Affinage

BLNK

B-cell linker protein · UniProt Q8WV28

Length
456 aa
Mass
50.5 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BLNK (also SLP-65/BASH) is the central cytoplasmic scaffold adaptor that couples the activated B cell antigen receptor to its downstream effector machinery, and its loss arrests B lymphopoiesis at the pro-B to pre-B transition in both mice and humans (PMID:9697839, PMID:10583957, PMID:10583958). Upon BCR engagement, the Syk tyrosine kinase phosphorylates BLNK on multiple tyrosines that act as docking sites, converting it into a nucleation platform for SH2-containing effectors including PLCγ2, Vav, Grb2, and Nck (PMID:9697839, PMID:12456653). BLNK is recruited to the receptor through its C-terminal SH2 domain binding phospho-Y204 of the Igα signaling subunit outside the ITAM, with the tetraspanning membrane protein CMTM7 acting as a transmembrane linker between surface IgM and BLNK (PMID:11909947, PMID:11449366, PMID:22363743). Membrane and vesicle positioning is set before stimulation by an N-terminal leucine-zipper/lipid-binding module that associates with intracellular vesicles and the plasma membrane, working within a constitutive SLP65/CIN85 complex that phase-separates through multivalent SH3–proline-rich-motif interactions and is required for BLNK phosphorylation and inducible membrane translocation (PMID:15654340, PMID:21822214, PMID:25140054, PMID:38463037). Once assembled, BLNK drives PLCγ2 activation by anchoring its N-terminal SH2 and Ca2+-regulated C2 domains (PMID:10023776, PMID:10438904, PMID:24166973), serves as the scaffold that lets Syk phosphorylate Btk-Y551 to activate Btk (PMID:10498607, PMID:11226282), localizes Vav3 to membrane rafts for Rac1 activation (PMID:12818159), binds GTP-loaded H-Ras through a discrete Ras-binding domain to sustain ERK signaling (PMID:19218240), and recruits phospho-HPK1 to activate IKKβ and NF-κB, controlling cell-cycle and survival gene expression (PMID:11274146, PMID:11514608). BLNK output is curtailed by an HPK1–14-3-3–ubiquitination circuit: HPK1 phosphorylates BLNK-T152 to create a 14-3-3 docking site, promoting ubiquitination at K37/38/42 and proteasomal degradation (PMID:22334673, PMID:33176192). In pre-B cells BLNK is a Pax5 target that functions as a tumor suppressor, restraining IL-7-driven proliferation by directly inhibiting JAK3 and antagonizing PI3K–PKB–Foxo signaling to permit immunoglobulin light-chain rearrangement (PMID:12436112, PMID:12387741, PMID:19047679, PMID:18488031). Beyond B cells, BLNK couples C-type lectin/Syk signaling in macrophages to inhibition of migration via c-Cbl–Fyn antagonism (PMID:39413134).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Established BLNK's foundational identity as the adaptor bridging BCR-activated Syk to downstream effectors, defining the core of B cell signaling architecture.

    Evidence Co-immunoprecipitation and biochemical pulldowns in B cells identifying Syk-induced tyrosine phosphorylation and binding of PLCγ, Vav, Grb2, and Nck

    PMID:9697839 PMID:9705962

    Open questions at the time
    • Did not map which specific tyrosines bind which effectors
    • Did not establish in vivo developmental requirement
  2. 1999 High

    Showed BLNK is functionally required for BCR-induced PLCγ2 and JNK activation and acts by controlling PLCγ2 membrane localization via its SH2-N interaction.

    Evidence Reconstitution of BLNK-deficient and PLCγ2-deficient B cell lines with membrane-targeted or domain-mutant PLCγ2, calcium flux, IP3 and JNK assays

    PMID:10023776 PMID:10438904

    Open questions at the time
    • Mechanism of Rac1 contribution to JNK not resolved
    • Structural basis of SH2-N/BLNK contact not defined
  3. 1999 High

    Demonstrated BLNK is non-redundantly required for B cell development in vivo in both mouse and human, fixing its place at the pro-B to pre-B checkpoint.

    Evidence BLNK knockout mice and human homozygous splice-defect patient analysis with developmental immunophenotyping

    PMID:10583957 PMID:10583958

    Open questions at the time
    • Which downstream pathway failure causes the block not pinpointed
  4. 2001 High

    Resolved how BLNK is recruited to the receptor and how it activates Btk, NF-κB, and HPK1/IKKβ, converting it from a binding hub into a defined signal-routing platform.

    Evidence Chimeric Igα receptors with mutant Y204, scaffold reconstitution of Syk-mediated Btk-Y551 phosphorylation, and analysis of NF-κB/IκB and HPK1 in deficient B cells

    PMID:11226282 PMID:11274146 PMID:11449366 PMID:11514608 PMID:11909947

    Open questions at the time
    • Spatial coordination of these parallel complexes on one BLNK molecule not directly visualized
  5. 2002 High

    Defined the multi-tyrosine scaffold logic of BLNK and established its tumor-suppressor role downstream of Pax5 in pre-B cells.

    Evidence Systematic tyrosine mutagenesis with signaling readouts, plus SLP-65-deficient mouse lymphoma analysis and Pax5-dependent transcriptional regulation studies

    PMID:12387741 PMID:12436112 PMID:12456653

    Open questions at the time
    • Molecular target of tumor-suppressor activity not yet identified in 2002
  6. 2003 High

    Defined how BLNK directs Rac1 activation by cooperating with Grb2 to localize Vav3 to membrane rafts.

