Affinage

GRAP2

GRB2-related adapter protein 2 · UniProt O75791

Length
330 aa
Mass
37.9 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRAP2 (Gads) is a hematopoietic-specific SH3-SH2-SH3 adaptor protein that functions as the essential molecular bridge coupling SLP-76 to phosphorylated LAT in immunoreceptor signaling. Its C-terminal SH3 domain constitutively binds a non-canonical R-X-X-K motif in SLP-76 with nanomolar affinity via a unique 3₁₀-helical recognition mode, while its SH2 domain inducibly engages phospho-Tyr171 and phospho-Tyr191 on LAT following TCR engagement, thereby recruiting SLP-76 to lipid raft–localized LAT and enabling PLC-γ1 activation, calcium flux, and NFAT/NF-κB-driven transcription (PMID:10021361, PMID:12176364, PMID:10811803, PMID:11239162). Gads dimerizes through its SH2 domain to cooperatively engage dually phosphorylated LAT, is positively regulated by Itk-mediated Y45 phosphorylation, and is negatively regulated by caspase-3 cleavage that uncouples SLP-76 from the membrane during apoptosis (PMID:28951535, PMID:33931484, PMID:11313864). Beyond TCR signaling, Gads is required for FcεRI-mediated mast cell degranulation and anaphylaxis, contributes redundantly with Grb2 to platelet hemITAM signaling, participates in CD28 costimulatory NF-κB activation, and promotes BCR-ABL-driven lymphoid leukemogenesis through an SLP-76-containing signaling complex (PMID:18664516, PMID:31948362, PMID:16818765, PMID:23399893).

Mechanistic history

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

    Identification of GRAP2 as a novel Grb2-family SH3-SH2-SH3 adaptor with hematopoietic-restricted expression established that a new signaling node existed downstream of phosphotyrosine-bearing receptors including Shc, Bcr-Abl, c-Kit, and M-CSFR.

    Evidence Expression library screening, yeast two-hybrid, co-IP, and Northern blot across multiple labs

    PMID:9857184 PMID:9872323 PMID:9878555

    Open questions at the time
    • Physiological substrates and signaling pathways in lymphocytes were unknown
    • Functional distinction from Grb2 was unclear
  2. 1999 High

    Discovery that Gads constitutively binds SLP-76 via its C-terminal SH3 domain and inducibly binds phospho-LAT via its SH2 domain established the bridging model: Gads couples cytosolic SLP-76 to membrane-anchored LAT to activate NFAT/IL-2 transcription.

    Evidence Reciprocal co-IP, domain mutagenesis, and NFAT/IL-2 reporter assays in Jurkat T cells

    PMID:10021361 PMID:10224278

    Open questions at the time
    • The in vivo requirement for Gads had not been tested genetically
    • Which LAT tyrosines mediate Gads binding was unknown
  3. 2000 High

    Mapping of Gads SH2 binding to LAT pTyr171 and pTyr191, demonstration that Gads recruits SLP-76 to lipid raft microdomains, and identification of the HPK1-Gads interaction expanded the mechanistic picture of how Gads organizes signalosome assembly at the membrane.

    Evidence Systematic LAT Tyr-to-Phe mutagenesis in LAT-null Jurkat cells, sucrose gradient raft fractionation, co-IP and kinase assays for HPK1

    PMID:10811803 PMID:10903746 PMID:10993915

    Open questions at the time
    • Whether Gads is essential in vivo for T cell development was untested
    • Structural basis of the SLP-76 interaction was unknown
  4. 2001 High

    Gads-knockout mice revealed an essential, non-redundant role: loss of Gads uncouples SLP-76 from LAT and blocks thymocyte development, positive/negative selection, and TCR-driven proliferation.

    Evidence Gene-targeted Gads-null mice with co-IP showing loss of SLP-76–LAT association and thymocyte developmental analysis

    PMID:11239162

    Open questions at the time
    • Peripheral T cell and mast cell phenotypes in KO mice were not yet characterized
    • Whether Gads cleavage during apoptosis is physiologically relevant in vivo was unknown
  5. 2001 High

    Caspase-3 cleaves Gads within its unique linker region during apoptosis, removing the C-terminal SH3 domain and thereby uncoupling SLP-76 from the membrane; this established a negative-regulatory mechanism that terminates TCR signaling upon death receptor engagement.

