Affinage

BLNK

B-cell linker protein · UniProt Q8WV28

Length
456 aa
Mass
50.5 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BLNK (also known as SLP-65/BASH) is a central scaffolding adaptor protein in B cell receptor (BCR) signaling that coordinates activation of multiple downstream effector pathways essential for B cell development, activation, and tumor suppression. Upon BCR engagement, BLNK is recruited to the plasma membrane via its SH2 domain binding to phospho-Tyr204 of Igα and is phosphorylated on multiple tyrosines by Syk, creating docking sites that nucleate a macromolecular signaling complex containing PLCγ2 (via SH2 and Ca²⁺-regulated C2 domain interactions), Btk (facilitating Syk-dependent Btk Tyr551 phosphorylation), Vav/Grb2 (directing Rac1 activation at membrane rafts), H-Ras (sustaining ERK signaling), and HPK1 (mediating negative feedback through Thr152 phosphorylation, 14-3-3 binding, and ubiquitin-proteasomal degradation of BLNK) (PMID:9697839, PMID:10438904, PMID:11226282, PMID:12818159, PMID:19218240, PMID:22334673, PMID:24166973). BLNK preassembles with CIN85 as a phase-separated condensate on intracellular vesicles in resting B cells through multivalent proline-rich motif–SH3 domain interactions, and its N-terminal lipid-binding module directs vesicular localization that is prerequisite for signal transduction (PMID:25140054, PMID:21822214, PMID:38463037). Loss-of-function mutations in human BLNK cause agammaglobulinemia with a block at the pro-B to pre-B cell transition, and BLNK acts as a tumor suppressor in pre-B cells by directly inhibiting JAK3/STAT5 signaling and activating the RHOA–PTEN axis to counteract PI3K, thereby promoting Foxo-dependent immunoglobulin light chain recombination and limiting leukemogenic proliferation (PMID:10583958, PMID:12436112, PMID:19047679, PMID:18488031, PMID:35371049). Beyond B cells, Syk-phosphorylated BLNK in macrophages competitively disrupts the Fyn–c-Cbl interaction to inhibit podosome formation and migration (PMID:39413134).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 High

    The identification of BLNK as a Syk substrate that docks PLCγ, Vav, Grb2, and Nck established that a single adaptor protein bridges BCR-proximal kinase signaling to multiple effector pathways, resolving how Syk communicates with diverse downstream targets.

    Evidence Biochemical purification, reciprocal Co-IP, and tyrosine phosphorylation mapping in B cell lines

    PMID:9697839 PMID:9705962

    Open questions at the time
    • Specific phosphotyrosine–effector assignments not yet mapped
    • In vivo requirement not yet tested
  2. 1999 High

    Genetic studies in BLNK-knockout mice and a human patient with BLNK splice-site mutation demonstrated that BLNK is non-redundantly required for the pro-B to pre-B cell transition, establishing it as essential for early B cell development and a cause of human agammaglobulinemia.

    Evidence BLNK knockout mouse phenotyping by flow cytometry; human patient genetic and immunophenotypic analysis

    PMID:10583957 PMID:10583958

    Open questions at the time
    • Downstream signaling events mediating the developmental block not yet dissected
    • Whether BLNK has roles beyond early B cell development unknown
  3. 1999 High

    Reconstitution experiments in BLNK-deficient DT40 cells showed that BLNK controls PLCγ2 activation by directing its membrane localization and that BLNK scaffolds the Btk–PLCγ2 axis, resolving the mechanism by which the BCR activates phospholipase C.

    Evidence Membrane-targeted PLCγ2 rescue in BLNK-deficient DT40 cells; PLCγ2 SH2 domain mutagenesis; Btk-SH2/BLNK binding assays

    PMID:10023776 PMID:10438904 PMID:10498607

    Open questions at the time
    • Whether PLCγ2 engagement involves additional regulatory domains beyond SH2 not yet known
    • Stoichiometry of the BLNK–Btk–PLCγ2 complex undefined
  4. 2001 High

    Mapping of the BLNK–Igα interaction to phospho-Tyr204 (a non-ITAM tyrosine) via the BLNK SH2 domain resolved how BLNK is recruited to the BCR complex, establishing a mechanism distinct from classical ITAM-dependent signaling.