    Evidence Grb2- and BLNK-deficient B cells with raft fractionation and raft-targeted Vav3 rescue of Rac1 activation

    PMID:12818159

    Open questions at the time
    • Direct BLNK-Vav3 versus Grb2-bridged interaction not fully separated
  7. 2005 High

    Identified the N-terminal leucine zipper as an autonomous membrane-targeting module, explaining how BLNK is pre-positioned for signaling.

    Evidence N-terminus mutagenesis, GFP live imaging, myristoylation rescue, and domain transfer to SLP-76 in DT40 cells

    PMID:15654340

    Open questions at the time
    • Lipid/membrane partner of the leucine zipper not yet identified at this stage
  8. 2007 High

    Revealed a bidirectional Syk-BLNK relationship in which the BLNK C-terminal SH2 domain governs phosphorylation and membrane recruitment while Syk also acts as a downstream adaptor for Ca2+/NFAT signaling.

    Evidence SH2 mutagenesis in DT40 cells and SLP-65 reconstitution in SLP-76-deficient T cells with Ca2+ and NFAT readouts

    PMID:17681949

    Open questions at the time
    • Structural basis of kinase-independent Syk adaptor role not defined
  9. 2008 High

    Established the mechanistic basis of BLNK tumor suppression and its role in light-chain rearrangement via JAK3 inhibition and PI3K-PKB-Foxo antagonism.

    Evidence BLNK-deficient leukemia cells with reconstitution, BLNK-JAK3 co-IP, STAT5-CA transgenic mice, and Foxo/PKB activity and recombination assays in pre-B cells

    PMID:18488031 PMID:19047679

    Open questions at the time
    • How BLNK both scaffolds activating BCR signals and suppresses cytokine signaling in the same cell not reconciled
  10. 2009 High

    Defined the H-Ras-binding domain enabling sustained ERK signaling and mapped temporally distinct BLNK phosphorylation dynamics including serine checkpoints.

    Evidence H-Ras co-IP with domain mutagenesis and chimeric receptor rescue, plus MS phosphosite mapping with site-specific mutagenesis in DT40 cells

    PMID:19218240 PMID:19372136

    Open questions at the time
    • Kinases for individual serine sites not all assigned
    • Physiological trigger of resting-state dephosphorylation unclear
  11. 2011 High

    Showed BLNK functions within a constitutive, preformed SLP65/CIN85 complex required for its own phosphorylation and inducible membrane translocation.

    Evidence Quantitative in vivo interactomics, CIN85-knockout B cells, live imaging, and Ca2+/NF-κB functional readouts

    PMID:21822214

    Open questions at the time
    • Physical organization of the preformed complex not yet structurally resolved
  12. 2012 High

    Defined the negative-feedback circuit terminating BLNK signaling and identified CMTM7 as the transmembrane linker coupling surface IgM to BLNK-Syk.

    Evidence HPK1-deficient cells with T152/K37-42 mutagenesis and ubiquitination assays, and CMTM7 knockdown/mutant rescue with co-IP and signaling readouts

    PMID:22334673 PMID:22363743

    Open questions at the time
    • E3 ligase responsible for K37/38/42 ubiquitination not identified
    • How CMTM7 coordinates with Igα-Y204 recruitment not resolved
  13. 2013 High

    Resolved a Ca2+-regulated feed-forward loop in which the PLCγ2 C2 domain anchors to a distinct BLNK phosphotyrosine to amplify and then self-terminate signaling.

    Evidence PLCγ2 C2 domain mutagenesis, Ca2+ flux, and PLCγ2-SLP65 binding assays

    PMID:24166973

    Open questions at the time
    • Identity of the specific BLNK phosphotyrosine bound by C2 not fully pinned
  14. 2014 High

    Showed BLNK associates with intracellular vesicles in resting cells through a disordered N-terminal module that folds upon binding noncharged membrane lipids, establishing vesicular preformed scaffolds.

    Evidence Subcellular fractionation, live imaging, and NMR of the N-terminal domain with membrane lipids in B cells

    PMID:25140054

    Open questions at the time
    • Identity of the specific vesicle compartment not defined
  15. 2024 High

    Provided the biophysical basis for vesicular scaffold formation through SLP65/CIN85 multivalent phase separation and extended BLNK function to macrophage migration control.

    Evidence Quantified SH3-PRM dissociation constants with phase-separation modeling, and monocyte-specific BLNK knockout mice with c-Cbl/Fyn co-IP and Candida infection model