    Evidence CD95/Fas ligation, caspase inhibitor experiments, site-directed mutagenesis of caspase site, in vitro cleavage assay, and NFAT reporter assay

    PMID:11313864 PMID:11391000

    Open questions at the time
    • In vivo significance of caspase cleavage for immune homeostasis was not demonstrated
    • Whether other proteases target Gads was unknown
  6. 2002 High

    Quantitative binding studies revealed that the Gads C-SH3/SLP-76 interaction is mediated by a non-proline-based R-X-X-K motif (Kd ~240 nM, later refined to 8–20 nM) with 40-fold higher affinity than the equivalent Grb2 interaction, explaining Gads's non-redundant role.

    Evidence Peptide arrays, SPR/ITC affinity measurements, point mutagenesis with in vivo co-IP and functional rescue

    PMID:12176364

    Open questions at the time
    • Atomic-level structural basis for the high affinity was not yet resolved
  7. 2003 High

    NMR and crystal structures of the Gads C-SH3/SLP-76 complex revealed a unique binding mode: the SLP-76 RSTK motif adopts a right-handed 3₁₀ helix rather than the canonical PPII helix, engaging four distinct pockets on the SH3 surface, providing an atomic explanation for binding specificity.

    Evidence NMR (Liu et al.) and 1.7 Å X-ray crystallography (Harkiolaki et al.) with supporting mutagenesis

    PMID:12620234 PMID:12773374

    Open questions at the time
    • Full-length Gads structure and how it orients between LAT and SLP-76 remained unknown
    • Structural basis of SH2 domain engagement with LAT phosphosites was unresolved
  8. 2004 High

    Crystal structures of the Gads SH2 domain bound to LAT phosphopeptides (pTyr171, pTyr191, pTyr226) provided the structural basis for preferential LAT site recognition and explained selectivity differences from Grb2, while a separate structure revealed that the C-SH3 domain binds HPK1 via a dual R/KXXK + PXXP motif distinct from SLP-76 binding.

    Evidence X-ray crystallography and isothermal titration calorimetry

    PMID:15029250 PMID:15100220

    Open questions at the time
    • How Gads integrates signals from multiple binding partners simultaneously was unclear
    • Cooperative or competitive binding between SLP-76 and HPK1 for Gads C-SH3 was not addressed
  9. 2006 High

    The Gads–SLP-76 interaction was shown to be required for FcεRI-induced mast cell signaling (calcium flux, degranulation, cytokine production) and for immunoreceptor but not integrin signaling in vivo, establishing the generality of the bridging function beyond TCR signaling and delineating pathway-specific requirements.

    Evidence Confocal imaging and functional perturbation in mast cells; in vivo knock-in mice expressing domain-deleted SLP-76

    PMID:16479002 PMID:16943434

    Open questions at the time
    • Whether Gads contributes to non-ITAM receptor signaling pathways was not established
  10. 2008 High

    Gads-knockout studies in mast cells and platelets extended its requirement to FcεRI-dependent anaphylaxis in vivo and to GPVI/CLEC-2 platelet signaling at submaximal stimulation, while revealing redundancy with Grb2 in platelets under strong activation.

    Evidence Gads-KO bone marrow-derived mast cells and in vivo passive cutaneous anaphylaxis model; Gads-KO platelet aggregation and secretion assays

    PMID:18664516 PMID:18826392

    Open questions at the time
    • Molecular basis for the threshold-dependent Gads requirement in platelets was unclear
    • Full redundancy with Grb2 had not been genetically tested
  11. 2013 High

    GADS was shown to bind BCR-ABL at Y177 and selectively promote BCR-ABL-driven lymphoid leukemogenesis; Gads-/- bone marrow transduced with BCR-ABL developed only myeloid disease, establishing Gads as a lineage-specific oncogenic effector.