    Evidence Direct binding assays with phospho-peptides, Igα mutagenesis, chimeric receptor reconstitution

    PMID:11449366 PMID:11909947

    Open questions at the time
    • How Tyr204 phosphorylation is itself regulated was unknown
    • Whether additional BCR subunit contacts contribute to BLNK recruitment not tested
  5. 2001 High

    Demonstration that BLNK scaffolds Syk-dependent phosphorylation of Btk at Tyr551 and that BLNK is required for NF-κB activation and cell cycle entry clarified that BLNK integrates BCR signals for both Ca²⁺ and NF-κB/survival pathways.

    Evidence Reconstitution/kinase assays in BLNK-deficient cells; NF-κB, cyclin D2, and Bcl-xL readouts in BLNK-KO B cells

    PMID:11226282 PMID:11274146 PMID:11514608

    Open questions at the time
    • Precise mechanism linking BLNK to IKK activation via HPK1 not fully resolved
    • Whether BLNK-independent NF-κB pathways compensate in vivo unknown
  6. 2002 High

    Systematic tyrosine mutagenesis of five BLNK phosphosites revealed that distinct phosphotyrosines nucleate different effector combinations, establishing a combinatorial phosphorylation code that amplifies PLCγ signaling through cis-interactions within a macromolecular complex.

    Evidence Individual and combinatorial Tyr-to-Phe mutagenesis with functional reconstitution in BLNK-deficient cells

    PMID:12456653

    Open questions at the time
    • Which kinase phosphorylates each individual tyrosine not fully determined
    • Temporal order of phosphorylation events unresolved
  7. 2002 High

    Discovery that SLP-65 deficiency leads to pre-B cell lymphoma and that its reintroduction restores differentiation established BLNK as a tumor suppressor, linking its signaling scaffold function to control of pre-B cell proliferation.

    Evidence SLP-65 knockout mouse tumor incidence, ex vivo proliferation assays, retroviral reconstitution

    PMID:12436112

    Open questions at the time
    • Molecular mechanism of tumor suppression not yet identified
    • Whether tumor suppression is cell-autonomous not fully confirmed
  8. 2003 High

    Showing that BLNK and Grb2 cooperate to relocalize Vav3 into membrane rafts for Rac1 activation clarified how BLNK couples BCR signaling to cytoskeletal and JNK pathways through spatial control of a GEF.

    Evidence Raft fractionation and raft-targeted Vav3 rescue in BLNK- and Grb2-deficient DT40 cells

    PMID:12818159

    Open questions at the time
    • Whether Vav1/Vav2 are similarly regulated by BLNK not tested
    • In vivo relevance of raft targeting for B cell function not established
  9. 2005 High

    Identification of a leucine zipper-like N-terminal module as the autonomous membrane-targeting domain of SLP-65 resolved how this cytosolic adaptor achieves membrane association independently of BCR stimulation.

    Evidence N-terminal deletion/substitution mutagenesis with GFP localization and functional reconstitution in SLP-65-deficient cells

    PMID:15654340

    Open questions at the time
    • Lipid specificity of the N-terminal module not yet defined
    • Whether membrane targeting occurs at plasma membrane or intracellular vesicles not distinguished
  10. 2008 High

    Identification of direct BLNK–JAK3 binding and demonstration that BLNK inhibits JAK3/STAT5 signaling provided the molecular mechanism for BLNK's tumor suppressor function, explaining how its loss leads to constitutive proliferative signaling in pre-B cells.

