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Showing LCP2 — SLP76 is a alias.

LCP2

Lymphocyte cytosolic protein 2 · UniProt Q13094

Length
533 aa
Mass
60.2 kDa
Annotated
2026-06-10
100 papers in source corpus 56 papers cited in narrative 56 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

LCP2 (SLP-76) is a hematopoietic-specific cytosolic scaffolding adaptor that nucleates the signaling complex coupling ITAM-bearing immunoreceptors to the actin cytoskeleton, calcium flux, and transcriptional activation (PMID:7706237, PMID:9665884). It is organized into three functional modules: an N-terminal acidic region whose tyrosines (Y113, Y128, Y145) are phosphorylated by ZAP-70 (and Syk in non-T lineages) upon receptor ligation (PMID:8702662, PMID:8892604, PMID:9047237), a central proline-rich region, and a C-terminal SH2 domain, each mediating distinct interactions required for downstream signaling (PMID:9257823). Phosphorylation of the N-terminal tyrosines creates docking sites for the GEF Vav1/Vav3 and the adaptor Nck, assembling a trimolecular complex of defined stoichiometry that drives PAK1 activation and Arp2/3-dependent actin polymerization through Nck-WASP and Fyb/SLAP-Ena/VASP branches (PMID:9846482, PMID:10747096, PMID:20562827, PMID:22534133). SLP-76 is recruited to the membrane and lipid-raft microdomains via a constitutive, non-canonical high-affinity R-X-X-K motif (R237/K240) that binds the Gads C-terminal SH3 domain, which in turn bridges SLP-76 to tyrosine-phosphorylated LAT—an interaction structurally resolved as a 3(10)-helix inserting into the SH3 domain and genetically required for thymocyte signaling (PMID:10021361, PMID:11239162, PMID:12176364, PMID:12773374). The proline-rich P-1 domain directly engages the PLC-γ1 SH3 domain, and together with N-terminal-tyrosine-dependent recruitment of active ITK, SLP-76 enables PLC-γ1 Y783 phosphorylation, calcium mobilization, and NFAT/ERK activation (PMID:11390650, PMID:17420479, PMID:17148460). Its SH2 domain additionally recruits ADAP for integrin inside-out and outside-in signaling (PMID:19667077, PMID:22291096). SLP-76 activity is restrained by SHP-1-mediated dephosphorylation and by an HPK1-driven negative-feedback loop in which S376 phosphorylation recruits 14-3-3 and triggers K30 ubiquitination and proteasomal degradation (PMID:9765283, PMID:17353368, PMID:22902619). Genetic ablation establishes SLP-76 as essential for pre-TCR-driven thymocyte development (PMID:9665885, PMID:9695951, PMID:10523607), collagen- and CLEC-2-dependent platelet function and blood-lymphatic vascular separation (PMID:9884330, PMID:12522250, PMID:20363774), FcεRI-mediated mast cell degranulation (PMID:10377180, PMID:16479002), and Fcγ-receptor and integrin signaling in neutrophils (PMID:14614862, PMID:22291096).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1995 High

    Established the existence and basic architecture of SLP-76 as a hematopoietic adaptor, answering whether a dedicated SH2-containing linker connects tyrosine kinases to Grb2 and PLC-γ1.

    Evidence Molecular cloning with GST pulldown, in vitro translation, and co-IP in Jurkat lysates

    PMID:7706237

    Open questions at the time
    • Did not place SLP-76 in a receptor signaling pathway
    • Upstream kinase unidentified
  2. 1996 High

    Identified ZAP-70 as the kinase phosphorylating SLP-76 and mapped the functionally critical N-terminal tyrosines, defining how receptor proximal kinases activate the adaptor.

    Evidence In vitro kinase assays, dominant-negative ZAP-70, site-directed mutagenesis (Y113/Y128/Y145), and NFAT/IL-2 reporter assays in T cell lines

    PMID:8666952 PMID:8702662 PMID:8892604

    Open questions at the time
    • Did not identify all phosphotyrosine-binding partners
    • Membrane recruitment mechanism unresolved
  3. 1996 High

    Linked phosphorylated SLP-76 to the Rho-GEF Vav, establishing a route from the adaptor to cytoskeletal and transcriptional control.

    Evidence Co-IP with Vav SH2 mutants and synergistic NF-AT/IL-2 reporter activation

    PMID:8673706 PMID:8703037

    Open questions at the time
    • Exact tyrosines mediating Vav binding not yet mapped
    • Functional consequence for actin not yet shown
  4. 1997 High

    Mapped Vav SH2 binding to phospho-Y113/Y128 and assigned ZAP-70 (not Lck/Fyn) as the responsible kinase, defining the molecular specificity of complex assembly.

    Evidence In vitro kinase assays, phosphopeptide competition, and co-IP with domain dissection

    PMID:9047237 PMID:9257823

    Open questions at the time
    • Role of Y145 and its binding partner unresolved
    • Calcium pathway coupling not yet explained
  5. 1998 High

    Demonstrated by loss-of-function that SLP-76 is genetically required to couple TCR kinases to PLC-γ1/Ras and to thymocyte development, moving it from a positive regulator to an essential node.

    Evidence SLP-76-deficient T cell line reconstitution and knockout mice with thymic and hemorrhage phenotypes

    PMID:9665884 PMID:9665885 PMID:9695951

    Open questions at the time
    • Mechanism of PLC-γ1 activation not biochemically defined
    • Cause of hemorrhage not identified
  6. 1998 High

    Resolved how SLP-76 drives actin remodeling by showing it assembles a Nck-Vav trimolecular complex activating PAK1 and actin polymerization.

    Evidence Co-IP, actin polymerization and PAK1 kinase assays with dominant-negative constructs

    PMID:9846482

    Open questions at the time
    • Effectors downstream of Nck not yet defined
    • Stoichiometry of the complex unknown
  7. 1998 High

    Identified SHP-1 as a phosphatase that directly dephosphorylates SLP-76, establishing the first negative-regulatory mechanism and linking it to KIR-mediated inhibition.

    Evidence In vitro phosphatase and binding assays plus cytotoxicity readouts in T/NK cells

    PMID:9765283

    Open questions at the time
    • Constitutive vs inducible association context partly unresolved
    • Other phosphatases not excluded
  8. 1999 High

    Defined the SLP-76/LAT bridge by showing Gads constitutively binds SLP-76's proline-rich region and links it to phospho-LAT, explaining membrane recruitment.

    Evidence Co-IP, domain mutants, and NFAT reporter assays

    PMID:10021361

    Open questions at the time
    • Affinity and structural basis of Gads binding not yet quantified
    • Other proline-rich partners not characterized
  9. 1999 High

    Extended SLP-76 function beyond T cells, establishing it as a Syk-dependent regulator of PLC-γ2 in platelets and PLC-γ1 in mast cells with defined physiological phenotypes.

    Evidence Syk- and SLP-76-deficient platelets and mast cells with aggregation, granule release, calcium, and phospho-PLC readouts

    PMID:10026222 PMID:10377180 PMID:9884330

    Open questions at the time
    • Receptor identity in collagen response not fully defined here
    • Cross-lineage adaptor differences unresolved
  10. 1999 Medium

    Characterized SLP-76 SH2-domain ligands (SLAP-130/Fyb, HPK1) and Nck recruitment, expanding the regulatory and effector network and identifying negative regulators.