    Evidence Gads-KO bone marrow transplantation, co-IP with BCR-ABL Y177F mutant, disease phenotyping in mice and patient samples

    PMID:23399893

    Open questions at the time
    • Whether Gads inhibition could be therapeutically exploited in B-ALL was not tested
    • Downstream signaling pathways uniquely engaged by the Gads–SLP-76 complex in leukemia were not defined
  12. 2014 High

    TALEN-generated Gads-null Jurkat cells demonstrated that Gads functions as a dose-dependent signal amplifier that confers responsiveness to weak TCR stimuli rather than acting as an on/off switch, and identified T262 phosphorylation as a negative regulatory modification.

    Evidence TALEN KO in Jurkat, quantitative dose–response calcium flux and CD69 assays, mass spectrometry phosphosite identification, T262 mutagenesis

    PMID:25452106

    Open questions at the time
    • The kinase phosphorylating T262 was not identified
    • Whether T262 phosphorylation affects Gads dimerization or LAT binding was unknown
  13. 2017 High

    Gads was found to dimerize via its SH2 domain, enabling cooperative preferential binding to dually phosphorylated LAT; this provided a mechanism for digital signal discrimination at the LAT signalosome level.

    Evidence Biochemical dimerization assays, mathematical cooperativity modeling, mutagenesis of dimerization interface, functional validation in T cells and mast cells

    PMID:28951535

    Open questions at the time
    • Structural basis for SH2-mediated dimerization was not determined at atomic resolution
    • Whether Gads dimerization is regulated dynamically during signaling was unknown
  14. 2020 High

    Double conditional knockout of Grb2 and Gads in platelets virtually abolished hemITAM signaling and impaired hemostasis, formally establishing functional redundancy between the two adaptors in this lineage.

    Evidence Megakaryocyte/platelet-specific Grb2/Gads double conditional KO mice with in vitro and in vivo hemostasis and thrombosis assays

    PMID:31948362

    Open questions at the time
    • Whether compensatory mechanisms exist in other hematopoietic lineages was not addressed
  15. 2021 High

    Itk was identified as the kinase phosphorylating Gads at Y45 downstream of TCR activation; Y45 phosphorylation depends on prior SLP-76 binding and LAT engagement and positively regulates RE/AP-dependent transcription, establishing a feedforward regulatory loop within the LAT signalosome.

    Evidence Mass spectrometry phosphosite identification, Y45 mutagenesis, co-IP in Itk-deficient cells, RE/AP reporter in human T cells and primary mouse T cells

    PMID:33931484

    Open questions at the time
    • The phosphatase that dephosphorylates Y45 was not identified
    • How Y45 phosphorylation alters Gads conformation or N-SH3 binding properties was not determined structurally