    Evidence Co-IP, JAK3 kinase assays, JAK3 inhibitor treatment, and retroviral BLNK reconstitution in leukemia cells

    PMID:19047679

    Open questions at the time
    • Structural basis of BLNK–JAK3 inhibition unknown
    • Whether JAK3 inhibition is the sole tumor-suppressive mechanism not determined
  11. 2008 High

    Linking SLP-65 to the PI3K–PKB–Foxo axis showed that BLNK counteracts PKB to promote Foxo-dependent light chain recombination, connecting the scaffold's signaling role to V(D)J recombination and B cell differentiation.

    Evidence SLP-65 reconstitution in deficient pre-B cells with PKB inhibitor epistasis and Foxo reporter assays

    PMID:18488031

    Open questions at the time
    • How SLP-65 inhibits PI3K/PKB mechanistically not fully resolved
    • Relative contributions of Foxo1 versus Foxo3a not distinguished
  12. 2009 High

    Discovery that the SLP-65/CIN85 complex is constitutively preassembled in resting B cells and is required for subsequent BCR-induced membrane translocation and signaling revealed that BLNK operates from a pre-organized signaling platform rather than being assembled de novo upon stimulation.

    Evidence Quantitative mass spectrometry interactome, FRAP live imaging, CIN85-deficient cell functional analysis

    PMID:21822214

    Open questions at the time
    • Subcellular identity of the pre-formed complex compartment not defined
    • How BCR engagement triggers translocation of the preassembled complex unknown
  13. 2012 High

    Characterization of HPK1-mediated Thr152 phosphorylation leading to 14-3-3 binding and ubiquitin-proteasomal degradation of BLNK defined a negative feedback loop that terminates BCR signaling, answering how BLNK activity is extinguished.

    Evidence In vitro kinase assays, Thr152 mutagenesis, ubiquitination site mapping, HPK1-deficient B cell analysis

    PMID:22334673

    Open questions at the time
    • Identity of the E3 ubiquitin ligase targeting BLNK not determined
    • Kinetics of degradation versus dephosphorylation not compared
  14. 2013 High

    Demonstrating that the PLCγ2 C2 domain docks to a phospho-SLP-65 site in a Ca²⁺-dependent manner established a feed-forward amplification loop: initial Ca²⁺ release reinforces PLCγ2 anchoring, while Ca²⁺ decline terminates the interaction regardless of sustained phosphorylation.

    Evidence C2 domain mutagenesis, Ca²⁺-regulated binding assays, functional reconstitution

    PMID:24166973

    Open questions at the time
    • Whether the C2 domain interaction is the dominant mechanism of PLCγ2 signal termination not established
    • Structural basis of Ca²⁺-regulated docking not resolved
  15. 2014 High

    NMR characterization showed that the SLP-65 N-terminus undergoes a disorder-to-order transition upon binding non-charged vesicle lipids, localizing SLP-65 to intracellular vesicles in resting cells and resolving the pre-stimulation compartment of the signaling scaffold.

    Evidence NMR spectroscopy with lipid vesicles, live cell imaging, mutagenesis with functional reconstitution

    PMID:25140054

    Open questions at the time
    • Specific lipid species mediating vesicular targeting not identified
    • How vesicle-to-plasma-membrane transfer occurs upon BCR engagement not resolved
  16. 2020 High

    Crystal structure of the BLNK pThr152 peptide bound to 14-3-3σ and biophysical characterization of cooperativity with AKT-mediated pSer285 provided the structural basis for the gatekeeper model of BLNK negative regulation.

    Evidence X-ray crystallography, fluorescence polarization, isothermal titration calorimetry

    PMID:33176192

    Open questions at the time
    • Full-length BLNK structure in complex with 14-3-3 not determined
    • In vivo significance of pSer285 cooperativity not tested
  17. 2022 High

    Placing SLP-65 upstream of a RHOA–PTEN axis that counteracts PI3K in pre-B cells provided a second tumor-suppressive mechanism complementary to JAK3 inhibition, explaining how BLNK controls the PI3K–Foxo balance for light chain recombination.