    Evidence Cloning, co-IP, SH2 pulldown, yeast two-hybrid, phosphopeptide competition, and reporter assays

    PMID:10229072 PMID:10347175 PMID:10409671 PMID:11487585 PMID:8760799 PMID:9115214

    Open questions at the time
    • Most interactions from single labs
    • Functional hierarchy among SH2 ligands unresolved
  11. 2000 High

    Showed membrane compartmentalization is the essential function of LAT for SLP-76, since a LAT/SLP-76 chimera reconstitutes signaling, formalizing the spatial logic of the complex.

    Evidence LAT/SLP-76 chimera reconstitution in LAT-deficient Jurkat with GEM fractionation and multiple reporters

    PMID:11015445

    Open questions at the time
    • Residual signaling without GEM recruitment not fully explained
  12. 2000 High

    Connected SLP-76 to integrin and Fcγ-receptor-driven cytoskeletal remodeling through Fyb/SLAP-Ena/VASP-WASP-Arp2/3 branches, generalizing its actin role across cell types.

    Evidence CHO reconstitution, platelet immunofluorescence, EVH1 binding, and macrophage phagocytosis assays

    PMID:10747096 PMID:11113155 PMID:11739662

    Open questions at the time
    • Relative contribution of Nck vs Fyb branches not quantified
    • Macrophage data from single lab
  13. 2001 High

    Defined the direct SLP-76-PLC-γ1 contact via the P-1 domain and the genetic requirement of Gads for the SLP-76-LAT association in vivo, completing the dual-contact model for PLC-γ1 activation.

    Evidence SLP-76 point/deletion mutants in deficient T cells plus GADS-knockout mice

    PMID:11239162 PMID:11390650

    Open questions at the time
    • Kinase phosphorylating PLC-γ1 Y783 not yet identified
    • WASP activation mechanism not yet resolved
  14. 2002 High

    Quantified and structurally explained the non-canonical R-X-X-K/Gads SH3 interaction, defining the high-affinity epitope that anchors SLP-76 at the membrane.

    Evidence Peptide arrays, SPR affinity measurement, mutagenesis, and 1.7 Å crystal structure

    PMID:12176364 PMID:12773374

    Open questions at the time
    • Regulatory role of SH3 dimerization not established in cells
  15. 2003 High

    Reconstructed the TCR-to-WASP pathway and established SLP-76 as a hematopoietic-cell-autonomous factor for blood-lymphatic vascular separation and neutrophil effector function.

    Evidence Vav-1-deficient T cells, Cdc42 assays, knockout/bone-marrow-reconstitution mice, and neutrophil ROS/spreading assays

    PMID:12522250 PMID:12874226 PMID:14614862

    Open questions at the time
    • Receptor driving the vascular phenotype not yet identified
    • Cell type responsible not yet pinpointed
  16. 2006 High

    Identified ITK as the SLP-76-recruited kinase that directly phosphorylates PLC-γ1 Y783, resolving the long-standing question of which kinase completes PLC-γ1 activation.

    Evidence In vitro kinase reconstitution (ITK vs ZAP-70), SLP-76 mutants, and complex reconstitution in T cells

    PMID:15708849 PMID:17148460 PMID:17420479

    Open questions at the time
    • Mechanism sustaining ITK activity within the complex partly defined
    • Vav3 module from single lab
  17. 2007 High

    Defined a serine-phosphorylation negative-feedback arm in which HPK1 phosphorylates S376 to recruit 14-3-3 and dampen signaling, complementing tyrosine-based control.

    Evidence In vitro kinase assay, mass spectrometry, RNAi, and S376A mutagenesis with reporter readouts

    PMID:17353368

    Open questions at the time
    • Downstream consequence of 14-3-3 binding not yet linked to degradation here
  18. 2008 High

    Established that VLA-4 costimulation and actin flow govern the spatiotemporal dynamics of SLP-76 microclusters, and that N-terminal tyrosines partition into separable Vav1- vs ITK-dependent developmental pathways.

    Evidence Live-cell TIRF/FCS imaging, single-molecule tracking, and Y145F/Y112-128F knock-in mice with in-trans complementation

    PMID:16273097 PMID:18342008 PMID:18549800

    Open questions at the time
    • Molecular basis of multi-SLP-76 cooperativity not yet structurally defined
  19. 2009 High

    Distinguished integrin-driven SLP-76 recruitment as ADAP-dependent and LAT-independent, separating outside-in integrin signaling from TCR signaling at the adaptor level.

    Evidence SLP-76 and ADAP-binding mutants with live-cell microcluster imaging and adhesion assays

    PMID:11487585 PMID:15699071 PMID:15933714 PMID:16479002 PMID:16914752 PMID:19667077

    Open questions at the time
    • Integrin-specific kinase requirements partly defined
    • Some interactions from single labs
  20. 2012 High

    Resolved the stoichiometry and assembly logic of SLP-76 signaling clusters and established the platelet CLEC-2/PODOPLANIN-SLP-76 axis as the in vivo driver of lymphatic separation.

    Evidence Analytical ultracentrifugation/SEC, 3FRET in live T cells, ADAP multipoint binding, and platelet-specific Slp-76 knockout with CLEC-2/PDPN analysis

    PMID:20363774 PMID:20562827 PMID:22291096 PMID:22534133 PMID:22786724 PMID:22902619 PMID:23979596

    Open questions at the time
    • How oligomerization couples to downstream output not fully defined
    • K30 ubiquitin ligase not identified
  21. 2021 Medium

    Extended SLP-76 function to innate inflammatory signaling by identifying it as a SAM-domain-mediated partner of the RAGE cytosolic tail driving cytokine release and sepsis.

    Evidence Reciprocal co-IP, RAGE/SLP-76 knockout mice, TAT-SAM blocking peptide, and a cecal ligation sepsis model

    PMID:33436632

    Open questions at the time
    • Single-lab finding awaiting independent confirmation
    • Structural basis of SAM-RAGE interaction not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct SLP-76 microcluster assemblies, oligomerization states, and competing positive/negative modifications are integrated into receptor-specific signaling outputs across lineages remains unresolved.
  • No unified structural model of the full membrane-anchored complex
  • K30 ubiquitin ligase identity unknown
  • Quantitative rules linking cluster dynamics to transcriptional output undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2
Pathway
R-HSA-109582 Hemostasis 4 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4
Partners
FYB1GRAP2ITKLCP2NCK1PLCG1PTPN6VAV1
Complex memberships
LAT-Gads-SLP-76 complexSLP-76-Nck-Vav1 complex