    PMID:38463037 PMID:39413134

    Open questions at the time
    • In vivo relevance of phase separation to B cell activation not directly tested
    • Whether macrophage c-Cbl/Fyn mechanism generalizes to other receptors unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BLNK's positive BCR-scaffolding role and its context-dependent tumor-suppressor/anoikis-promoting and oncogenic-cooperative functions in non-B-cell cancers are mechanistically integrated remains unresolved.
  • Non-B-cell roles (breast anoikis, NSCLC Met signaling, CLL CK2/CD5/STAT3) rest on single-lab studies
  • No unifying structural model of the full activated BLNK signaling complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
BTKCD79ACIN85CMTM7GRB2HPK1PLCG2SYK
Complex memberships
CK2/CD5/BLNK/STAT3 complexSLP65/CIN85 complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 BLNK (B cell linker protein) was identified as a novel adaptor protein that interfaces the BCR-associated Syk tyrosine kinase with PLCγ, Vav guanine nucleotide exchange factor, and the Grb2 and Nck adaptor proteins. Tyrosine phosphorylation of BLNK by Syk creates docking sites for these SH2-containing effector molecules. Co-immunoprecipitation, biochemical pulldown, identification of protein interactions in B cells Immunity High 9697839
1998 SLP-65/BLNK is a B cell adaptor protein that requires expression of the B cell antigen receptor (BCR) for its tyrosine phosphorylation; phosphorylation was induced by BCR engagement or pervanadate and SLP-65 forms a signaling complex involving Grb2 and Vav. BCR-inducible expression system, pervanadate stimulation, co-immunoprecipitation, 2D gel electrophoresis, peptide sequencing The Journal of experimental medicine High 9705962
1999 BLNK is essential for BCR-induced PLCγ2 activation and JNK activation in B cells. PLCγ2 activation (but not JNK) was restored by membrane-targeted PLCγ2 in BLNK-deficient cells, indicating BLNK regulates PLCγ2 localization. JNK activation requires both Rac1 and PLCγ2 downstream of BLNK. BLNK-deficient B cell lines, reconstitution with membrane-targeted PLCγ2, calcium flux assay, JNK kinase assay Immunity High 10023776
1999 The N-terminal SH2 domain (SH2-N) of PLCγ2 is required for its association with BLNK, and this association is critical for inositol-1,4,5-trisphosphate generation upon BCR engagement. Loss of SH2-N abolishes PLCγ2-BLNK interaction and IP3 production. PLCγ2 SH2 domain mutants in PLCγ2-deficient B cells, co-immunoprecipitation, IP3 measurement, reconstitution with membrane-targeted forms Journal of immunology High 10438904
1999 BLNK is identified as a major binding partner of the Btk SH2 domain in B cells. The interaction between BLNK and Btk-SH2 domain contributes to complete tyrosine phosphorylation of PLCγ2 upon BCR stimulation. Affinity purification with Btk-SH2 domain, co-immunoprecipitation, tyrosine phosphorylation assays Blood High 10498607
1999 BLNK is required for B cell development in vivo; BLNK-deficient mice show a block at the pro-B to pre-B cell transition. BLNK links BCR-activated Syk kinase to phosphoinositide and MAP kinase pathways. BLNK knockout mice generation, flow cytometric analysis of B cell developmental stages Science High 10583957
1999 Human BLNK deficiency (homozygous splice defect) causes a developmental block at the pro-B to pre-B cell transition, with normal pro-B cells but absent pre-B and mature B cells, establishing BLNK's non-redundant role in human B cell development. Patient genetic analysis, bone marrow immunophenotyping, splice defect characterization Science High 10583958
2001 BLNK mediates Syk-dependent Btk activation by acting as a scaffold: coexpression of BLNK allows Syk to phosphorylate Btk on tyrosine 551 via Btk-SH2 domain interaction with BLNK, enhancing Btk kinase activity. BCR-induced Btk phosphorylation and activation are reduced in BLNK-deficient B cells. Reconstitution cell system, BLNK-deficient B cells, Btk phosphorylation assays, kinase activity assays, mutagenesis of Btk Y551 Proceedings of the National Academy of Sciences High 11226282
2001 BLNK is directly recruited to the BCR signaling subunit Igα through non-ITAM tyrosine Y204 (phosphorylated upon BCR ligation). The BLNK SH2 domain binds phospho-Y204 of Igα, coupling Syk activation to BLNK-dependent downstream pathways. Chimeric receptors with wild-type and mutant Igα cytoplasmic tails, co-immunoprecipitation, direct binding assays, reconstitution of downstream signaling Molecular and cellular biology High 11449366 11909947
2001 SLP-65/BLNK associates directly with the BCR signaling subunit Igα/Igβ heterodimer; the SLP-65 SH2 domain binds phosphorylated Igα tyrosine 204 (outside the ITAM), providing a mechanism for SLP-65 membrane recruitment. Co-immunoprecipitation after B cell stimulation, domain mapping with SH2 domain of SLP-65, phosphopeptide binding European journal of immunology High 11449366