    Evidence Conditional RhoA knockout mice, PTEN membrane translocation assays, reconstitution in RhoA-deficient cells

    PMID:35371049

    Open questions at the time
    • Direct physical link between SLP-65 and RHOA activation not identified
    • Whether RHOA-PTEN and JAK3 inhibition act redundantly or synergistically in tumor suppression unknown
  18. 2024 High

    Thermodynamic dissection of SLP-65/CIN85 multivalent interactions demonstrated that 18 individual SH3–PRM contacts drive liquid–liquid phase separation at vesicles, providing a quantitative biophysical framework for how the preassembled signaling scaffold forms.

    Evidence Individual Kd measurements for all PRM/SH3 pairs, LASSI computational modeling of phase separation, designer-construct phase separation assays

    PMID:38463037

    Open questions at the time
    • Whether phase separation is required for signaling or is a byproduct of multivalency not functionally tested
    • How BCR stimulation modulates condensate properties unknown
  19. 2024 High

    Extension of BLNK function beyond B cells to macrophages showed that Syk-phosphorylated BLNK disrupts Fyn–c-Cbl interaction to inhibit podosome formation and migration, revealing a broader innate immune role.

    Evidence Monocyte-specific conditional BLNK knockout mice, Co-IP, podosome and migration assays, Candida infection model

    PMID:39413134

    Open questions at the time
    • Whether BLNK functions in other myeloid or non-hematopoietic cells in vivo remains open
    • Structural basis of BLNK–c-Cbl competition with Fyn not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of BLNK, how BCR engagement triggers translocation of the vesicular SLP-65/CIN85 condensate to the plasma membrane, the identity of the E3 ligase mediating BLNK ubiquitination, and the relative contributions of JAK3 inhibition versus RHOA-PTEN activation to tumor suppression.
  • No full-length BLNK structure available
  • Mechanism of condensate-to-membrane translocation undefined
  • E3 ubiquitin ligase for BLNK not identified
  • Functional integration of multiple tumor-suppressive mechanisms not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 6 R-HSA-1643685 Disease 2
Partners
BTKCIN85GRB2HPK1JAK3PLCG2SYKVAV3
Complex memberships
BCR signalosomeSLP-65/CIN85 vesicular condensate