Evidence

Reading pass · 56 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 SLP-76 (pp76) was molecularly cloned as a novel 533-amino acid hematopoietic-specific protein containing a single C-terminal SH2 domain. In vitro translation confirmed direct association of SLP-76 with GST/Grb2 fusion protein. The SH2 domain of SLP-76 precipitated tyrosine phosphoproteins from Jurkat lysates, and anti-PLC-γ1 antibody co-precipitated a protein with identical electrophoretic mobility to SLP-76, establishing SLP-76 as a Grb2-associated adaptor that also interacts with PLC-γ1. GST pulldown, in vitro translation, co-immunoprecipitation, SH2 domain fusion protein precipitation The Journal of biological chemistry High 7706237
1996 SLP-76 is a direct substrate of ZAP-70 tyrosine kinase. SLP-76 phosphorylation is diminished in T cells expressing catalytically inactive ZAP-70, SLP-76 is preferentially phosphorylated by ZAP-70 in vitro and in heterologous cells. Overexpression of wild-type SLP-76 hyperactivates TCR signaling, while a tyrosine-phosphorylation-deficient SLP-76 attenuates it. SLP-76 interacts with both Grb2 and PLC-γ1, linking ZAP-70 to Ras and calcium pathways. In vitro kinase assay, dominant-negative ZAP-70 expression, overexpression/loss-of-function in T cell lines, co-immunoprecipitation The Journal of biological chemistry High 8702662
1996 Vav and SLP-76 physically interact in TCR-stimulated T cells. The Vav SH2 domain is required for this interaction and for TCR-mediated Vav tyrosine phosphorylation. Co-overexpression of Vav and SLP-76 synergistically activates NF-AT and IL-2 promoter activity, placing Vav-SLP-76 in a shared signaling complex controlling lymphocyte activation. Co-immunoprecipitation, overexpression, reporter gene assays (NF-AT/IL-2 promoter), domain mutagenesis Immunity High 8673706
1996 SLP-76 tyrosines 113, 128, and 145 in the N-terminal acidic region are phosphorylated upon TCR ligation. Mutation of Y113/Y128 together significantly decreases SLP-76 function; mutation of Y145 alone has the most potent impact on SLP-76 augmentation of NFAT promoter activity. Site-directed mutagenesis, TCR stimulation, NFAT reporter assay, phosphorylation mapping Journal of immunology High 8892604
1996 Grb2 constitutively associates with unphosphorylated SLP-76. After TCR stimulation, SLP-76 undergoes rapid tyrosine phosphorylation and associates via its SH2 domain with tyrosine phosphoproteins of 62 kDa and 130 kDa as well as a serine/threonine kinase. A functional SLP-76 SH2 domain is required for enhancement of TCR-mediated NFAT and IL-2 promoter activity. Co-immunoprecipitation, in vitro SH2 domain binding assay, reporter gene assay (NFAT/IL-2 promoter), domain deletion mutants The Journal of experimental medicine High 8666952
1996 SLP-76 is differentially regulated by CD45 isoforms: T cells expressing CD45(ABC) show increased tyrosine phosphorylation of SLP-76 and enhanced physical association of SLP-76 with Vav compared to CD45(0)-expressing cells, establishing a link between CD45 isoform activity and the Vav-SLP-76 complex. Jurkat T cell clones expressing distinct CD45 isoforms, co-immunoprecipitation, Western blot of tyrosine phosphorylation The Journal of biological chemistry Medium 8703037
1997 SLP-76 function requires three distinct domains: the N-terminal tyrosine-containing region, the proline-rich region, and the C-terminal SH2 domain. Each mediates protein-protein interactions required for augmentation of TCR-induced NFAT activity. SLP-76 acts downstream of TCR-stimulated PTKs and augments ERK activity and AP-1-driven transcription without affecting calcium signaling. Domain deletion mutants, Jurkat overexpression, reporter assays (NFAT, AP-1), ERK kinase assay Journal of immunology Medium 9257823
1997 ZAP-70 phosphorylates SLP-76 at two pYESP motifs (Y113 and Y128), enabling Vav SH2 domain binding; Y113 is more efficient. A third pYEPP motif (Y145) does not bind the Vav SH2 domain. In vitro and in vivo analysis shows that ZAP-70, but not Lck or Fyn, is responsible for Vav-SLP-76 complex formation. In vitro kinase assay, phosphopeptide competition, co-immunoprecipitation, dominant-kinase constructs Immunity High 9047237
1997 SLAP-130 (a 130-kDa hematopoietic-specific phosphoprotein) was molecularly cloned and shown to associate with the SH2 domain of SLP-76. SLAP-130 is a substrate of TCR-induced PTKs. Overexpression of SLAP-130 diminishes TCR-induced IL-2 promoter activity and interferes with SLP-76-mediated augmentation, identifying SLAP-130 as a negative regulator recruited by the SLP-76 SH2 domain. Molecular cloning, co-immunoprecipitation, SH2 domain pulldown, overexpression reporter assay The Journal of biological chemistry Medium 9115214
1998 SLP-76 deficiency in a mutant T cell line uncouples TCR-activated PTKs from PLC-γ1 and Ras pathway activation. SLP-76 is required for optimal tyrosine phosphorylation and activation of PLC-γ1, Ras pathway activation, and TCR-inducible gene expression, but is not required for tyrosine phosphorylation of most other TCR-stimulated proteins. SLP-76-deficient T cell line, reconstitution, Western blot for PLC-γ1 phosphorylation, calcium flux, gene expression assays Science High 9665884
1998 SLP-76 knockout mice lack peripheral T cells due to an early block in thymopoiesis, while macrophage and NK cell compartments remain intact. This demonstrates SLP-76 is specifically required for pre-TCR signals driving thymocyte development and expansion. Gene targeting/knockout mice, flow cytometric analysis of thymus and peripheral lymphoid tissues Science High 9665885
1998 SLP-76-null mice generated by homologous recombination exhibit subcutaneous and intraperitoneal hemorrhaging, impaired viability, and a profound block in thymic development at the CD4-CD8- stage. The block cannot be overcome by anti-CD3 treatment in vivo. V-D-J rearrangement of TCRβ is unaffected, placing SLP-76 downstream of pre-TCR assembly. Homologous recombination knockout, in vivo anti-CD3 treatment, flow cytometry, Southern blot for TCRβ rearrangement Cell High 9695951
1998 SLP-76 linker protein interacts with both Nck (an adaptor) and Vav (a GEF for Rho-family GTPases), forming a trimolecular complex. Assembly of this complex mediates activation of PAK1 and actin polymerization downstream of TCR. SLP-76 thus provides a scaffold integrating distinct signaling complexes to regulate the T cell cytoskeleton. Co-immunoprecipitation, actin polymerization assay, PAK1 kinase activation assay, dominant-negative expression Immunity High 9846482
1998 SLP-76 is a direct substrate for dephosphorylation by SHP-1 in T cells and NK cells. SHP-1 is recruited to killer cell inhibitory receptors (KIRs) and directly dephosphorylates tyrosine-phosphorylated SLP-76. Tyrosine-phosphorylated SLP-76 is required for optimal cytotoxic lymphocyte activation, establishing targeted SLP-76 dephosphorylation by SHP-1 as a mechanism for KIR-mediated negative regulation. Direct binding assay, in vitro phosphatase assay, functional cytotoxicity assays, SLP-76 mutant analysis The Journal of biological chemistry High 9765283
1999 Gads (Grb2 family member) constitutively associates with SLP-76 via the Gads C-terminal SH3 domain binding a 20-amino-acid proline-rich region of SLP-76. Gads also co-immunoprecipitates tyrosine-phosphorylated LAT via its SH2 domain following TCR stimulation. Co-overexpression of Gads and SLP-76 synergistically augments NFAT activation, establishing Gads as a bridge linking the LAT and SLP-76 signaling complexes. Co-immunoprecipitation, domain mutant analysis, NFAT reporter assay Current biology High 10021361
