Medium 26246128
2015 A BLK variant (L3P) found in CVID patients causes reduced BCR crosslinking-induced Syk phosphorylation, impaired B-cell proliferation, accelerated destruction of BCR-internalized antigen, and reduced ability to elicit antigen-specific CD4+ T-cell responses. Functional analysis of L3P-BLK in primary B cells and B-LCLs, Syk phosphorylation assay, antigen presentation assay, proliferation assay Oncotarget Medium 25926555
2016 The Ala71Thr variant in BLK SH3 domain causes hyperphosphorylation and kinase activation, leading to enhanced ubiquitination and proteasomal degradation (reduced protein half-life by half); the 71Thr variant also severely reduces binding to the adaptor protein BANK1. In vitro protein stability assay, ubiquitination assay, co-immunoprecipitation of BLK and BANK1, mutagenesis Genes and Immunity High 26821283
2016 Ibrutinib inhibits pre-BCR+ B-ALL progression by targeting both BTK and BLK; CRISPR-Cas9 gene editing of BTK and BLK individually demonstrated both are relevant ibrutinib targets in pre-BCR+ ALL, with inhibition deactivating PI3K/Akt signaling and reducing BCL6 levels. CRISPR-Cas9 gene editing, drug sensitivity assays, PI3K/Akt signaling analysis, mouse xenograft model Blood High 28031181
2016 Bakuchiol directly binds to BLK kinase in an ATP-competitive manner and inhibits EGF-induced signaling pathways including MEK/ERK, p38 MAPK/MSK1, and AKT/p70S6K downstream of BLK. Kinase profiling, direct binding assay (ATP-competitive), in vitro kinase assay, in vivo xenograft Oncotarget Medium 26910280
2019 Rare missense variants in BLK found in SLE patients (but not controls) impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice; BLK and BANK1 interact physically and functionally to regulate these pathways. Functional assay of rare variants in B cell lines (IRF5/IFN suppression), lupus-prone mouse model with variant introduction, Co-IP Nature Communications High 31101814
2023 BLK phosphorylates IRF3 at tyrosine 107 following viral infection; BLK first undergoes autophosphorylation at Y309 upon viral infection, then directly binds and phosphorylates IRF3-Y107, which promotes TBK1-induced IRF3 S386/S396 phosphorylation and downstream antiviral response; BLK-deficient mice show lower serum cytokines and higher lethality after VSV infection. In vitro kinase assay, mutagenesis (Y309 and Y107), co-immunoprecipitation, BLK knockout cells and mice, viral infection models PLoS Pathogens High 37871014
2023 BLK is pre-associated with IL1R1 and IL1RAcP in resting cells; IL-1β stimulation induces BLK autophosphorylation at Y309, after which activated BLK directly phosphorylates TOLLIP at Y76/86/152, promoting TOLLIP dissociation from IRAK1 and facilitating TLR/IL-1R-mediated signal transduction. Co-immunoprecipitation, in vitro kinase assay, mutagenesis (Y309, Y76/86/152), BLK-deficient mice (IL-1β challenge), signaling analysis The Journal of Cell Biology High 38078859
2023 BLK forms a complex with CLDN6 via the C-terminal cytoplasmic domain through direct protein-protein interaction (independent of phosphotyrosine); BLK is essential for CLDN6-triggered epithelial differentiation and retinoid acid receptor target gene expression. Immunoprecipitation, pull-down assay with recombinant proteins, CRISPR knockout of Blk in F9:Cldn6 cells, gene expression analysis Cells High 37443730
2025 BLK is activated by FAK through complex formation in TGF-β1-induced endometrial stromal cells; FAK-BLK complex formation leads to BLK phospho-activation, which drives endoplasmic reticulum stress (GRP78/CHOP upregulation) and endometrial fibrosis; BLK knockdown attenuates fibrosis in vitro and in an intrauterine adhesion mouse model. Co-immunoprecipitation (FAK-BLK complex), siRNA knockdown, in vivo Blk knockdown mouse model, ERS marker analysis Cell & Bioscience Medium 41174819
2002 Mouse DAM1 interacts with BLK (identified by yeast two-hybrid) and confirmed by in vitro protein binding assay; co-expression of mDAM1 and BLK increases cell death compared to BLK alone in mammary epithelial cells, indicating mDAM1 promotes BLK pro-apoptotic function. Yeast two-hybrid screening, in vitro protein binding assay, stable transfection, cell death assay Cancer Letters Medium 12406557
2014 Two lupus-associated BLK promoter variants are functionally causal: rs922483 in the proximal BLK promoter reduces promoter activity and modulates alternative promoter usage; rs1382568 (tri-allelic) in the upstream alternative BLK promoter alters promoter activity in B progenitor cell lines. Trans-population mapping, sequencing, luciferase reporter assay in B cell lines American Journal of Human Genetics High 24702955

Source papers