Evidence

Reading pass · 36 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 Grb2 and Nck adapter proteins. Tyrosine phosphorylation of BLNK by Syk provides docking sites for these SH2-containing effector molecules. Biochemical identification, Co-immunoprecipitation, tyrosine phosphorylation assays Immunity High 9697839
1998 SLP-65/BLNK is a BCR signaling component that becomes tyrosine-phosphorylated upon BCR stimulation only when the BCR is expressed on the cell surface, and forms a signaling complex with Grb2 and Vav; phosphorylation requires BCR expression and is downstream of the BCR signaling subunit. Biochemical characterization, Co-immunoprecipitation, pervanadate stimulation assays The Journal of experimental medicine High 9705962
1999 BLNK is required for BCR-induced PLCγ2 activation and JNK activation in B cells. The BCR-induced PLCγ2 activation (but not JNK activation) was restored by membrane-targeted PLCγ2 in BLNK-deficient B cells, indicating BLNK modulates PLCγ2 localization. JNK activation requires both Rac1 and PLCγ2, placing BLNK upstream of the Rac1-JNK pathway. Genetic reconstitution in BLNK-deficient DT40 B cells, membrane-targeted PLCγ2 rescue experiments Immunity High 10023776
1999 BLNK is required in vivo for the pro-B to pre-B cell transition; BLNK-deficient mice are blocked at the B220+CD43+ progenitor B to B220+CD43- precursor B cell stage. BLNK links BCR-activated Syk kinase to the phosphoinositide and mitogen-activated kinase pathways. BLNK knockout mouse generation, flow cytometry of bone marrow B cell populations Science High 10583957
1999 Loss-of-function splice defect in human BLNK causes a block at the pro-B to pre-B cell transition, establishing an essential non-redundant role of BLNK in human B cell development. Patient genetic analysis, bone marrow immunophenotyping Science High 10583958
1999 BLNK was identified as a major SH2 domain-binding protein of Bruton's tyrosine kinase (Btk); the interaction of BLNK with the SH2 domain of Btk contributes to complete tyrosine phosphorylation of PLCγ in BCR signaling. Protein purification, Co-immunoprecipitation, in vitro binding assays Blood High 10498607
1999 The N-terminal SH2 domain of PLCγ2 mediates association with BLNK, and this interaction is required for inositol 1,4,5-trisphosphate generation upon BCR engagement; membrane-associated PLCγ2 with SH2(N) mutation still required BCR-CD16 co-ligation for activation, indicating BLNK directs PLCγ2 into proximity of the BCR signaling complex. Reconstitution in PLCγ2-deficient DT40 cells with SH2 domain mutants, IP3 generation assays Journal of immunology High 10438904
2001 BLNK mediates Syk-dependent Btk activation: BLNK allows Syk to phosphorylate Btk on tyrosine 551, enhancing Btk kinase activity. This requires the Btk-SH2 domain interaction with BLNK, and BCR-induced Btk phosphorylation and activation are significantly reduced in BLNK-deficient B cells. Reconstitution cell system, co-expression assays, phosphorylation analysis in BLNK-deficient cells, kinase activity assays Proceedings of the National Academy of Sciences of the United States of America High 11226282
2001 BLNK associates directly with the BCR signaling subunit Igα/Igβ heterodimer; this interaction is mediated by the SH2 domain of SLP-65 and the phosphorylated Igα tyrosine 204, which is located outside the ITAM, providing a mechanism for SLP-65 recruitment to the plasma membrane. Co-immunoprecipitation, direct binding assays with phospho-peptides, mutational analysis of Igα European journal of immunology High 11449366
2001 BLNK is required for BCR-activated NF-κB activation, cell cycle entry (cyclin D2, CDK4 expression), and Bcl-xL upregulation. BLNK-deficient B cells show intact Akt and MAPK activation but impaired PLCγ2 and NF-κB activation, suggesting BLNK orchestrates a Btk-PLCγ2 signaling axis that regulates NF-κB. BLNK-knockout B cells, proliferation assays, Western blotting for cell cycle proteins and NF-κB pathway components The Journal of biological chemistry High 11274146
2002 The non-ITAM tyrosines Y176 and Y204 of Igα are required for BLNK-dependent signaling pathways; BLNK binds directly to phospho-Y204 of Igα. Fusing BLNK to mutated Igα reconstituted downstream signaling, and BCR ligation induces Y204 phosphorylation and BLNK recruitment. Chimeric receptor reconstitution, mutational analysis of Igα, direct binding assays, Co-immunoprecipitation Molecular and cellular biology High 11909947
2002 Phosphorylation of five tyrosine residues within human BLNK nucleates distinct signaling effectors following BCR activation. Multiple tyrosine phosphorylations amplify PLCγ-mediated signaling and support 'cis'-mediated interaction between distinct signaling effectors within a large macromolecular complex. Mutagenesis of BLNK tyrosines, reconstitution in BLNK-deficient cells, biochemical analysis The EMBO journal High 12456653
2002 BLNK is a direct transcriptional target of Pax5 (BSAP); Pax5-dependent activation of BLNK expression is required for coupling Syk to downstream effector pathways during the pro-B to pre-B cell transition triggered by pre-BCR signaling. Genetic reconstitution of BLNK in Pax5-/- pro-B cells, inducible BLNK-ER fusion protein, gene expression analysis Immunity High 12387741