1999 Nck SH2 domain directly mediates interaction with tyrosine-phosphorylated SLP-76 in activated T cells. Phosphopeptides corresponding to Y113 and Y128 of SLP-76 compete binding of SLP-76 to the Nck SH2 domain, identifying these as the Nck-binding phosphotyrosine residues. Co-immunoprecipitation, in vitro SH2 domain binding, phosphopeptide competition assay European journal of immunology Medium 10229072
1999 In collagen-stimulated platelets, SLP-76 tyrosine phosphorylation is downstream of Syk (absent in Syk-deficient platelets). SLP-76 associates with SLAP-130, Vav, Fyn, Lyn, and the FcR γ-chain. SLP-76 functions upstream of PLC-γ2 and SLAP-130; CRP-induced PLC-γ2 phosphorylation and Ca2+ mobilization are markedly attenuated in SLP-76-deficient platelets. Syk-deficient platelets, SLP-76-deficient platelets, co-immunoprecipitation, Western blot for PLC-γ2 phosphorylation, calcium mobilization assay The Journal of biological chemistry High 10026222
1999 SLP-76 is required for collagen-induced platelet aggregation and granule release. SLP-76-deficient platelets fail to show tyrosine phosphorylation of PLC-γ2 after collagen stimulation, placing SLP-76 upstream of PLC-γ2 in platelet signaling and providing a mechanism for fetal hemorrhage in SLP-76-null mice. SLP-76 knockout mice, platelet aggregometry, granule release assay, PLC-γ2 phosphorylation by Western blot The Journal of clinical investigation High 9884330
1999 SLP-76 deficiency in mast cells impairs FcεRI-mediated signaling: tyrosine phosphorylation of PLC-γ1 (but not Syk) and calcium mobilization are reduced in SLP-76-null bone marrow-derived mast cells, placing SLP-76 downstream of Syk and upstream of PLC-γ1 in FcεRI signaling. SLP-76 knockout mice, bone marrow-derived mast cell culture, beta-hexosaminidase release assay, phospho-Western blot, calcium flux The Journal of clinical investigation High 10377180
1999 FYB/SLAP (FYN-T-binding protein/SLP-76-associated protein) is selectively phosphorylated by FYN-T, providing a template for FYN-T and SLP-76 SH2 domain binding. Co-expression of FYN-T, FYB, and SLP-76 synergistically up-regulates TCR-driven IL-2 transcription, defining a FYN-T–FYB–SLP-76 pathway. Co-immunoprecipitation, in vitro kinase assay, IL-2 transcription reporter assay, domain mutants The Journal of biological chemistry Medium 10409671
1999 SLP-76 tyrosines Y113 and Y128 are required for binding to Vav (both in vitro and in cells). However, the SLP-76–Vav interaction is not required for their cooperation in augmenting IL-2 promoter activity: SLP-76 potentiates NFAT and AP-1, while Vav only potentiates NFAT, suggesting they operate in separate but overlapping pathways upstream of IL-2 gene expression. Site-directed mutagenesis, in vitro binding assay, co-immunoprecipitation, NFAT/AP-1 reporter assays The Journal of biological chemistry Medium 10347175
1999 Hematopoietic progenitor kinase 1 (HPK1) physically and functionally interacts with SLP-76 in T cells. This interaction requires Tyr379 of HPK1 and the SH2 domain of SLP-76. HPK1 inhibits AP-1 activation in a manner partially dependent on its interaction with SLP-76, placing HPK1 as a negative regulator in the SLP-76 signaling pathway. Yeast two-hybrid, co-transfection/co-IP in COS cells and T cells, reporter assays (AP-1, NFAT), domain mutagenesis The Journal of biological chemistry Medium 11487585
1999 SLP-76 is constitutively associated with SHP-1 in B cells via the SHP-1 SH2 domains; this association is stable during early BCR signaling. Significant tyrosine phosphorylation of SLP-76 occurs after BCR ligation, suggesting SHP-1 may modulate BCR-induced SLP-76 phosphorylation. Co-immunoprecipitation, GST-SH2 domain pulldown, Western blot The Journal of experimental medicine Medium 8760799
1999 SLP-76 is required for TCR-beta allelic exclusion. In SLP-76-null mice, DN thymocytes express pre-TCR on the surface, but a TCRαβ transgene fails to drive DN thymocyte expansion or allelic exclusion, demonstrating SLP-76 is required for pre-TCR signal transduction leading to allelic exclusion. SLP-76 knockout mice, TCRαβ transgene introduction, flow cytometry, Southern blot for TCRβ rearrangement in single cells The Journal of experimental medicine High 10523607
2000 Recruitment of SLP-76 to the membrane and glycolipid-enriched membrane microdomains (GEMs) replaces the requirement for LAT in TCR signaling. A LAT/SLP-76 chimeric protein reconstitutes PLC-γ1 phosphorylation, ERK activation, and NFAT activity in LAT-deficient Jurkat cells. Mutation precluding GEM recruitment diminishes but does not eliminate signaling, while mutation of SLP-76 PTK phosphorylation sites abolishes TCR function, demonstrating that membrane compartmentalization of SLP-76 is functionally critical. LAT/SLP-76 chimera expression in LAT-deficient cells, GEM fractionation, PLC-γ1 phosphorylation, ERK assay, NFAT reporter, domain mutagenesis The Journal of experimental medicine High 11015445
2000 SLP-76 relays signals from platelet integrin αIIbβ3 to the actin cytoskeleton. αIIbβ3 engagement stimulates SLP-76 tyrosine phosphorylation requiring co-expression of Syk. Phosphorylated SLP-76 then associates with Nck and Vav1, promoting lamellipodia formation and PAK kinase activation. In human platelets, fibrinogen adhesion drives SLP-76 association with SLAP-130 and VASP at the cell periphery. CHO cell expression system, co-immunoprecipitation, lamellipodia morphology quantification, PAK kinase assay, immunofluorescence in platelets The Journal of biological chemistry High 11113155
2000 Fyb/SLAP is a new ligand for Ena/VASP EVH1 domains. In activated T cells, Fyb/SLAP localizes at the T cell–APC interface and is present in complexes containing WASP, Nck, and SLP-76. Inhibition of Fyb/SLAP–Ena/VASP or WASP–Arp2/3 interactions impairs TCR-dependent actin rearrangement, establishing a Fyb/SLAP–Ena/VASP–WASP–Arp2/3 pathway linking SLP-76 to actin cytoskeleton remodeling. EVH1 domain binding assay, co-immunoprecipitation, immunofluorescence/localization at T cell-APC interface, dominant-negative inhibition, actin polymerization assay The Journal of cell biology High 10747096
2001 SLP-76 directly interacts with the SH3 domain of PLC-γ1 via a 67-amino-acid 'P-1 domain' within the proline-rich region of SLP-76. This P-1 domain constitutively mediates SLP-76–PLC-γ1 SH3 interaction and is required for TCR-mediated PLC-γ1 activation, ERK activation, and NFAT activation. The adjacent Gads-binding domain recruits SLP-76 to a LAT-PLC-γ1 complex, providing dual SLP-76-dependent contacts necessary for optimal PLC-γ1 activation. SLP-76 deletion/point mutants in SLP-76-deficient T cells, co-immunoprecipitation, NFAT/ERK reporter assays, PLC-γ1 phosphorylation Molecular and cellular biology High 11390650
2001 In phagocytic macrophages, Fcγ receptor engagement forms a large molecular complex containing Fyb/SLAP, SLP-76, Nck, Ena/VASP proteins, and WASP. VASP proteins are required for actin remodeling, pseudopodium extension, and efficient particle internalization, with SLP-76 present at forming phagosomes. Two converging signaling branches (Fyb/SLAP→VASP/profilin; Nck→WASP) regulate actin polymerization during phagocytosis. Immunofluorescence/co-localization, co-immunoprecipitation, dominant-negative inhibition, video microscopy of phagocytosis Journal of cell science Medium 11739662