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length Gads structure showing domain arrangement and conformational dynamics remains undetermined; the mechanistic basis for how Gads dimerization, Y45 phosphorylation, and T262 phosphorylation are integrated to tune signaling output is unknown; and the therapeutic potential of targeting Gads in BCR-ABL+ B-ALL or FLT3-ITD+ AML has not been explored.
  • No full-length structure of Gads exists
  • Integration of multiple post-translational modifications on Gads function is unresolved
  • In vivo therapeutic targeting of Gads in leukemia has not been tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 6 R-HSA-109582 Hemostasis 2 R-HSA-1643685 Disease 2
Partners
BCR-ABLGAB2GAB3GRB2HPK1ITKLATSLP76
Complex memberships
LAT signalosomeSLP-76/Gads/LAT complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 GRAP2/Gads was identified as a novel SH3-SH2-SH3 adaptor protein that binds tyrosine-phosphorylated Shc via its SH2 domain; the SH2 domain has similar binding specificity to Grb2 and mediates interaction with Shc, Bcr-Abl, and c-kit; the C-terminal SH3 domain differs from Grb2 and does not interact with Sos or Cbl in vivo Expression library screen with phosphopeptides, co-immunoprecipitation, in vitro binding assays Oncogene High 9872323
1998 Mona/GRAP2 was cloned via yeast two-hybrid and shown to interact with the M-CSF receptor (Fms) at phosphorylated Tyr697 (the Grb2-binding site); overexpression of Mona in bone marrow cells strongly reduced M-CSF-dependent macrophage production in vitro, implicating it in monocyte/macrophage development Yeast two-hybrid screen, co-immunoprecipitation, overexpression in bone marrow progenitors with functional readout The EMBO journal High 9857184
1998 Human GRAP2 was cloned using Gab-1 as bait; the C-terminal SH3 domain of GRAP2 alone is sufficient to bind Gab-1; expression is restricted to leukocyte-rich tissues Yeast two-hybrid, domain truncation binding assays, Northern blot Biochemical and biophysical research communications Medium 9878555
1999 Gads/GRAP2 constitutively interacts with SLP-76 via its C-terminal SH3 domain binding a 20 amino-acid proline-rich region in SLP-76; Gads SH2 domain binds tyrosine-phosphorylated LAT following TCR cross-linking; overexpression of Gads and SLP-76 synergistically augments NFAT activation requiring a functional Gads SH2 domain Co-immunoprecipitation, domain mutagenesis, overexpression with NFAT reporter assay Current biology : CB High 10021361
1999 Grf40 (GRAP2 ortholog) binds SLP-76 via its C-terminal SH3 domain more tightly than Grb2, and binds LAT via its SH2 domain; deletion of the C-terminal SH3 abolished IL-2 promoter activation, while SH2 deletion caused dominant-negative inhibition of NF-AT and IL-2 promoter activity Co-immunoprecipitation, deletion mutants, reporter gene assays in Jurkat cells The Journal of experimental medicine High 10224278
2000 Gads SH2 domain binds LAT at Tyr171 and Tyr191 (but not Tyr226 and other sites) following TCR activation; mutation of individual Grb2-binding sites (Tyr171, Tyr191, Tyr226) had no functional effect alone, but combined mutation affected ERK and NF-AT activation; mutation of Tyr132 abolished PLC-γ1 binding Tyrosine-to-phenylalanine mutagenesis of LAT, reconstitution in LAT-deficient Jurkat cells, co-immunoprecipitation, ERK and calcium flux assays The Journal of biological chemistry High 10811803
2000 Gads/GRAP2 interacts with hematopoietic progenitor kinase 1 (HPK1) via its C-terminal SH3 domain binding the fourth proline-rich region of HPK1; HPK1 becomes inducibly tyrosine-phosphorylated and its kinase activity is upregulated after TCR activation; a Gads SH2 mutant inhibits TCR-induced HPK1 phosphorylation Expression library screen, co-immunoprecipitation, kinase activity assay, dominant-negative mutant expression Journal of immunology High 10903746
2000 Gads/GRAP2 (together with LAT) is required for SLP-76 compartmentation to glycolipid-enriched microdomains (GEMs/lipid rafts); addition of both LAT and Gads to SLP-76 allows SLP-76 to be recruited into GEMs and reconstitutes BCR function in BLNK-deficient B cells; Gads function can be replaced by Grb2 overexpression Sucrose gradient fractionation of GEMs, functional reconstitution in BLNK-deficient B cells, co-expression studies The Journal of experimental medicine High 10993915
2000 GCIP (Grap2 Cyclin-D Interacting Protein) was identified as a novel binding partner of GRAP2; GCIP binds via the C-terminal unique domain (QC domain) of GRAP2; GCIP also binds cyclin D and inhibits E2F1-mediated transcription by reducing Rb phosphorylation by cyclin D-dependent kinase Yeast two-hybrid, co-immunoprecipitation from mammalian cells, GST pulldown, E2F reporter assay, Rb phosphorylation assay The Journal of biological chemistry Medium 10801854