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 high incidence of pre-B lymphoma; reintroduction of SLP-65 led to pre-BCR downregulation and enhanced differentiation. SLP-65-/- mouse analysis, ex vivo proliferation assays, retroviral reconstitution Nature immunology High 12436112
2001 BASH/BLNK SH2 domain interacts with hematopoietic progenitor kinase 1 (HPK1) upon BCR ligation through binding to phospho-Tyr379 of HPK1 (phosphorylated by Syk). This interaction activates HPK1 catalytically and subsequently activates IKKβ, defining a BCR signaling pathway from BASH to HPK1 to NF-κB. Co-immunoprecipitation, kinase activation assays, BASH- and Syk-deficient B cell analysis, mutational analysis The Journal of experimental medicine High 11514608
2003 BLNK and Grb2 cooperate to localize Vav3 into membrane rafts, which is required for efficient Rac1 activation upon BCR stimulation. Loss of either Grb2 or BLNK reduces Vav3 translocation to rafts; raft-targeted Vav3 restores defective Rac1 activation in Grb2- or BLNK-deficient cells. Membrane raft fractionation, epistasis via raft-targeted Vav3 rescue in BLNK/Grb2-deficient B cells Immunity High 12818159
2005 A leucine zipper motif in the N-terminus of SLP-65 is responsible for its membrane association. Mutations in the N-terminus abolished SLP-65 membrane localization and activity; replacement with a myristoylation signal restored both. The N-terminus is a transferable autonomous domain that confers specific localization. Mutational analysis of SLP-65 N-terminus, GFP fusion localization, functional reconstitution in SLP-65-deficient cells 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, placing Syk both upstream and downstream of SLP-65. Mutational analysis in DT40 B cells; reconstitution of SLP-65 in SLP-76-deficient T cells; genetic epistasis The Journal of biological chemistry High 17681949
2008 BLNK suppresses pre-B cell leukemogenesis through direct physical binding to JAK3, inhibiting JAK3/STAT5 signaling and autocrine IL-7-driven proliferation. BLNK deficiency leads to constitutive JAK3/STAT5 activation; exogenous BLNK inhibited JAK3 activity dependent on the BLNK-JAK3 interaction. Co-immunoprecipitation, JAK3 kinase assays, JAK3 inhibitor treatment, STAT5-CA transgenic mouse, retroviral BLNK reconstitution in leukemia cells Blood High 19047679
2008 SLP-65 counteracts PKB activation and promotes Foxo3a and Foxo1 activity in pre-B cells, thereby regulating light chain recombination. SLP-65-dependent signaling is linked to the PI(3)K-PKB-Foxo pathway, wherein PKB suppresses light chain recombination by phosphorylating Foxo proteins. Reconstitution of SLP-65 in deficient cells, epistasis with PKB inhibitors, Foxo reporter assays Nature immunology High 18488031
2009 The SLP-65/CIN85 complex is constitutively (stimulation-independently) associated in resting B cells. This pre-formed complex is required for SLP-65 phosphorylation and inducible plasma membrane translocation. In the absence of a SLP-65/CIN85 complex, BCR-induced Ca2+ and NF-κB responses are abrogated. Quantitative mass spectrometry interactome, live cell imaging (FRAP), Co-immunoprecipitation, CIN85-deficient cell analysis The EMBO journal High 21822214
2009 Mass spectrometry-based phosphoproteomics of SLP-65 revealed differential and dynamic engagement of numerous phospho-acceptor sites, including constitutive and BCR-induced phosphorylations. Serine 170 phosphorylation of SLP-65 acts as a BCR-distal checkpoint controlling some but not all B cell responses. Mass spectrometric phosphorylation mapping on DT40 cells, mutational analysis of phospho-sites with functional readouts Molecular & cellular proteomics : MCP High 19372136
2009 BLNK binds the active (GTP-bound) form of H-Ras through a 10-amino acid Ras-binding domain. This interaction, facilitated by BCR cross-linking, is required for sustained ERK activation and BCR capping. The Ras-binding domain is necessary for restoring ERK activation and anti-apoptotic signaling in BLNK-deficient B cells. Pulldown assays, mutational analysis of BLNK Ras-binding domain, reconstitution in BLNK-deficient cells, BCR capping assay The Journal of biological chemistry High 19218240
2011 CMTM7, a tetra-spanning membrane protein, co-localizes with sIgM at the plasma membrane and links sIgM to BLNK. CMTM7 knockdown impairs BLNK-Syk interaction and BLNK phosphorylation. CMTM7 is constitutively associated with sIgM, and this is required for BLNK recruitment to sIgM. RNAi knockdown, Co-immunoprecipitation, mutational analysis of CMTM7 domains, functional rescue experiments PloS one High 22363743
2012 HPK1 phosphorylates BLNK at threonine 152, which mediates BLNK/14-3-3 binding. Thr152-phosphorylated BLNK is then ubiquitinated at lysines 37, 38, and 42, leading to BLNK degradation and attenuation of MAPK and IKK activation during BCR signaling (negative feedback). Kinase assays, site-directed mutagenesis, ubiquitination assays, HPK1-deficient B cell analysis, Co-immunoprecipitation The Journal of biological chemistry High 22334673