2001 BLNK is required for BCR-induced NF-κB activation; BLNK-deficient B cells fail to degrade IκB upon BCR stimulation, cannot induce cyclin D2/CDK4 or Bcl-xL expression, and show high spontaneous apoptosis. BLNK orchestrates a Btk-PLCγ2 signaling axis regulating NF-κB. BLNK-deficient B cells, cell cycle analysis, NF-κB reporter assays, IκB degradation assays, cyclin/CDK expression analysis Journal of Biological Chemistry High 11274146
2001 BASH/BLNK links BCR signaling to activation of hematopoietic progenitor kinase 1 (HPK1): BCR ligation induces Syk/Lyn-mediated tyrosine phosphorylation of HPK1 at Y379, which then associates with the BASH SH2 domain. BASH-recruited HPK1 activates IKKβ. HPK1 activation is impaired in Syk- or BASH-deficient B cells. Co-immunoprecipitation, kinase assays, site-directed mutagenesis of HPK1 Y379, analysis in Syk- and BASH-deficient B cells Journal of experimental medicine High 11514608
2002 Phosphorylation of five tyrosine residues within human BLNK nucleates distinct signaling effectors after BCR activation. Multiple tyrosine phosphorylations amplify PLCγ-mediated signaling and support 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. Systematic mutagenesis of BLNK tyrosines, reconstitution in BLNK-deficient B cells, signaling readouts (Ca2+ mobilization, MAP kinase activation) The EMBO journal High 12456653
2002 SLP-65/BLNK acts as a tumor suppressor in pre-B cells: SLP-65-deficient pre-B cells show enhanced IL-7-dependent proliferative capacity and SLP-65-deficient mice have high incidence of pre-B cell lymphoma. Reintroduction of SLP-65 promotes pre-BCR downregulation and enhanced differentiation. SLP-65-deficient mice analysis, ex vivo proliferation assays, retroviral reconstitution of SLP-65 expression, tumor incidence monitoring Nature immunology High 12436112
2002 BLNK is a direct transcriptional target of the transcription factor Pax5 (BSAP); Pax5 activates BLNK expression to control pre-BCR signaling and the pro-B to pre-B cell transition. Pax5-deficient pro-B cells, BLNK restoration experiments, Pax5-BLNK promoter analysis, BLNK-estrogen receptor fusion for inducible signaling Immunity High 12387741
2003 Adaptor molecules Grb2 and BLNK cooperate to localize Vav3 to membrane rafts, which is required for efficient Rac1 activation in response to BCR stimulation. Expression of raft-targeted Vav3 rescues defective Rac1 activation in Grb2- or BLNK-deficient B cells. Grb2- and BLNK-deficient B cells, Rac1 activation assays, membrane raft fractionation, raft-targeted Vav3 reconstitution Immunity High 12818159
2005 A conserved leucine zipper in the N-terminus of SLP-65 is responsible for its association with the plasma membrane. Alterations in the N-terminus abolish SLP-65 membrane localization and activity; replacement with a myristoylation signal restores both. The N-terminus is an autonomous domain sufficient to confer membrane localization. Mutational analysis of SLP-65 N-terminus in DT40 B cells, live cell imaging of GFP fusions, functional reconstitution assays, domain transfer experiments to SLP-76 Nature immunology High 15654340
2007 The C-terminal SH2 domain of SLP-65 controls efficient tyrosine phosphorylation by Syk, plasma membrane recruitment, and downstream signaling to NFAT. A kinase-independent adaptor function of Syk is required to link phosphorylated SLP-65 to Ca2+ mobilization, making Syk both upstream and downstream of SLP-65. SH2 domain mutational analysis in DT40 B cells, reconstitution of SLP-65 in SLP-76-deficient T cells, Ca2+ mobilization assays, NFAT reporter assays Journal of Biological Chemistry High 17681949
2008 BLNK suppresses pre-B cell leukemia through direct binding to and inhibition of JAK3. BLNK-deficient pre-B leukemia cells have constitutively active JAK3/STAT5 due to autocrine IL-7 production; exogenous BLNK inhibits JAK3 signaling in a binding-dependent manner, inducing p27Kip1, cell cycle arrest, and apoptosis. BLNK-deficient leukemia cells, JAK3 inhibition experiments, BLNK reconstitution, co-immunoprecipitation of BLNK-JAK3, STAT5-CA transgenic mice, IL-7R signaling analyses Blood High 19047679
2008 SLP-65 counteracts PKB/Akt activation and promotes Foxo3a and Foxo1 activity in pre-B cells, thereby enabling Ig light chain rearrangement. SLP-65-dependent signaling antagonizes PI(3)K-PKB-Foxo pathway, establishing a mechanistic link between SLP-65 and immunoglobulin recombination. SLP-65 reconstitution in deficient pre-B cells, Foxo phosphorylation analysis, PKB activity measurements, light chain recombination assays, Foxo transcription factor activity assays Nature immunology High 18488031
2009 SLP-65 phosphorylation occurs at multiple sites with different dynamics (early/transient, early/sustained, or late). Serine 170 phosphorylation acts as a BCR-distal checkpoint for some B cell responses but not others. Some sites are phosphorylated in resting cells and undergo rapid dephosphorylation upon BCR ligation. Mass spectrometric analysis of SLP-65 phospho-sites in DT40 B cells, site-specific mutagenesis, functional assays for B cell responses Molecular & cellular proteomics High 19372136