2001 GADS is required for the physical association between SLP-76 and LAT in thymocytes. In GADS-deficient mice, the SLP-76–LAT association is uncoupled, CD4-CD8- thymocytes are blocked in proliferation but still differentiate, and positive/negative selection is impaired. This establishes GADS as the critical adaptor bridging SLP-76 to LAT in TCR signaling. GADS-knockout mice, co-immunoprecipitation from thymocytes, in vivo proliferation and selection assays Science High 11239162
2001 WASP recruitment to the T cell–APC contact site requires binding to the C-terminal SH3 domain of Nck, while WASP activation requires Vav-1-dependent Cdc42 activation. Tyrosine-phosphorylated SLP-76 functions as a scaffold that coordinates WASP recruitment (via Nck) and activation (via Vav-1/Cdc42-GTP), reconstructing the signaling pathway from TCR to localized WASP activation. Vav-1-deficient T cells, dominant-negative constructs, co-immunoprecipitation, immunofluorescence at T cell-APC contact site, Cdc42 activation assay Journal of immunology High 12874226
2002 A non-proline-based R-X-X-K motif in SLP-76 (residues R237/K240) binds the Gads C-terminal SH3 domain with high affinity (Kd = 240 ± 45 nM), which is 40-fold higher than Grb2's C-terminal SH3 domain for the same motif. Single point mutations in R237 or K240 completely abrogate SLP-76–Gads association in vivo and impair SLP-76 function downstream of TCR. Peptide arrays, surface plasmon resonance/affinity measurements, site-directed mutagenesis, co-immunoprecipitation, TCR signaling reporter assays Current biology High 12176364
2003 Crystal structure of Mona/Gads C-terminal SH3 domain complexed with SLP-76 peptide solved to 1.7 Å. The SLP-76 peptide lacks a canonical PxxP motif; instead the central R-X-X-K motif forms a 3(10) helix that inserts into a negatively charged double pocket on the SH3 domain, creating a uniquely high-affinity binding epitope. The SH3C also displays ion-dependent dimerization, suggesting a regulatory mechanism. X-ray crystallography (1.7 Å resolution), solution biophysics The EMBO journal High 12773374
2003 Mice lacking SLP-76 or Syk develop blood-filled lymphatics due to failure of blood-lymphatic vascular separation. SLP-76 cannot be detected in endothelial cells, and blood-filled lymphatics arise in WT mice reconstituted with SLP-76-deficient bone marrow, establishing SLP-76 as a hematopoietic cell signaling protein required for separation of blood and lymphatic vasculature during embryogenesis. Knockout mice, bone marrow reconstitution, histological and vascular analysis Science High 12522250
2003 SLP-76 is required for Fcγ receptor and integrin signaling in neutrophils. FcγR and integrin stimulation induces SLP-76 tyrosine phosphorylation and cytoplasmic relocalization. SLP-76-null neutrophils show decreased FcγR-induced calcium flux and reactive oxygen species (ROS) production, and fail to produce ROS, spread, or activate downstream regulators upon integrin ligation. SLP-76 knockout mice, primary neutrophil isolation, calcium flux, ROS assay, spreading assay, phospho-Western blot Immunity High 14614862
2004 The Gads-binding domain and P-1 domain within the SLP-76 proline-rich region are both necessary for optimal SLP-76 function; in their absence SLP-76 is functionally inert. SLP-76 subcellular localization and function are directly dependent on its association with Gads, demonstrated by directed localization experiments. Domain deletion mutants reconstituted in SLP-76-deficient cells, dominant-negative expression, directed localization constructs, functional reporter assays, fluorescence microscopy The Journal of biological chemistry Medium 14722089
2005 The Yersinia virulence factor YopH (a tyrosine phosphatase) specifically dephosphorylates LAT and SLP-76 in T cells. A catalytically inactive YopH introduced via type III secretion primarily binds LAT and SLP-76. Tyrosine phosphorylation of LAT and SLP-76 is most affected in T cells exposed to low numbers of Yersinia, identifying these adaptors as the primary targets for immune evasion. Catalytically inactive YopH trap, FACS, single-cell video microscopy, phospho-Western blot The Journal of experimental medicine Medium 15699071
2005 VLA-4 (α4β1 integrin) costimulation prevents centralization of SLP-76 microclusters, promotes microcluster persistence, prolongs SLP-76–ZAP-70 lateral interactions, and retains SLP-76 in tyrosine-phosphorylated peripheral structures. SLP-76 centralization is driven by dynamic actin polymerization and inward actin flows; VLA-4 ligation retards these flows, sustaining peripheral SLP-76 signaling. Live cell TIRF/confocal imaging of SLP-76 microclusters, pharmacological actin manipulation, integrin ligand conditions, fluorescence correlation spectroscopy Immunity High 18549800
2005 TCR-induced activation of T cells initiates and sustains signaling in TCR-containing microclusters generated at initial contact sites and the immunological synapse periphery. These microclusters recruit Zap70 and SLP-76 and are continuously generated at the periphery. Zap70 and SLP-76 dissociate from microclusters before they coalesce with the central supramolecular cluster. Inhibition of signaling prevents ZAP-70 (and hence SLP-76) recruitment into microclusters. Single-molecule live-cell imaging (TIRFM, single-particle tracking), fluorescence labeling, pharmacological inhibition Nature immunology High 16273097
2005 Receptor-stimulated ROS generation leads to transient SHP-2 inactivation (oxidation). SHP-2 is recruited to the LAT-Gads-SLP-76 complex and directly regulates phosphorylation of Vav1 and ADAP. ADAP association with SLP-76 is regulated by SHP-2 in a redox-dependent manner, establishing a redox-signaling pathway to integrin activation through the SLP-76 complex. Co-immunoprecipitation, ROS measurement, phosphatase oxidation assay, integrin adhesion assay The EMBO journal Medium 15933714
2005 CD6 costimulatory activity is mediated through phosphorylation-dependent binding of CD6 cytoplasmic tyrosine 662 to SLP-76. The Kd of SLP-76 SH2 domain for the CD6 phosphopeptide is 0.5 μM. Both costimulation and CD6–SLP-76 interaction require Y662 in murine T-cell hybridoma functional assays and in normal human T cells. Phosphopeptide binding (Kd measurement), co-immunoprecipitation with native phospho-CD6, mutagenesis of Y662, T cell hybridoma functional assay Molecular and cellular biology Medium 16914752
2006 SLP-76 mediates and maintains activation of the Tec family kinase ITK. SLP-76 N-terminal tyrosines are required for TCR-induced ITK phosphorylation and activation but are not required for ZAP-70 activation. ITK efficiently phosphorylates PLC-γ1 at Y783 and Y775 (critical activation sites), while ZAP-70 does not. A small fraction of active ITK associates with SLP-76; catalytic activity is lost upon mild elution but restored upon complex reconstitution. In vitro kinase assay (ITK vs. ZAP-70 on PLC-γ1), SLP-76 mutants in T cells, ITK activation assay, complex reconstitution, phospho-Western blot Proceedings of the National Academy of Sciences High 17420479
2006 Vav3 membrane/IS translocation depends on its association with SLP-76. Vav3 mutants lacking SH2-SH3-SH3 domains fail to bind SLP-76, do not translocate to the membrane or immunological synapse, and fail to activate NFAT. Vav3 membrane translocation is abrogated in Lck-, ZAP-70-, LAT-, and SLP-76-deficient T cells where Vav3–SLP-76 binding is disrupted. Domain mutants, co-immunoprecipitation, subcellular localization (live imaging), knockdown with reconstitution, NFAT reporter, SLP-76-deficient T cells The Journal of biological chemistry Medium 15708849