Stage 0 corpus · 95 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. The New England journal of medicine 743 18204098
1990 Specific expression of a tyrosine kinase gene, blk, in B lymphoid cells. Science (New York, N.Y.) 238 2404338
2009 Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proceedings of the National Academy of Sciences of the United States of America 134 19667185
1999 Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination. Proceedings of the National Academy of Sciences of the United States of America 134 10449731
1996 Catalytic specificity of phosphotyrosine kinases Blk, Lyn, c-Src and Syk as assessed by phage display. Journal of molecular biology 118 8709147
2009 Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations. Journal of autoimmunity 106 19796918
2004 Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death. Molecular and cellular biology 99 14749373
2010 Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome. Genes and immunity 98 20861858
1998 Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. The Journal of biological chemistry 90 9525867
2019 Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nature communications 88 31101814
2016 Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK. Blood 72 28031181
2012 Gene-gene interaction of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in systemic lupus erythematosus. Arthritis and rheumatism 70 21905002
1992 Structure and developmental regulation of the B-lymphoid tyrosine kinase gene blk. The Journal of biological chemistry 67 1537861
2000 The B-cell-specific Src-family kinase Blk is dispensable for B-cell development and activation. Molecular and cellular biology 65 10648608
2011 Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK. Annals of the rheumatic diseases 64 21978998
2012 The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells. Nature genetics 63 22797726
2009 Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome. Arthritis and rheumatism 63 19644876
1994 Specific recognition of the blk promoter by the B-lymphoid transcription factor B-cell-specific activator protein. The Journal of biological chemistry 60 8195169
2003 Mimicry of pre-B cell receptor signaling by activation of the tyrosine kinase Blk. The Journal of experimental medicine 59 14662906
1993 Antisense oligodeoxynucleotides to the blk tyrosine kinase prevent anti-mu-chain-mediated growth inhibition and apoptosis in a B-cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America 59 7690139
2022 Evaluation of Evidence for Pathogenicity Demonstrates That BLK, KLF11, and PAX4 Should Not Be Included in Diagnostic Testing for MODY. Diabetes 55 35108381
1998 Malignant transformation of early lymphoid progenitors in mice expressing an activated Blk tyrosine kinase. Proceedings of the National Academy of Sciences of the United States of America 55 9636152
1999 AML1 (CBFalpha2) cooperates with B cell-specific activating protein (BSAP/PAX5) in activation of the B cell-specific BLK gene promoter. The Journal of biological chemistry 54 10455134
2014 Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. American journal of human genetics 53 24702955
2013 Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility. PloS one 53 24023612
2009 Replication of the association between the C8orf13-BLK region and systemic lupus erythematosus in a Japanese population. Arthritis and rheumatism 48 19180478
2008 The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFNgamma-induced cell death. The Journal of cell biology 46 18981230
1994 Tyrosine phosphorylation of Blk and Fyn Src homology 2 domain-binding proteins occurs in response to antigen-receptor ligation in B cells and constitutively in pre-B cells. Proceedings of the National Academy of Sciences of the United States of America 44 7514299
2011 C8orf13-BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: results from a large french cohort and meta-analysis. Arthritis and rheumatism 43 21480188
1995 Differential expression of the blk and ret tyrosine kinases during B lineage development is dependent on Ig rearrangement. Journal of immunology (Baltimore, Md. : 1950) 43 7608542
2013 BANK1 and BLK act through phospholipase C gamma 2 in B-cell signaling. PloS one 41 23555801
2015 Autoimmune disease-associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class-switched B cells. Arthritis & rheumatology (Hoboken, N.J.) 40 26246128
2013 Association studies of TNFSF4, TNFAIP3 and FAM167A-BLK polymorphisms with primary Sjogren's syndrome in Han Chinese. Journal of human genetics 36 23635951
2012 Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein. Annals of the rheumatic diseases 36 22696686