2009 BLNK binds the active (GTP-loaded) form of H-Ras via a 10-amino acid Ras-binding domain. This interaction is facilitated by BCR crosslinking and is required for sustained ERK phosphorylation, BCR capping, and anti-apoptotic signaling. The Ras-binding domain fused to a CD8α-Igα chimeric receptor reconstitutes these activities in BLNK-deficient cells. Co-immunoprecipitation with active H-Ras, domain mutagenesis of BLNK Ras-binding region, reconstitution in BLNK-deficient B cells, ERK phosphorylation assays, BCR capping imaging Journal of Biological Chemistry High 19218240
2011 SLP65/BLNK forms a stimulation-independent, constitutive complex with CIN85. This preformed SLP65/CIN85 complex is required for SLP65 phosphorylation and its inducible plasma membrane translocation. In the absence of the SLP65/CIN85 complex, BCR-induced Ca2+ and NF-κB responses are abrogated. Mass spectrometry identified ~30 SLP65 interaction partners with predominantly dynamic interactions. Quantitative in vivo interactomics by mass spectrometry, co-immunoprecipitation, live cell imaging, CIN85 knockout B cells, Ca2+ flux assays, NF-κB reporter assays The EMBO journal High 21822214
2012 HPK1 phosphorylates BLNK at threonine 152, which mediates BLNK binding to 14-3-3 proteins. Threonine 152-phosphorylated BLNK is subsequently ubiquitinated at lysines 37, 38, and 42, leading to its degradation and attenuation of MAPK and IKK activation in B cells during BCR signaling. HPK1-deficient B cells, site-directed mutagenesis of BLNK T152 and K37/38/42, ubiquitination assays, co-immunoprecipitation with 14-3-3, signaling assays Journal of Biological Chemistry High 22334673
2012 CMTM7 (a tetra-spanning membrane protein) co-localizes with sIgM at the plasma membrane and acts as a transmembrane linker between sIgM and BLNK. CMTM7 knockdown impairs BLNK-Syk interaction and BLNK tyrosine phosphorylation, and a C-terminal deletion of CMTM7 (defective in membrane localization) abolishes these functions, while N-terminal deletion does not. RNAi knockdown of CMTM7, reconstitution with CMTM7 mutants (ΔN, ΔC), co-immunoprecipitation of BLNK-Syk and CMTM7-sIgM-BLNK complexes, JNK/ERK activation assays, fluorescence colocalization PloS one High 22363743
2013 The C2 domain of PLCγ2 binds in a Ca2+-regulated manner to a distinct phosphotyrosine of SLP65, providing feed-forward signal amplification. Early Ca2+ flux promotes C2 domain anchoring to phospho-SLP65, amplifying PLCγ2 activity; as Ca2+ resources are exhausted, the C2-phosphotyrosine interaction terminates despite sustained SLP65 phosphorylation. PLCγ2 C2 domain mutational analysis, Ca2+ flux assays, co-immunoprecipitation of PLCγ2-SLP65, biochemical binding studies Journal of immunology High 24166973
2014 SLP-65 associates with intracellular vesicles in resting B cells via a ~50 amino acid N-terminal module. NMR spectroscopy showed the N-terminus is structurally disordered in solution but binds in a structured manner to noncharged lipid components of cellular membranes. Vesicle-associated preformed signaling scaffolds are required for B cell activation. Subcellular fractionation, live cell imaging, NMR spectroscopy of SLP-65 N-terminal domain with membrane lipids, mutational analysis, B cell activation assays Science signaling High 25140054
2017 In CLL cells, BLNK forms a complex with CK2, CD5, and STAT3. CK2 phosphorylates STAT3 on serine 727 constitutively in CLL cells; this requires co-expression of CD5 and BLNK (not present in normal B or T cells). siRNA knockdown of CD5 or BLNK, or CD5-neutralizing antibodies, significantly reduced serine-phosphorylated STAT3. The CK2/CD5/BLNK/STAT3 complex is cytoplasmic; serine-phosphorylated STAT3 translocates to the nucleus. Mass spectrometry co-immunoprecipitation, CK2 in vitro kinase assay with recombinant STAT3, siRNA knockdown, confocal microscopy, subcellular fractionation Molecular cancer research High 28130399
2020 The crystal structure of a BLNK pT152 peptide bound to 14-3-3σ was solved. Biophysical assays (fluorescence polarization, ITC) showed that BLNK interacts with 14-3-3 via a gatekeeper model: HPK1-mediated phosphorylation of T152 anchors BLNK to 14-3-3, and additional AKT-mediated phosphorylation of S285 further improves affinity. X-ray crystallography of BLNK peptide-14-3-3σ complex, fluorescence polarization, isothermal titration calorimetry with mono- and di-phosphorylated BLNK peptides Journal of structural biology High 33176192
2022 ECM detachment of non-malignant breast epithelial cells upregulates BLNK; ErbB2 blocks this upregulation by reducing IRF6 levels. BLNK promotes anoikis by activating p38 MAP kinase. ErbB2-dependent BLNK downregulation blocks breast cancer cell anoikis, and BLNK upregulation blocks tumor formation in mice. ErbB2 overexpression/knockdown, IRF6 manipulation, BLNK forced expression/knockdown, p38 inhibitor experiments, anoikis assays, 3D tumor growth, in vivo tumor formation Cell death & disease Medium 35933456