2006 SLP-76 forms signaling clusters at the cell membrane upon FcεRI cross-linking in mast cells, colocalizing with FcεRI, Syk, LAT, and phosphotyrosine. Disruption of the SLP-76–Gads interaction (by SLP-76 mutation or Gads-binding region expression) prevents SLP-76 translocation and clustering, abolishing FcεRI-induced calcium flux, degranulation, and cytokine secretion. Real-time confocal imaging in RBL cells and primary bone marrow-derived mast cells, SLP-76 mutant expression, calcium flux, degranulation assay, cytokine ELISA Molecular and cellular biology High 16479002
2007 HPK-1 phosphorylates SLP-76 at serine 376, which induces binding of 14-3-3ε and ζ proteins to SLP-76. This constitutes a negative feedback loop: S376A mutation or HPK-1 knockdown results in increased TCR-induced tyrosine phosphorylation of SLP-76 and PLC-γ1, and elevated IL-2 gene transcription. RNAi knockdown, in vitro phosphorylation assay, co-immunoprecipitation, TCR reporter assay, mass spectrometry (phosphorylation site identification) The Journal of experimental medicine High 17353368
2006 SLP-76 has a dual role in PLC-γ1 activation: (1) the Gads-binding domain of SLP-76 is required for PLC-γ1 recruitment to GEMs/lipid rafts; (2) the N-terminal tyrosine phosphorylation sites and P-I region of SLP-76 are required for PLC-γ1 phosphorylation at Y783, independently of GEM recruitment. SLP-76 N-terminal tyrosines mediate inducible association with both Vav and active ITK, which efficiently phosphorylates PLC-γ1 Y783 in vitro. SLP-76 domain mutants, GEM fractionation, in vitro kinase assay (ITK on PLC-γ1), co-immunoprecipitation, NFAT reporter The Journal of biological chemistry High 17148460
2008 SLP-76 N-terminal tyrosines Y112-128 and Y145 are required for thymocyte development via separable molecular mechanisms: Y112-128 are critical for Vav1 phosphorylation, while Y145 is more important for Itk-dependent pathways. Knock-in mice expressing one Y145F allele and one Y112-128F allele revealed that the two mutant SLP-76 molecules can complement each other in trans, demonstrating cooperative multi-SLP-76 complex function. Knock-in mice (Y145F; Y112-128F), flow cytometry of thymus/periphery, TCR signaling assays, complementation analysis in compound heterozygotes Immunity High 18342008
2009 SLP-76 mediates 'outside-in' integrin signaling in T cells. SLP-76-deficient T cells fail to adhere to integrin ligands. In response to integrin stimulation, SLP-76 relocalizes to surface microclusters via an ADAP-dependent, LAT-independent mechanism. An SLP-76 mutant unable to bind ADAP forms clusters after TCR but not integrin engagement and fails to support T cell adhesion to integrin ligands. SLP-76 domain mutants, co-immunoprecipitation, live-cell imaging of SLP-76 microclusters, T cell adhesion assay Molecular and cellular biology High 19667077
2010 Platelets regulate lymphatic vascular development through the CLEC-2–SLP-76 signaling pathway. Platelet CLEC-2 receptors bind lymphatic endothelial PODOPLANIN to activate SLP-76 signaling. Platelet-specific deletion of Slp-76 (via PF4-Cre) confers embryonic lymphatic vascular defects identical to those in global Slp-76 knockouts, identifying platelets as the specific cell type requiring SLP-76 signaling for blood-lymphatic vascular separation. Platelet-specific Cre-loxP conditional knockout, CLEC-2 knockout mice, PDPN binding assay, histological vascular analysis, platelet aggregate formation on lymphatic endothelium ex vivo/in vivo Blood High 20363774
2010 The SLP-76, Nck, and VAV1 complex can contain one SLP-76, two Nck, and two VAV1 molecules. Direct interaction between Nck and VAV1 is mediated by the C-terminal SH3 domain of Nck and the VAV1 N-terminal SH3 domain. Disruption of the VAV1–Nck interaction deleteriously affects actin polymerization. Analytical ultracentrifugation, analytical size exclusion chromatography (biophysical reconstitution), co-immunoprecipitation, actin polymerization assay, domain mutagenesis The EMBO journal High 20562827
2012 SLP-76 is required for E-selectin-mediated integrin activation and slow leukocyte rolling in neutrophils, contributing to ischemia-reperfusion-induced acute kidney injury. ADAP, the two N-terminal tyrosines, and the SH2 domain of SLP-76 are required for downstream signaling. The Tec kinase BTK acts downstream of SLP-76 and, together with ADAP, regulates PI3Kγ- and PLCγ2-dependent pathways for integrin activation. SLP-76-knockout mice, primary leukocyte transduction with SLP-76 domain mutants, intravital microscopy of leukocyte rolling, integrin affinity/avidity assays, kidney injury models The Journal of experimental medicine High 22291096
2012 In NK cells, SLP-76 is required for synergistic activation by co-activation receptor pairs (NKG2D + 2B4). Each receptor in a synergistic pair selectively phosphorylates distinct tyrosine residues (Y113 or Y128) of SLP-76, enabling Vav1 binding. Combined phosphorylation of both Y113 and Y128 underlies synergistic Ca2+ mobilization and NK cell cytotoxicity. SLP-76 knockdown and reconstitution with Y113F, Y128F, and double mutants, Ca2+ flux assay, cytotoxicity assay, co-immunoprecipitation (SLP-76–Vav1) Science signaling Medium 22786724
2012 SLP-76 is ubiquitinated at lysine 30 and targeted for proteasomal degradation during TCR signaling. This ubiquitination is mediated by HPK-1-induced serine 376 phosphorylation. Loss of K30 ubiquitination results in enhanced anti-CD3-induced ERK and JNK activation, establishing a two-step negative feedback: HPK1→S376 phosphorylation→K30 ubiquitination→proteasomal degradation of SLP-76. Ubiquitination assay, proteasome inhibitor treatment, K30 and S376 mutagenesis, Western blot for ERK and JNK phosphorylation The Journal of biological chemistry Medium 22902619
2012 Triple-color FRET in live human T cells revealed that Nck and Vav1 form constitutive dimers independently of T cell activation and independently of SLP-76–Nck association. After TCR stimulation, SLP-76 phosphorylation enables Nck binding, and the trimolecular SLP-76–Nck–Vav1 complex forms. A point mutation in Vav1 abolishing Nck binding impaired actin rearrangement, confirming functional importance of Nck–Vav1 dimers. Triple-color FRET (3FRET) in live T cells, site-directed mutagenesis, actin polymerization assay Science signaling Medium 22534133
2013 ADAP contains three binding sites for the SLP-76 SH2 domain, and multipoint binding to ADAP oligomerizes SLP-76 in vitro. All three ADAP binding sites are critical for SLP-76 microcluster assembly in stimulated T cells, with any combination of two sites partially inducing microclusters. This multipoint SLP-76–ADAP interaction facilitates assembly of SLP-76 signaling microclusters. Analytical ultracentrifugation, analytical size exclusion chromatography, confocal imaging of SLP-76 microclusters, ADAP mutagenesis, T cell functional assays Molecular and cellular biology High 23979596
2021 SLP-76 is a binding partner for the cytosolic tail of RAGE. SLP-76 binds RAGE through its sterile α motif (SAM) domain to mediate downstream signaling. Genetic deficiency of RAGE or SLP-76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2, and IKKα/β as well as cytokine release. Delivery of TAT-SAM peptide (blocking RAGE–SLP-76 interaction) attenuates inflammatory cytokine production and protects mice from lethal sepsis. Co-immunoprecipitation (in vitro and in vivo), knockout mice (RAGE and SLP-76), TAT-SAM peptide delivery, cytokine ELISA, cecal ligation and puncture sepsis model Nature communications Medium 33436632