2001 GADS-deficient mice exhibit a severe block in thymocyte proliferation; in GADS-deficient thymocytes, the association between SLP-76 and LAT is uncoupled (shown by immunoprecipitation); GADS-deficient thymocytes fail to respond to CD3 cross-linking and are impaired in positive and negative selection Gene-targeted knockout mouse, co-immunoprecipitation, in vivo CD3 cross-linking, thymocyte developmental analysis Science High 11239162
2001 Grap2/Gads interacts with HPK1 in vitro and in Jurkat T cells via the C-terminal SH3 domain of Grap2 and the second proline-rich motif of HPK1; coexpression of Grap2 with HPK1 increases HPK1 kinase activity and has an additive effect on HPK1-mediated JNK activation and c-Jun transcription Co-immunoprecipitation, in vitro kinase assay, JNK reporter and c-Jun transcription assays Oncogene Medium 11313918
2001 Gads contains a caspase-3 cleavage site in its unique 120 aa region; apoptosis induction in lymphocytes leads to caspase-3-dependent Gads cleavage within 60 min; mutation of the caspase-3 site prevents cleavage; expression of Gads cleavage products in Jurkat cells inhibits NFAT activation following TCR cross-linking Apoptosis induction, caspase inhibitor treatment, site-directed mutagenesis of cleavage site, in vitro caspase cleavage assay, NFAT reporter assay Oncogene High 11313864
2001 CD95/Fas ligation leads to caspase-3-mediated cleavage of GrpL/Gads, removing the C-terminal SH3 domain and uncoupling SLP-76 recruitment to the membrane; expression of truncated GrpL in Jurkat T cells blocks TCR-induced NF-AT activation CD95 ligation, caspase inhibitor experiments, co-immunoprecipitation, NF-AT reporter assay, dominant-negative truncation expression PNAS High 11391000
2002 The Gads C-terminal SH3 domain binds a non-proline-based R-X-X-K motif (RSTK) in SLP-76 (centered on Arg237 and Lys240) with high affinity (Kd = 240 ± 45 nM), which is 40-fold higher than the Grb2 C-SH3 interaction with the same motif; single point mutations of R237 or K240 completely abolish SLP-76/Gads association in vivo and impair SLP-76 function Peptide arrays, surface plasmon resonance/ITC affinity measurements, point mutagenesis, in vivo co-immunoprecipitation, chimeric Grb2/Gads protein rescue experiments Current biology : CB High 12176364
2002 Mona/Gads specifically interacts with Gab3 (but not Gab2) during monocyte/macrophage differentiation; the interaction requires the C-terminal SH3 domain of Mona and the atypical proline-rich domain of Gab3; Mona interaction with M-CSFR requires pY697; M-CSFR Y697F mutation greatly reduces Mona protein induction GST pulldown, co-immunoprecipitation, M-CSFR point mutants (Y697F, Y807F), bone marrow differentiation assays Molecular and cellular biology High 11997510
2003 Crystal/NMR structure of the Gads C-terminal SH3 domain complexed with SLP-76 RSTK-containing peptide: the SLP-76 peptide adopts a unique right-handed 3(10) helix at the RSTK locus (not the canonical polyproline II helix), engaging four distinct binding pockets on the Gads SH3 surface; mutagenesis confirms the structural model NMR structure determination, mutagenesis, peptide binding assays Molecular cell High 12620234
2003 Crystal structure (1.7 Å) of the Mona/Gads C-terminal SH3 domain complexed with SLP-76 peptide: the peptide lacks the canonical PxxP motif, adopts a clamp-like shape around the SH3 beta-barrel, and the central R-x-x-K motif inserts into a negatively charged double pocket as a 3(10) helix; the SH3C also shows ion-dependent dimerization in crystal and solution X-ray crystallography, solution studies of dimerization The EMBO journal High 12773374
2003 Gab2 associates with LAT upon TCR stimulation through constitutive association with Gads/Grb2 via a PXXXR motif in Gab2's Met-binding domain (MBD); through this Gads association, Gab2 is recruited to lipid rafts and exerts inhibitory function on T cell responses; Gab2-deficient T cells show enhanced proliferative responses Co-immunoprecipitation, Gab2 mutant analysis, lipid raft fractionation, transgenic mice, Gab2 KO mice Molecular and cellular biology High 12640133
2003 Grap-2/GADS binds the RET receptor tyrosine kinase (co-immunoprecipitation from medullary thyroid carcinoma cells; direct association in pulldown with in vitro translated proteins); overexpression of Grap-2 inhibits RET-induced NF-κB activation and reduces focus formation by oncogenic RET in NIH 3T3 cells Yeast two-hybrid, co-immunoprecipitation, GST pulldown with in vitro translated proteins, NF-κB reporter assay, focus formation assay Oncogene Medium 12917638