1998 Activation of lyn, blk, and btk but not syk in CD72-stimulated B lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 36 9531290
2016 Bakuchiol suppresses proliferation of skin cancer cells by directly targeting Hck, Blk, and p38 MAP kinase. Oncotarget 35 26910280
1993 SH2 domains of the protein-tyrosine kinases Blk, Lyn, and Fyn(T) bind distinct sets of phosphoproteins from B lymphocytes. The Journal of biological chemistry 35 8226767
2014 Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice. PloS one 33 24637841
2013 Variants in TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3 interact to confer risk of systemic lupus erythematosus in Chinese population. Rheumatology international 32 24091983
2015 Gene-gene interaction of ATG5, ATG7, BLK and BANK1 in systemic lupus erythematosus. International journal of rheumatic diseases 31 26420661
2011 Blk haploinsufficiency impairs the development, but enhances the functional responses, of MZ B cells. Immunology and cell biology 31 21894171
2004 Isoforms of the Ets transcription factor NERF/ELF-2 physically interact with AML1 and mediate opposing effects on AML1-mediated transcription of the B cell-specific blk gene. The Journal of biological chemistry 31 14970218
1998 The transcription factor NF-kappaB/p50 interacts with the blk gene during B cell activation. The Journal of biological chemistry 30 9660839
2012 Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes. Diabetologia 29 23224494
2001 Cutting edge: A/WySnJ transitional B cells overexpress the chromosome 15 proapoptotic Blk gene and succumb to premature apoptosis. Journal of immunology (Baltimore, Md. : 1950) 27 11714762
2013 Epistatic interaction between BANK1 and BLK in rheumatoid arthritis: results from a large trans-ethnic meta-analysis. PloS one 24 23646104
1995 Transcription of the blk gene in human B lymphocytes is controlled by two promoters. The Journal of biological chemistry 24 7592787
2014 The effect of inversion at 8p23 on BLK association with lupus in Caucasian population. PloS one 23 25545785
2010 The association of the BLK gene with SLE was replicated in Chinese Han. Archives of dermatological research 23 20130895
1995 Molecular cloning, characterization, and chromosomal localization of a human lymphoid tyrosine kinase related to murine Blk. Journal of immunology (Baltimore, Md. : 1950) 23 7822795
2017 A novel BLK-induced tumor model. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 28670978
2016 Molecular characterization and growth optimization of halo-tolerant protease producing Bacillus Subtilis Strain BLK-1.5 isolated from salt mines of Karak, Pakistan. Extremophiles : life under extreme conditions 20 27114252
2020 Association of BLK and BANK1 Polymorphisms and Interactions With Rheumatoid Arthritis in a Latin-American Population. Frontiers in genetics 17 32153635
2016 Association of FAM167A-BLK rs2736340 Polymorphism with Susceptibility to Autoimmune Diseases: A Meta-Analysis. Immunological investigations 17 27105348
2018 The rheumatic disease-associated FAM167A-BLK locus encodes DIORA-1, a novel disordered protein expressed highly in bronchial epithelium and alveolar macrophages. Clinical and experimental immunology 16 29663334
2015 Single nucleotide polymorphisms in the FAM167A-BLK gene are associated with polymyositis/dermatomyositis in the Han Chinese population. Immunologic research 16 25846585
2010 Association of BLK (rs13277113, rs2248932) polymorphism with systemic lupus erythematosus: a meta-analysis. Molecular biology reports 16 21152986
1995 Molecular cloning and chromosomal localization of the human homologue of a B-lymphocyte specific protein tyrosine kinase (blk). Oncogene 16 7845672
2010 Association of IRF5, STAT4 and BLK with systemic lupus erythematosus and other rheumatic diseases. Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 15 20453440
2015 Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help. Oncotarget 13 25926555
2013 Polymorphisms in the FAM167A-BLK, but not BANK1, are associated with primary Sjögren's syndrome in a Han Chinese population. Clinical and experimental rheumatology 13 23899688
2012 Expression of RUNX1 isoforms and its target gene BLK in childhood acute lymphoblastic leukemia. Leukemia research 13 22748822
2019 Identification of a new family of pyrazolo[3,4-d]pyrimidine derivatives as multitarget Fyn-Blk-Lyn inhibitors active on B- and T-lymphoma cell lines. European journal of medicinal chemistry 12 31400706
2017 Interaction analysis between BLK rs13277113 polymorphism and BANK1 rs3733197 polymorphism, MMEL1/TNFRSF14 rs3890745 polymorphism in determining susceptibility to rheumatoid arthritis. Autoimmunity 12 28925718