2022 BLNK is a positive regulator of Met receptor signaling in NSCLC cells: BLNK modulates Met localization and ligand-dependent trafficking. The BLNK-GRB2 constitutive interaction is increased by active Met, and the Met-GRB2 interaction is increased in the presence of BLNK. BLNK contributes to anchorage-independent growth and chemotaxis of NSCLC cells. Mammalian Membrane Two-Hybrid (MaMTH) assay, BLNK knockdown, Met trafficking assays, co-immunoprecipitation of BLNK-GRB2 and Met-GRB2, anchorage-independent growth assays, chemotaxis assays iScience Medium 36388990
2024 SLP65 and CIN85 form phase-separated condensates at intracellular vesicles in resting B cells via 6 proline-rich motifs (PRMs) of SLP65 interacting with 3 SH3 domains of CIN85 (18 individual SH3-PRM interactions). Quantified individual dissociation constants of these interactions model the phase-separation behavior. A previously unknown intramolecular interaction was also identified. Biophysical measurement of individual SH3-PRM dissociation constants, LASSI phase-separation modeling, designer construct analysis, identification of intramolecular interaction PNAS nexus High 38463037
2024 In macrophages, CLR (C-type lectin receptor) signaling activates Syk-mediated BLNK activation, which impedes macrophage migration by disrupting podosome ring formation. BLNK associates with c-Cbl and competitively disrupts Fyn-c-Cbl interaction, blocking Fyn-mediated c-Cbl phosphorylation and c-Cbl-associated F-actin assembly. BLNK deficiency in monocytes enhances macrophage migration and resistance to Candida albicans infection. Monocyte-specific BLNK conditional knockout mice, co-immunoprecipitation of BLNK-c-Cbl and Fyn-c-Cbl, podosome ring imaging, macrophage migration assays, Candida albicans infection model, F-actin assembly assays Proceedings of the National Academy of Sciences High 39413134
2001 In EBV-latently infected B cells, LMP2A causes constitutive tyrosine phosphorylation of one SLP-65 isoform and complex formation between SLP-65 and CrkL, leading to Cbl and C3G phosphorylation. However, PLCγ2 activation is completely blocked by LMP2A, demonstrating selective activation and repression of distinct SLP-65-regulated signaling pathways. Mouse model of LMP2A expression, biochemical analysis of SLP-65 phosphorylation and complex formation, PLCγ2 activation assays Journal of experimental medicine Medium 11489945
2006 The two human SLP-65 isoforms differ functionally: the long isoform contains an atypical SH3-binding motif that mediates Grb2 association and suppresses p38/JNK MAP kinase activation and c-Fos expression, whereas the short isoform more potently activates AP1- and NF-κB-driven transcription. The long isoform promotes BCR-induced apoptosis more than the short isoform. Reconstitution of SLP-65 isoforms in SLP-65-deficient B cells, kinase activity assays, reporter gene assays, mutagenesis of SH3-binding motif, apoptosis assays Blood Medium 16912232
2004 BNAS2, a novel protein with four transmembrane domains and MARVEL domain localizing to the ER, binds the conserved N-terminal domain of BASH/BLNK, co-precipitates with Btk and ERK2, and overexpression enhances BCR-induced Elk1 but not NF-κB transcriptional activation. Yeast two-hybrid, co-immunoprecipitation from B cell lysates, confocal microscopy, transcriptional reporter assays in DT40 B cells Journal of Biological Chemistry Low 15087455
2006 BNAS1, a novel protein with four transmembrane domains and a leucine zipper, binds the conserved N-terminal domain of BASH/BLNK via its LZ motif and localizes to the ER and nuclear envelope. BNAS1 overexpression suppresses BCR-induced Elk-1 activation; BNAS1-deficient DT40 cells show augmented Elk-1 activation that is selectively blocked by JNK inhibitor. Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, BNAS1-deficient DT40 cells, reporter assays, JNK inhibitor experiments International immunology Low 16481341
2022 SLP65 induces RHOA activity in pre-B cells, which activates PTEN by enabling its translocation to the plasma membrane, thereby counteracting PI3K signaling. This SLP65-RHOA-PTEN axis is required for pre-B cell development and survival. Conditional RhoA-deficient mice, SLP65-deficient B cells, PTEN localization by imaging, reconstitution with RhoA and Foxo1, in vitro and in vivo survival assays Frontiers in immunology Medium 35371049
2006 BASH/BLNK mediates a pre-BCR signaling pathway involving novel PKC (nPKC) and MEK (but not Ras) to induce kappa light chain gene rearrangement. Reconstitution of BLNK in pre-B leukemia cells or PMA treatment induces PKCη translocation to the plasma membrane and kappa gene rearrangement. BASH-deficient pre-B leukemia cell lines, specific inhibitors for nPKC/MEK/Ras, retroviral transduction of active PKCη/PKCε/Raf-1, tamoxifen-inducible BASH reconstitution, kappa chain expression assays Blood Medium 16794253
2000 BLNK is expressed in macrophages and becomes tyrosine-phosphorylated upon FcγRI and FcγRII/III ligation, indicating coupling to FcγR signaling pathways in these cells. Flow cytometry and Western blotting for BLNK expression in macrophages, FcγR ligation experiments, tyrosine phosphorylation assays Proceedings of the National Academy of Sciences Medium 10677525