2004 Crystal structures (1.8–1.9 Å) of Gads-SH2 complexed with phosphopeptides representing LAT sites Tyr171, Tyr191, and Tyr226 reveal that Gads-SH2 binds Tyr171 and Tyr191 with higher affinity than other sites; the structures explain preferential recognition and the greater promiscuity of Grb2 (which requires Asn at +2 position) Isothermal titration calorimetry, X-ray crystallography The EMBO journal High 15029250
2004 Mona/Gads SH3C binds HPK1 via both an R/KXXK motif and a complementary PXXP motif embedded in a polyproline II helix; this binding mode differs from the SLP-76 interaction and was characterized by ITC and crystal structure, demonstrating the SH3 domain versatility Isothermal titration calorimetry, X-ray crystallography The Journal of biological chemistry High 15100220
2006 Disruption of the SLP-76/Gads interaction (by SLP-76 mutation or expression of the Gads-binding region of SLP-76) inhibits FcεRI-induced translocation and clustering of SLP-76 to the plasma membrane; this disruption inhibits FcεRI-induced calcium flux, degranulation, and cytokine secretion in mast cells Confocal real-time imaging, mutant SLP-76 expression, dominant-negative peptide expression, calcium flux, degranulation and cytokine assays in RBL and primary bone marrow-derived mast cells Molecular and cellular biology High 16479002
2006 Gads is required for CD28-mediated NF-κB activation; binding of Gads to CD28 requires both the YMNM motif and the PXXP motifs in the CD28 cytoplasmic domain; mutations in N- or C-terminal PXXP motifs reduce Gads association while maintaining Grb2 association; a Gads dominant-negative specifically inhibits NF-κB reporter activity Mutagenesis of CD28 cytoplasmic motifs, co-immunoprecipitation, dominant-negative expression, NF-κB/NFAT reporter assays Journal of immunology Medium 16818765
2006 The Gads-SLP-76 interaction (via the SLP-76 Gads-binding domain) is required for immunoreceptor signaling but dispensable for integrin signaling in hematopoietic cells in vivo; Syk and SLP-76 are required for blood-lymphatic vascular separation downstream of ITAMs In vivo structure-function analysis with knock-in mice expressing domain-deleted SLP-76, integrin and immunoreceptor functional assays Molecular and cellular biology High 16943434
2007 The Gads C-SH3/SLP-76 RxxK interaction affinity (Kd = 8–20 nM) is essential for efficient TCR signaling in Jurkat cells; TCR signaling declines proportionally with decreasing binding affinity; the SLP-76 RxxK motif has high specificity for the Gads C-SH3 domain; TCR signaling can tolerate SLP-76 crossreactivity only if very high affinity for Gads C-SH3 is maintained Mutagenesis of SLP-76 RxxK motif, quantitative affinity measurements (ITC/SPR), TCR signaling assays in Jurkat cells The EMBO journal High 17235283
2008 CD28 triggers NF-κB activation through a CARMA1-PKCθ-Grb2/Gads axis; genetic studies show Grb2/Gads binding (not PI3K binding) to CD28 is important for this pathway; Bcl10 over-expression enables CD28-alone-induced NF-κB activation blocked by dominant-negative PKCθ or CARMA1 Over-expression of Bcl10 in Jurkat, dominant-negative mutants of PKCθ and CARMA1, NF-κB reporter assays International immunology Medium 18829987
2008 Gads is required for efficient GPVI- and CLEC-2-induced platelet aggregation and secretion at submaximal stimulation but dispensable at strong stimulation; LAT is required for full platelet activation over a wider agonist range; Gads-deficient platelets show that Gads links LAT to SLP-76 under weak activation conditions Gads knockout mice, platelet aggregation and secretion assays, collagen-perfusion at arteriolar shear Journal of thrombosis and haemostasis High 18826392
2008 Gads-deficient mast cells fail to induce Ca2+ mobilization, degranulation, and cytokine production upon FcεRI cross-linking; in vivo passive cutaneous anaphylaxis is greatly impaired in Gads-/- mice; Gads is dispensable for TLR-mediated cytokine production in mast cells Gads knockout mice, bone marrow-derived mast cells, Ca2+ flux, degranulation, cytokine assays, in vivo PCA model International immunology High 18664516
2010 Bcr-Abl regulates the actin cytoskeleton and non-apoptotic membrane blebbing via a GADS/SLP-76/Nck1 adaptor pathway; GADS binding to Bcr-Abl requires Bcr-Abl tyrosine kinase activity and is sensitive to imatinib; GADS/SLP-76 and SLP-76/Nck1 interactions are tyrosine-phosphorylation independent; all three adaptors co-localize with cortical actin in blebs; knockdown of each adaptor disrupts actin cytoskeleton and blebbing similarly to imatinib Functional interaction proteomics, co-immunoprecipitation, imatinib treatment, RNAi knockdown, confocal microscopy of actin and blebbing Cellular signalling Medium 20079431