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nature immunology 567 16273097
1998 Uncoupling of nonreceptor tyrosine kinases from PLC-gamma1 in an SLP-76-deficient T cell. Science (New York, N.Y.) 342 9665884
1998 Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Science (New York, N.Y.) 340 9665885
2010 Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood 332 20363774
2003 Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science (New York, N.Y.) 322 12522250
1996 Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. The Journal of biological chemistry 312 8702662
1998 Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Cell 302 9695951
1995 Molecular cloning of SLP-76, a 76-kDa tyrosine phosphoprotein associated with Grb2 in T cells. The Journal of biological chemistry 289 7706237
1996 Vav and SLP-76 interact and functionally cooperate in IL-2 gene activation. Immunity 286 8673706
1999 The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Current biology : CB 254 10021361
2000 Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton. The Journal of cell biology 247 10747096
2006 SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nature reviews. Immunology 221 16493428
1997 Molecular cloning of SLAP-130, an SLP-76-associated substrate of the T cell antigen receptor-stimulated protein tyrosine kinases. The Journal of biological chemistry 213 9115214
1998 Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity 202 9846482
1997 Regulation of Vav-SLP-76 binding by ZAP-70 and its relevance to TCR zeta/CD3 induction of interleukin-2. Immunity 190 9047237
1996 Implication of the GRB2-associated phosphoprotein SLP-76 in T cell receptor-mediated interleukin 2 production. The Journal of experimental medicine 167 8666952
2001 Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT. Molecular and cellular biology 164 11390650
2001 Evidence for a molecular complex consisting of Fyb/SLAP, SLP-76, Nck, VASP and WASP that links the actin cytoskeleton to Fcgamma receptor signalling during phagocytosis. Journal of cell science 164 11739662
1996 p95vav associates with tyrosine-phosphorylated SLP-76 in antigen-stimulated T cells. The Journal of experimental medicine 163 9064333
1999 Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice. The Journal of clinical investigation 146 9884330
1999 SLP-76 deficiency impairs signaling via the high-affinity IgE receptor in mast cells. The Journal of clinical investigation 139 10377180
2003 SLP-76 coordinates Nck-dependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/Cdc42-dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact site. Journal of immunology (Baltimore, Md. : 1950) 126 12874226
1999 Grf40, A novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT. The Journal of experimental medicine 121 10224278
2001 Requirement for the SLP-76 adaptor GADS in T cell development. Science (New York, N.Y.) 116 11239162
2008 T cell costimulation via the integrin VLA-4 inhibits the actin-dependent centralization of signaling microclusters containing the adaptor SLP-76. Immunity 114 18549800
1996 Tyrosines 113, 128, and 145 of SLP-76 are required for optimal augmentation of NFAT promoter activity. Journal of immunology (Baltimore, Md. : 1950) 110 8892604
2002 A high-affinity Arg-X-X-Lys SH3 binding motif confers specificity for the interaction between Gads and SLP-76 in T cell signaling. Current biology : CB 106 12176364
1999 GrpL, a Grb2-related adaptor protein, interacts with SLP-76 to regulate nuclear factor of activated T cell activation. The Journal of experimental medicine 103 10209041
1999 Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets. The Journal of biological chemistry 101 10026222
2003 Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76. The EMBO journal 99 12773374
2001 Hematopoietic progenitor kinase 1 associates physically and functionally with the adaptor proteins B cell linker protein and SLP-76 in lymphocytes. The Journal of biological chemistry 97 11487585
2005 Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP. The EMBO journal 95 15933714
2000 Recruitment of SLP-76 to the membrane and glycolipid-enriched membrane microdomains replaces the requirement for linker for activation of T cells in T cell receptor signaling. The Journal of experimental medicine 94 11015445
2012 Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury. The Journal of experimental medicine 92 22291096
2000 The molecular adapter SLP-76 relays signals from platelet integrin alphaIIbbeta3 to the actin cytoskeleton. The Journal of biological chemistry 92 11113155
1998 SLP-76 is a direct substrate of SHP-1 recruited to killer cell inhibitory receptors. The Journal of biological chemistry 92 9765283
2010 Cooperative interactions at the SLP-76 complex are critical for actin polymerization. The EMBO journal 90 20562827
2007 A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76. The Journal of experimental medicine 89 17353368
2006 Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development. Developmental cell 88 16950126
1999 FYN-T-FYB-SLP-76 interactions define a T-cell receptor zeta/CD3-mediated tyrosine phosphorylation pathway that up-regulates interleukin 2 transcription in T-cells. The Journal of biological chemistry 88 10409671
2008 Complementation in trans of altered thymocyte development in mice expressing mutant forms of the adaptor molecule SLP76. Immunity 87 18342008
2001 A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT. The EMBO journal 86 11157752
1996 Differential regulation of activation-induced tyrosine phosphorylation and recruitment of SLP-76 to Vav by distinct isoforms of the CD45 protein-tyrosine phosphatase. The Journal of biological chemistry 86 8703037
2001 Differential requirement for SLP-76 domains in T cell development and function. Immunity 85 11754821
1999 Association of Nck with tyrosine-phosphorylated SLP-76 in activated T lymphocytes. European journal of immunology 83 10229072
1998 Molecular interaction between the Fyn-associated protein SKAP55 and the SLP-76-associated phosphoprotein SLAP-130. The Journal of biological chemistry 83 9748251
2006 CD6 regulates T-cell responses through activation-dependent recruitment of the positive regulator SLP-76. Molecular and cellular biology 81 16914752
2001 CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation. Immunity 80 11754814
2004 ADAP-SLP-76 binding differentially regulates supramolecular activation cluster (SMAC) formation relative to T cell-APC conjugation. The Journal of experimental medicine 77 15477347
1999 Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and SLP-76 in c-Cbl-deficient thymocytes. Journal of immunology (Baltimore, Md. : 1950) 77 10358158
2004 The SLP-76 family of adapter proteins. Seminars in immunology 74 15541653
2007 SLP-76 mediates and maintains activation of the Tec family kinase ITK via the T cell antigen receptor-induced association between SLP-76 and ITK. Proceedings of the National Academy of Sciences of the United States of America 73 17420479
2002 Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling. The Journal of experimental medicine 72 11901197
1997 Three domains of SLP-76 are required for its optimal function in a T cell line. Journal of immunology (Baltimore, Md. : 1950) 70 9257823