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 BLNK: a central linker protein in B cell activation. Immunity 426 9697839
1999 BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells. Immunity 266 10023776
1999 Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65. Immunity 242 10591180
1999 An essential role for BLNK in human B cell development. Science (New York, N.Y.) 236 10583958
1999 Requirement for B cell linker protein (BLNK) in B cell development. Science (New York, N.Y.) 224 10583957
2006 SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nature reviews. Immunology 221 16493428
1998 SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation. The Journal of experimental medicine 216 9705962
1999 Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK--functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling. Blood 159 10498607
2002 The adaptor protein SLP-65 acts as a tumor suppressor that limits pre-B cell expansion. Nature immunology 142 12436112
2008 SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway. Nature immunology 129 18488031
2002 Control of pre-BCR signaling by Pax5-dependent activation of the BLNK gene. Immunity 121 12387741
1998 BASH, a novel signaling molecule preferentially expressed in B cells of the bursa of Fabricius. Journal of immunology (Baltimore, Md. : 1950) 117 9834055
2001 BLNK mediates Syk-dependent Btk activation. Proceedings of the National Academy of Sciences of the United States of America 115 11226282
2000 B cell development and activation defects resulting in xid-like immunodeficiency in BLNK/SLP-65-deficient mice. International immunology 110 10700474
2001 Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha. European journal of immunology 106 11449366
2009 B and T lymphocyte attenuator regulates B cell receptor signaling by targeting Syk and BLNK. Journal of immunology (Baltimore, Md. : 1950) 105 19155498
2003 Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia. Nature 105 12761551
2000 The B cell-restricted adaptor BASH is required for normal development and antigen receptor-mediated activation of B cells. Proceedings of the National Academy of Sciences of the United States of America 105 10688901
2008 BLNK suppresses pre-B-cell leukemogenesis through inhibition of JAK3. Blood 99 19047679
2002 The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways. Molecular and cellular biology 92 11909947
2002 BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins. The EMBO journal 92 12456653
2007 CD303 (BDCA-2) signals in plasmacytoid dendritic cells via a BCR-like signalosome involving Syk, Slp65 and PLCgamma2. European journal of immunology 85 18022864
2003 Bruton's tyrosine kinase cooperates with the B cell linker protein SLP-65 as a tumor suppressor in Pre-B cells. The Journal of experimental medicine 84 12835482
2001 The adaptor protein BLNK is required for b cell antigen receptor-induced activation of nuclear factor-kappa B and cell cycle entry and survival of B lymphocytes. The Journal of biological chemistry 82 11274146
1998 Induction of the antigen receptor expression on B lymphocytes results in rapid competence for signaling of SLP-65 and Syk. The EMBO journal 66 9857187
1999 Cutting edge: association of phospholipase C-gamma 2 Src homology 2 domains with BLNK is critical for B cell antigen receptor signaling. Journal of immunology (Baltimore, Md. : 1950) 63 10438904
2011 The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85. The EMBO journal 60 21822214
2001 The absence of SLP65 and Btk blocks B cell development at the preB cell receptor-positive stage. European journal of immunology 53 11449370
2012 Down-regulation of B cell receptor signaling by hematopoietic progenitor kinase 1 (HPK1)-mediated phosphorylation and ubiquitination of activated B cell linker protein (BLNK). The Journal of biological chemistry 52 22334673
2001 B cell adaptor containing src homology 2 domain (BASH) links B cell receptor signaling to the activation of hematopoietic progenitor kinase 1. The Journal of experimental medicine 51 11514608
2003 Regulation of Vav localization in membrane rafts by adaptor molecules Grb2 and BLNK. Immunity 50 12818159
2001 Epstein-Barr virus latent membrane protein 2A (LMP2A) employs the SLP-65 signaling module. The Journal of experimental medicine 48 11489945
2001 Mechanisms of signaling by the hematopoietic-specific adaptor proteins, SLP-76 and LAT and their B cell counterpart, BLNK/SLP-65. Advances in immunology 48 11680012
2000 Adapter proteins SLP-76 and BLNK both are expressed by murine macrophages and are linked to signaling via Fcgamma receptors I and II/III. Proceedings of the National Academy of Sciences of the United States of America 44 10677525
2000 A BASH/SLP-76-related adaptor protein MIST/Clnk involved in IgE receptor-mediated mast cell degranulation. International immunology 40 10744659
2005 A leucine zipper in the N terminus confers membrane association to SLP-65. Nature immunology 37 15654340
2000 BLNK is associated with the CD72/SHP-1/Grb2 complex in the WEHI231 cell line after membrane IgM cross-linking. European journal of immunology 31 10820378
2000 Functional complementation of BLNK by SLP-76 and LAT linker proteins. The Journal of biological chemistry 30 10934198
2003 B cell defects in SLP65/BLNK-deficient mice can be partially corrected by the absence of CD22, an inhibitory coreceptor for BCR signaling. European journal of immunology 29 14635051
2014 The BLNK adaptor protein has a nonredundant role in human B-cell differentiation. The Journal of allergy and clinical immunology 28 24582315
2012 Identification of CMTM7 as a transmembrane linker of BLNK and the B-cell receptor. PloS one 28 22363743
2006 Bruton's tyrosine kinase and SLP-65 regulate pre-B cell differentiation and the induction of Ig light chain gene rearrangement. Journal of immunology (Baltimore, Md. : 1950) 27 16585544
2009 SLP-65 phosphorylation dynamics reveals a functional basis for signal integration by receptor-proximal adaptor proteins. Molecular & cellular proteomics : MCP 26 19372136
2004 Identification and characterization of a novel BASH N terminus-associated protein, BNAS2. The Journal of biological chemistry 24 15087455
2017 Constitutive Phosphorylation of STAT3 by the CK2-BLNK-CD5 Complex. Molecular cancer research : MCR 23 28130399
2004 Deficiency of BLNK hampers PLC-gamma2 phosphorylation and Ca2+ influx induced by the pre-B-cell receptor in human pre-B cells. Immunology 23 15270728
2009 BLNK binds active H-Ras to promote B cell receptor-mediated capping and ERK activation. The Journal of biological chemistry 21 19218240
2004 Expression of the adaptor protein BLNK/SLP-65 in childhood acute lymphoblastic leukemia. Leukemia 20 15029213
2020 Identification of BLNK and BTK as mediators of rituximab-induced programmed cell death by CRISPR screens in GCB-subtype diffuse large B-cell lymphoma. Molecular oncology 19 32585766
2015 B Cell Linker Protein (BLNK) Is a Selective Target of Repression by PAX5-PML Protein in the Differentiation Block That Leads to the Development of Acute Lymphoblastic Leukemia. The Journal of biological chemistry 19 26703467
2005 Involvement of SLP-65 and Btk in tumor suppression and malignant transformation of pre-B cells. Seminars in immunology 19 16300960
2004 Impaired receptor editing in the primary B cell repertoire of BASH-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 19 15528332