2013 GADS associates with BCR-ABL specifically through Y177 (the Grb2-binding site); BCR-ABL-driven lymphoid but not myeloid disease requires Gads; Gads-/- bone marrow transduced with BCR-ABL develops only myeloid disease; GADS mediates a unique BCR-ABL complex with SLP-76 in BCR-ABL-positive cell lines and B-ALL patient samples Gads knockout bone marrow transplantation, co-immunoprecipitation with BCR-ABL Y177F mutant, disease phenotyping Leukemia High 23399893
2015 GADS knockdown in human CD4+ HuT78 T cells impairs TCR-induced calcium mobilization and IL-2/IFN-γ production due to reduced recruitment of SLP-76 and PLC-γ1 to the LAT complex; TCR-induced SLP-76 and PLC-γ1 phosphorylation levels are maintained; GADS is not required for TCR-induced cellular adhesion shRNA knockdown in human T cells and primary murine CD8+ T cells, LAT complex immunoprecipitation, calcium flux, cytokine ELISA, adhesion assay Cellular signalling High 25636200
2016 GADS binds ligand-stimulated FLT3 at pY955 and pY969 (overlapping with Grb2 binding sites); GADS expression enhances FLT3-ITD-induced cell proliferation, colony formation, AKT/ERK/p38/STAT5 phosphorylation, and accelerates FLT3-ITD-dependent tumor formation in vivo Co-immunoprecipitation, FLT3 phosphosite mutants, cell proliferation and colony assays, mouse xenograft model, phospho-Western blotting Oncotarget Medium 26895103
2017 Gads undergoes SH2 domain-mediated dimerization; dimerization promotes cooperative, preferential binding of paired Gads to dually phosphorylated LAT over singly phosphorylated LAT; mutational inactivation of the dimerization interface reduced cooperativity and abrogated Gads signaling in T cells and mast cells Biochemical dimerization assays, mathematical modeling of cooperativity, co-immunoprecipitation with LAT phosphorylation variants, mutagenesis, functional assays in T cells and mast cells Science signaling High 28951535
2017 GADS SH2 domain binds CD6 phospho-Y629 (identified as dominant interaction by biochemical approach); SLP-76 is recruited to CD6 phospho-Y662; both Y629F and Y662F mutations abolish costimulation by CD6; bivalent recruitment of a GADS/SLP-76 complex is required for costimulation by CD6 Biochemical interaction mapping, CD6 tyrosine mutants, functional costimulation assays in Jurkat and primary human T cells Molecular and cellular biology Medium 28289074
2020 Grb2 and Gads have redundant roles in platelet (hem)ITAM signaling; megakaryocyte/platelet-specific Grb2/Gads double knockout (DKO) mice exhibit virtually abolished hemITAM signaling, impaired hemostasis, and partially defective arterial thrombosis, exceeding defects of either single KO; CLEC-2-dependent blood-lymphatic vascular separation is not affected in DKO Megakaryocyte/platelet-specific double conditional knockout mice, platelet aggregation/secretion assays, in vivo hemostasis and thrombosis models, phospho-Western blotting Platelets High 31948362
2021 Itk phosphorylates Gads at Y45 (within the N-terminal SH3 domain) in a TCR-inducible manner; Gads Y45 phosphorylation depends on Gads interaction with SLP-76 and on Gads dimerization-dependent binding to phospho-LAT; Itk acts through SLP-76 and Gads to promote TCR/CD28-induced RE/AP element activation; unphosphorylated monomeric Gads mediates RE/AP-directed inhibitory activity mitigated by dimerization and Y45 phosphorylation Mass spectrometry phosphosite identification, site-directed mutagenesis, co-immunoprecipitation, RE/AP reporter assay in human T cell line and mouse primary T cells Journal of immunology High 33931484
2005 Spi-1 and Spi-B transcription factors directly regulate GRAP2 gene expression in B cells via a binding element in the downstream promoter; ectopic GRAP2 expression in GRAP2-deficient B cells reduces BLNK recruitment to Igα and modulates BCR-induced phosphorylation; GRAP2 regulation of BLNK recruitment requires the proline-rich domain, while phosphorylation modulation requires both proline-rich and SH2 domains Promoter deletion analysis, EMSA, Spi-1/Spi-B KO mice, ectopic GRAP2 reconstitution, co-immunoprecipitation for BLNK/Igα, phospho-Western blotting Gene Medium 15936902
2014 Gads-deficient Jurkat T cells (created by TALEN gene editing) show that Gads is dispensable for TCR-induced SLP-76 phosphorylation but acts as a dose-dependent amplifier of TCR-induced CD69 expression; Gads confers responsiveness to weak TCR stimuli for PLC-γ1 phosphorylation and calcium flux; Gads is phosphorylated at T262 (identified by mass spectrometry) and mutation of T262 increases TCR responsiveness TALEN-directed genome editing in Jurkat, calcium flux, CD69 expression, PLC-γ1 phosphorylation, mass spectrometry, T262 mutagenesis Cellular signalling High 25452106