2009 SLP-76-ADAP adaptor module regulates LFA-1 mediated costimulation and T cell motility. Proceedings of the National Academy of Sciences of the United States of America 68 19617540
2000 Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane. The Journal of experimental medicine 68 10993915
2005 Dynamic recruitment of PAK1 to the immunological synapse is mediated by PIX independently of SLP-76 and Vav1. Nature immunology 67 15864311
2000 Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through alpha IIb beta 3 and collagen receptors. Proceedings of the National Academy of Sciences of the United States of America 67 11050236
1998 SLP-76 expression is restricted to hemopoietic cells of monocyte, granulocyte, and T lymphocyte lineage and is regulated during T cell maturation and activation. Journal of immunology (Baltimore, Md. : 1950) 67 9780153
2003 SLP-76 regulates Fcgamma receptor and integrin signaling in neutrophils. Immunity 66 14614862
1999 Novel isoform of lymphoid adaptor FYN-T-binding protein (FYB-130) interacts with SLP-76 and up-regulates interleukin 2 production. The Journal of biological chemistry 64 10497204
1999 Cutting edge: SLP-76 cooperativity with FYB/FYN-T in the Up-regulation of TCR-driven IL-2 transcription requires SLP-76 binding to FYB at Tyr595 and Tyr651. Journal of immunology (Baltimore, Md. : 1950) 63 10570256
2012 Complementary phosphorylation sites in the adaptor protein SLP-76 promote synergistic activation of natural killer cells. Science signaling 62 22786724
2009 The adapter protein SLP-76 mediates "outside-in" integrin signaling and function in T cells. Molecular and cellular biology 61 19667077
2004 Roles of the proline-rich domain in SLP-76 subcellular localization and T cell function. The Journal of biological chemistry 61 14722089
2002 Differential role of SLP-76 domains in T cell development and function. Proceedings of the National Academy of Sciences of the United States of America 60 11792851
1997 SLP-76 is a substrate of the high affinity IgE receptor-stimulated protein tyrosine kinases in rat basophilic leukemia cells. The Journal of biological chemistry 60 8995445
2005 The adaptor molecules LAT and SLP-76 are specifically targeted by Yersinia to inhibit T cell activation. The Journal of experimental medicine 58 15699071
2001 ZAP-70 and SLP-76 regulate protein kinase C-theta and NF-kappa B activation in response to engagement of CD3 and CD28. Journal of immunology (Baltimore, Md. : 1950) 57 11313406
1999 SLP-76 and Vav function in separate, but overlapping pathways to augment interleukin-2 promoter activity. The Journal of biological chemistry 57 10347175
1999 Evidence that phospholipase C-gamma2 interacts with SLP-76, Syk, Lyn, LAT and the Fc receptor gamma-chain after stimulation of the collagen receptor glycoprotein VI in human platelets. European journal of biochemistry 55 10469124
1999 Clnk, a novel SLP-76-related adaptor molecule expressed in cytokine-stimulated hemopoietic cells. The Journal of experimental medicine 55 10562326
2002 Differential SLP-76 expression and TCR-mediated signaling in effector and memory CD4 T cells. Journal of immunology (Baltimore, Md. : 1950) 54 11823482
2000 Functional association between SLAP-130 and SLP-76 in Jurkat T cells. The Journal of biological chemistry 52 10671560
2012 Attenuation of T cell receptor signaling by serine phosphorylation-mediated lysine 30 ubiquitination of SLP-76 protein. The Journal of biological chemistry 50 22902619
2006 Functional hierarchy of the N-terminal tyrosines of SLP-76. Journal of immunology (Baltimore, Md. : 1950) 49 16456002
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
2006 Dual role of SLP-76 in mediating T cell receptor-induced activation of phospholipase C-gamma1. The Journal of biological chemistry 45 17148460
2000 Resting lymphocyte kinase (Rlk/Txk) targets lymphoid adaptor SLP-76 in the cooperative activation of interleukin-2 transcription in T-cells. The Journal of biological chemistry 44 10660534
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
1999 SLP-76 binding to p56lck: a role for SLP-76 in CD4-induced desensitization of the TCR/CD3 signaling complex. Journal of immunology (Baltimore, Md. : 1950) 44 10477581
2001 Synergistic regulation of immunoreceptor signaling by SLP-76-related adaptor Clnk and serine/threonine protein kinase HPK-1. Molecular and cellular biology 43 11509653
2005 Conditional deletion reveals a cell-autonomous requirement of SLP-76 for thymocyte selection. The Journal of experimental medicine 42 16186188
2013 Multipoint binding of the SLP-76 SH2 domain to ADAP is critical for oligomerization of SLP-76 signaling complexes in stimulated T cells. Molecular and cellular biology 41 23979596
2010 Coordination of receptor signaling in multiple hematopoietic cell lineages by the adaptor protein SLP-76. Cold Spring Harbor perspectives in biology 41 20452948
2006 Disruption of SLP-76 interaction with Gads inhibits dynamic clustering of SLP-76 and FcepsilonRI signaling in mast cells. Molecular and cellular biology 41 16479002
2000 A BASH/SLP-76-related adaptor protein MIST/Clnk involved in IgE receptor-mediated mast cell degranulation. International immunology 40 10744659
2021 Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis. Nature communications 39 33436632
2012 Studying the dynamics of SLP-76, Nck, and Vav1 multimolecular complex formation in live human cells with triple-color FRET. Science signaling 39 22534133
2007 Efficient T-cell receptor signaling requires a high-affinity interaction between the Gads C-SH3 domain and the SLP-76 RxxK motif. The EMBO journal 38 17235283
2000 Roles of SLP-76, phosphoinositide 3-kinase, and gelsolin in the platelet shape changes initiated by the collagen receptor GPVI/FcR gamma-chain complex. Blood 38 11090061
2011 Role of two adaptor molecules SLP-76 and LAT in the PI3K signaling pathway in activated T cells. Journal of immunology (Baltimore, Md. : 1950) 37 21282515
1999 Allelic exclusion of the T cell receptor beta locus requires the SH2 domain-containing leukocyte protein (SLP)-76 adaptor protein. The Journal of experimental medicine 37 10523607
1999 NK cytokine secretion and cytotoxicity occur independently of the SLP-76 adaptor protein. European journal of immunology 36 10427985
1996 Hematopoietic cell phosphatase, SHP-1, is constitutively associated with the SH2 domain-containing leukocyte protein, SLP-76, in B cells. The Journal of experimental medicine 36 8760799
2007 Mitogenic CD28 signals require the exchange factor Vav1 to enhance TCR signaling at the SLP-76-Vav-Itk signalosome. Journal of immunology (Baltimore, Md. : 1950) 35 17237383
2007 Prevalence of ZAP-70, LAT, SLP-76, and DNA methyltransferase 1 expression in CD4+ T cells of patients with systemic lupus erythematosus. Clinical rheumatology 35 17492476
2005 Membrane localization and function of Vav3 in T cells depend on its association with the adapter SLP-76. The Journal of biological chemistry 35 15708849
2003 Structural requirements of SLP-76 in signaling via the high-affinity immunoglobulin E receptor (Fc epsilon RI) in mast cells. Molecular and cellular biology 34 12640123
2003 Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation. Immunological reviews 34 12670393

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