2022 Curcumin alleviates experimental colitis via a potential mechanism involving memory B cells and Bcl-6-Syk-BLNK signaling. World journal of gastroenterology 18 36353208
2008 Repression of B-cell linker (BLNK) and B-cell adaptor for phosphoinositide 3-kinase (BCAP) is important for lymphocyte transformation by rel proteins. Cancer research 18 18245482
2021 C/EBPβ induces B-cell acute lymphoblastic leukemia and cooperates with BLNK mutations. Cancer science 17 34653294
2014 Macromolecular assembly of the adaptor SLP-65 at intracellular vesicles in resting B cells. Science signaling 16 25140054
2006 Human SLP-65 isoforms contribute differently to activation and apoptosis of B lymphocytes. Blood 16 16912232
2001 Hematopoietic cell-specific adapter proteins, SLP-76 and BLNK, effectively activate NF-AT as well as NF-kappaB by Syk and Tec PTKs in non-lymphoid cell lines. FEBS letters 16 11240141
2016 Identification and characterisation of the immune response properties of Lampetra japonica BLNK. Scientific reports 15 27126461
2015 Enteroviral Infection in a Patient with BLNK Adaptor Protein Deficiency. Journal of clinical immunology 15 25893637
2007 SLP-65 signal transduction requires Src homology 2 domain-mediated membrane anchoring and a kinase-independent adaptor function of Syk. The Journal of biological chemistry 15 17681949
2001 Role of BLNK in oxidative stress signaling in B cells. Antioxidants & redox signaling 15 11813980
2020 A biophysical and structural analysis of the interaction of BLNK with 14-3-3 proteins. Journal of structural biology 14 33176192
2009 Malignant transformation of Slp65-deficient pre-B cells involves disruption of the Arf-Mdm2-p53 tumor suppressor pathway. Blood 13 20008789
2006 The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells. Oncogene 12 16568084
2006 SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells. Oncogene 12 16636677
2006 BASH-novel PKC-Raf-1 pathway of pre-BCR signaling induces kappa gene rearrangement. Blood 11 16794253
2003 Macrophage activation and Fcgamma receptor-mediated signaling do not require expression of the SLP-76 and SLP-65 adaptors. Journal of leukocyte biology 11 14694181
2022 ErbB2/Her2-dependent downregulation of a cell death-promoting protein BLNK in breast cancer cells is required for 3D breast tumor growth. Cell death & disease 10 35933456
2004 BASH-deficient mice: limited primary repertoire and antibody formation, but sufficient affinity maturation and memory B cell generation, in anti-NP response. International immunology 10 15237108
2022 B cell linker protein (BLNK) is a regulator of Met receptor signaling and trafficking in non-small cell lung cancer. iScience 9 36388990
2020 Involvement of Blnk and Foxo1 in tumor suppression in BCR‑ABL1‑transformed pro‑B cells. Oncology reports 9 33416167
2006 Phospholipase Cgamma2 dosage is critical for B cell development in the absence of adaptor protein BLNK. Journal of immunology (Baltimore, Md. : 1950) 9 16585562
2018 MicroRNA-106b overexpression alleviates inflammation injury of cardiac endothelial cells by targeting BLNK via the NF-κB signaling pathway. Journal of cellular biochemistry 8 29144032
2018 Identification and functional analysis of grouper (Epinephelus coioides) B-cell linker protein BLNK. Fish & shellfish immunology 8 30055251
2013 Cutting edge: feed-forward activation of phospholipase Cγ2 via C2 domain-mediated binding to SLP65. Journal of immunology (Baltimore, Md. : 1950) 8 24166973
2021 Silencing BLNK protects against interleukin-1β-induced chondrocyte injury through the NF-κB signaling pathway. Cytokine 7 34521030
2024 RNA tertiary structure and conformational dynamics revealed by BASH MaP. eLife 6 39625751
2024 BLNK negatively regulates innate antifungal immunity through inhibiting c-Cbl-mediated macrophage migration. Proceedings of the National Academy of Sciences of the United States of America 5 39413134
2021 Genomic DNA methylation analysis reveals that BLNK is a key potential gene in the regulation of autophagy-related thyroid cancer progression. Genome 5 33617368
2024 Quantitative description of the phase-separation behavior of the multivalent SLP65-CIN85 complex. PNAS nexus 4 38463037
2022 The RelB-BLNK Axis Determines Cellular Response to a Novel Redox-Active Agent Betamethasone during Radiation Therapy in Prostate Cancer. International journal of molecular sciences 4 35742868
2012 Highly restricted usage of Ig H chain VH14 family gene segments in Slp65-deficient pre-B cell leukemia in mice. Journal of immunology (Baltimore, Md. : 1950) 4 23066158
2006 Dual role of the adaptor protein SLP-65: organizer of signal transduction and tumor suppressor of pre-B cell leukemia. Immunologic research 4 16760574
1999 Characterization of the B cell-specific adaptor SLP-65 and other protein tyrosine kinase substrates by two-dimensional gel electrophoresis. Immunology letters 4 10397162
2022 The Small GTPase RHOA Links SLP65 Activation to PTEN Function in Pre B Cells and Is Essential for the Generation and Survival of Normal and Malignant B Cells. Frontiers in immunology 3 35371049
2020 Further delineation of primary B cell immunodeficiency caused by novel variants of the BLNK gene in two Chinese patients. Clinical immunology (Orlando, Fla.) 3 32194234
2025 Expression and regulation network of BLNK in CP/CPPS in animal, cell model and clinical samples. Inflammation 2 41003929
2024 Circ_BLNK is a Unique Molecular Marker in Non-small Cell Lung Cancer. Biochemical genetics 2 38411943
2024 Nextflow vs. plain bash: different approaches to the parallelization of SNP calling from the whole genome sequence data. NAR genomics and bioinformatics 2 38686136
2022 BLNK mutation associated with T-cell LGL leukemia and autoimmune diseases: Case report in hematology. Frontiers in medicine 2 36465938
2020 Lamprey VLRB participates in pathogen detection, VLRB/L-BLNK/L-NF-κB (B-like cells) signal transduction, and development. Fish & shellfish immunology 2 32512043
2006 The BASH/BLNK/SLP-65-associated protein BNAS1 regulates antigen-receptor signal transmission in B cells. International immunology 2 16481341
2024 RNA tertiary structure and conformational dynamics revealed by BASH MaP. bioRxiv : the preprint server for biology 1 38645201
2024 Cloud-based introduction to BASH programming for biologists. Briefings in bioinformatics 1 39041911
2010 Pre-B-cell leukemias in Btk/Slp65-deficient mice arise independently of ongoing V(D)J recombination activity. Leukemia 1 21030983
2025 SLP65/SLP76 Csk-interacting membrane protein promotes hepatic ischemia-reperfusion injury by activating TLR4/Erk1/2-mediated macrophages M1 polarization. Biochimica et biophysica acta. Molecular basis of disease 0 40403937
2025 A Novel Homozygous CGA > TGA Mutation at Codon 123 (Exon 6) of B-Linker Protein (BLNK) as a Potential Cause of ‎Hepatopathy and Rickets: A Case Report. Iranian journal of immunology : IJI 0 40546005
2022 A Novel BLNK Gene Mutation in a Four-Year-Old Child Who Presented with Late Onset of Severe Infections and High IgM Levels and Diagnosed and Followed as X-Linked Agammaglobulinemia for Two Years. Case reports in immunology 0 35719418
2006 Double knockout mice show BASH and PKCdelta have different epistatic relationships in B cell maturation and CD40-mediated activation. Immunology letters 0 16481047

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