2013 The C2 domain of PLCγ2 docks in a Ca2+-regulated manner to a distinct phosphotyrosine of SLP-65, providing feed-forward signal amplification: early Ca2+ flux promotes anchoring of the PLCγ2 C2 domain to phospho-SLP65, and declining Ca2+ terminates PLCγ2 activation despite sustained SLP65 phosphorylation. Mutational analysis of PLCγ2 C2 domain, Ca2+-regulated binding assays, Co-immunoprecipitation, functional reconstitution Journal of immunology High 24166973
2014 SLP-65 assembles at intracellular vesicular compartments in resting B cells through an ~50 amino acid N-terminal module that binds non-charged lipid components of cellular membranes in a structurally ordered manner (disordered in solution). Pre-formed vesicular signaling scaffolds are required for BCR activation. NMR spectroscopy of SLP-65 N-terminus with membrane lipids, live cell imaging, fractionation, mutational analysis Science signaling High 25140054
2020 The 14-3-3/BLNK interaction follows a gatekeeper model: HPK1-mediated phosphorylation of Thr152 (pT152) anchors BLNK to 14-3-3, and additional phosphorylation of Ser285 by AKT further improves affinity. Crystal structure of BLNKpT152 peptide bound to 14-3-3σ was solved. Fluorescent polarization, isothermal titration calorimetry, X-ray crystallography of BLNK peptide/14-3-3σ complex Journal of structural biology High 33176192
2024 SLP65 and CIN85 form phase-separated condensates at intracellular vesicles in resting B cells via multivalent interactions (6 proline-rich motifs of SLP65 engaging 3 SH3 domains of CIN85, establishing 18 individual SH3-PRM interactions). Thermodynamic characterization of individual PRM/SH3 interactions allowed modeling of phase-separation behavior, and a previously unknown intramolecular interaction within the system was discovered. Biophysical measurement of individual dissociation constants, LASSI computational modeling, phase-separation assays with designer constructs PNAS nexus High 38463037
2024 In macrophages, CLR (C-type lectin receptor)-activated Syk phosphorylates BLNK, which then associates with c-Cbl and competitively inhibits the Fyn-c-Cbl interaction, disrupting c-Cbl-associated F-actin assembly and podosome ring formation, thereby impeding macrophage migration. BLNK deficiency in monocytes enhances migration and resistance to Candida albicans infection. Co-immunoprecipitation, monocyte-specific BLNK conditional KO mice, podosome assays, migration assays, murine infection model Proceedings of the National Academy of Sciences of the United States of America High 39413134
2022 In breast cancer cells, BLNK promotes anoikis (detachment-induced cell death) by activating p38 MAP kinase. ErbB2 blocks BLNK upregulation upon ECM detachment by reducing IRF6 transcription factor levels. Bortezomib upregulates IRF6 and BLNK, inhibiting 3D tumor growth in a BLNK-dependent manner. siRNA knockdown, anoikis assays, p38 kinase pathway analysis, IRF6 manipulation, xenograft tumor assays Cell death & disease Medium 35933456
2022 BLNK interacts with Met receptor in non-small cell lung cancer cells, positively regulates Met signaling, and modulates ligand-dependent trafficking of Met. The BLNK-GRB2 constitutive interaction is increased in the presence of active Met, and Met-GRB2 interaction is increased in the presence of BLNK. Mammalian Membrane Two-Hybrid (MaMTH) interactome mapping, Co-immunoprecipitation, siRNA knockdown, trafficking and functional assays iScience Medium 36388990
2017 In CLL cells, BLNK participates in a CK2-CD5-BLNK-STAT3 complex that mediates constitutive serine 727 phosphorylation of STAT3. BLNK and CD5 are both required for STAT3 phosphorylation; siRNA knockdown of CD5 or BLNK significantly reduced pSTAT3 levels. Mass spectrometry identification of CK2 as STAT3 co-immunoprecipitant, in vitro CK2 kinase assay on STAT3, siRNA knockdown, fractionation studies, confocal microscopy Molecular cancer research : MCR Medium 28130399
2000 Neither SLP-76 nor LAT alone is sufficient to restore signaling deficits in BLNK-deficient B cells, but co-expression of SLP-76 and LAT together restores BCR-inducible calcium responses and activation of all three MAPK families, demonstrating functional complementation. Reconstitution of SLP-76 and LAT in BLNK-deficient B cells, Ca2+ flux assays, MAPK activation assays The Journal of biological chemistry High 10934198
2006 SLP-65 promotes B cell differentiation via a BASH-nPKC-Raf-1 pathway that induces kappa light chain gene rearrangement. Pre-BCR signaling through BASH activates novel PKC (nPKC) and MEK but not Ras; PKCη translocates to the plasma membrane upon BASH reconstitution. BASH-deficient pre-B cell lines, specific kinase inhibitors, retroviral transduction of active PKC/Raf-1, tamoxifen-inducible BASH reconstitution Blood High 16794253
2022 SLP65 activates the small GTPase RHOA, which activates PTEN by enabling its translocation to the plasma membrane, thereby counteracting PI3K signaling in pre-B cells. Conditional RhoA-deficient mice show a complete block in early B cell development and fail to activate Ig gene rearrangement. Conditional RhoA knockout mice, PTEN membrane translocation assays, RhoA/Foxo1 reconstitution in RhoA-deficient cells, flow cytometric phenotyping Frontiers in immunology High 35371049