2016 The SLE variant Ala71Thr of BLK severely decreases protein abundance and binding to BANK1 through impairment of the SH3 domain function. Genes and immunity 11 26821283
2014 A Blk-p190RhoGAP signaling module downstream of activated Gα13 functionally opposes CXCL12-stimulated RhoA activation and cell invasion. Cellular signalling 11 25025568
2012 Identify the association between polymorphisms of BLK and systemic lupus erythematosus through unlabelled probe-based high-resolution melting analysis. International journal of immunogenetics 11 22313735
2020 Associations of IL6 rs1800795, BLK rs13277113, TIMP3 rs9621532, IL1RL1 rs1041973 and IL1RAP rs4624606 single gene polymorphisms with laryngeal squamous cell carcinoma. Gene 10 32330537
2024 Improvement in organic solvent resistance of keratinase BLk by directed evolution. Journal of biotechnology 9 38244699
2017 Association between BLK polymorphisms and susceptibility to SLE : A meta-analysis. Zeitschrift fur Rheumatologie 9 27067206
2017 Association between TNFSF4 and BLK gene polymorphisms and susceptibility to allergic rhinitis. Molecular medicine reports 9 28713926
2014 Association between a C8orf13-BLK polymorphism and polymyositis/dermatomyositis in the Japanese population: an additive effect with STAT4 on disease susceptibility. PloS one 9 24632671
2010 Role of the C8orf13-BLK region in biopsy-proven giant cell arteritis. Human immunology 9 20156505
2012 Influence of BLK polymorphisms on the risk of rheumatoid arthritis. Molecular biology reports 8 22740142
2023 The Src-Family Kinases SRC and BLK Contribute to the CLDN6-Adhesion Signaling. Cells 7 37443730
2023 Tyrosine phosphorylation of IRF3 by BLK facilitates its sufficient activation and innate antiviral response. PLoS pathogens 7 37871014
2022 Halofuginone ameliorates systemic lupus erythematosus by targeting Blk in myeloid-derived suppressor cells. International immunopharmacology 7 36493694
2018 Assessment of the Clinical Heterogeneity of Kawasaki Disease Using Genetic Variants of BLK and FCGR2A. Korean circulation journal 7 30468029
2020 Polymorphisms of BLK are associated with renal disorder in patients with systemic lupus erythematosus. Journal of human genetics 6 32313195
2016 Genetic risk of TNFSF4 and FAM167A-BLK polymorphisms in children with asthma and allergic rhinitis in a Han Chinese population. The Journal of asthma : official journal of the Association for the Care of Asthma 6 27088737
2011 Multifocal motor neuropathy is not associated with genetic variation in PTPN22, BANK1, Blk, FCGR2B, CD1A/E, and TAG-1 genes. Journal of the peripheral nervous system : JPNS 6 22003931
1991 Genetic mapping of the gene for a novel tyrosine kinase, Blk, to mouse chromosome 14. Genomics 6 2037301
2024 Fyn, Blk, and Lyn kinase inhibitors: A mini-review on medicinal attributes, research progress, and future insights. Bioorganic & medicinal chemistry letters 5 38408513
2022 IgA Vasculitis: Influence of CD40, BLK and BANK1 Gene Polymorphisms. Journal of clinical medicine 4 36233442
2021 Discovery of selective irreversible inhibitors of B-Lymphoid tyrosine kinase (BLK). European journal of medicinal chemistry 4 34952433
2002 Mouse DAM1 regulates pro-apoptotic activity of BLK in mammary epithelial cells. Cancer letters 4 12406557
2023 BLK positively regulates TLR/IL-1R signaling by catalyzing TOLLIP phosphorylation. The Journal of cell biology 3 38078859
2021 Combined Single Nucleotide Variants of ORAI1 and BLK in a Child with Refractory Kawasaki Disease. Children (Basel, Switzerland) 2 34064199
2019 'Piperazining' the catalytic gatekeepers: unraveling the pan-inhibition of SRC kinases; LYN, FYN and BLK by masitinib. Future medicinal chemistry 1 31516031
2025 A novel BLK heterozygous mutation (p.Met121lle) in maturity-onset diabetes mellitus: A case report and literature review. Diabetic medicine : a journal of the British Diabetic Association 0 39754319
2025 Rare BLK, CEL, KLF11, PDX1, and PAX4 Gene Variants in Russian Patients with Monogenic Diabetes: Clinical and Molecular Characterization. Biomedicines 0 41153735
2025 FAK-dependent activation of src family kinase member BLK contributed to endometrial fibrosis via endoplasmic reticulum stress. Cell & bioscience 0 41174819
2025 Exploration of the regulatory function of genetic variants at FAM167A-BLK locus in systemic lupus erythematosus. Yi chuan = Hereditas 0 41250293
2024 Association of BLK and BANK1 gene polymorphisms with systemic lupus erythematous in Egyptian patients. The Egyptian journal of immunology 0 39417739
2023 The survival rate of laryngeal squamous cell carcinoma: impact of IL1RAP rs4624606, IL1RL1 rs1041973, IL-6 rs1800795, BLK rs13277113, and TIMP3 rs9621532 single nucleotide polymorphisms. Discover oncology 0 36682035