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 424 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 128 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 112 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
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
2009 B and T lymphocyte attenuator regulates B cell receptor signaling by targeting Syk and BLNK. Journal of immunology (Baltimore, Md. : 1950) 103 19155498
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 84 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 83 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 59 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
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
2017 Constitutive Phosphorylation of STAT3 by the CK2-BLNK-CD5 Complex. Molecular cancer research : MCR 22 28130399
2009 BLNK binds active H-Ras to promote B cell receptor-mediated capping and ERK activation. The Journal of biological chemistry 21 19218240
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 Expression of the adaptor protein BLNK/SLP-65 in childhood acute lymphoblastic leukemia. Leukemia 19 15029213
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
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 18 32585766
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
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
2021 C/EBPβ induces B-cell acute lymphoblastic leukemia and cooperates with BLNK mutations. Cancer science 15 34653294
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
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
2003 Macrophage activation and Fcgamma receptor-mediated signaling do not require expression of the SLP-76 and SLP-65 adaptors. Journal of leukocyte biology 10 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 9 35933456
2020 Involvement of Blnk and Foxo1 in tumor suppression in BCR‑ABL1‑transformed pro‑B cells. Oncology reports 9 33416167
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
2006 Phospholipase Cgamma2 dosage is critical for B cell development in the absence of adaptor protein BLNK. Journal of immunology (Baltimore, Md. : 1950) 8 16585562
2022 B cell linker protein (BLNK) is a regulator of Met receptor signaling and trafficking in non-small cell lung cancer. iScience 7 36388990
2024 RNA tertiary structure and conformational dynamics revealed by BASH MaP. eLife 6 39625751
2021 Silencing BLNK protects against interleukin-1β-induced chondrocyte injury through the NF-κB signaling pathway. Cytokine 6 34521030
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
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
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 3 35742868
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