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling. The Journal of biological chemistry 329 10811803
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
1991 Obesity, a disorder of nutrient partitioning: the MONA LISA hypothesis. The Journal of nutrition 211 1861165
1998 The MONA LISA hypothesis in the time of leptin. Recent progress in hormone research 136 9769705
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
2003 Structural basis for specific binding of the Gads SH3 domain to an RxxK motif-containing SLP-76 peptide: a novel mode of peptide recognition. Molecular cell 115 12620234
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
2003 Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76. The EMBO journal 98 12773374
2015 Results of the Valiant Mona LSA early feasibility study for descending thoracic aneurysms. Journal of vascular surgery 97 26483004
1998 Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc. Oncogene 92 9872323
1998 Mona, a novel hematopoietic-specific adaptor interacting with the macrophage colony-stimulating factor receptor, is implicated in monocyte/macrophage development. The EMBO journal 80 9857184
2003 Identification of a new simian immunodeficiency virus lineage with a vpu gene present among different cercopithecus monkeys (C. mona, C. cephus, and C. nictitans) from Cameroon. Journal of virology 78 14610175
2000 Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane. The Journal of experimental medicine 68 10993915
2006 Evidence for the requirement of ITAM domains but not SLP-76/Gads interaction for integrin signaling in hematopoietic cells. Molecular and cellular biology 64 16943434
2001 The role of Gads in hematopoietic cell signalling. Oncogene 63 11607830
2004 Mona/Gads SH3C binding to hematopoietic progenitor kinase 1 (HPK1) combines an atypical SH3 binding motif, R/KXXK, with a classical PXXP motif embedded in a polyproline type II (PPII) helix. The Journal of biological chemistry 61 15100220
2000 The adaptor protein Gads (Grb2-related adaptor downstream of Shc) is implicated in coupling hemopoietic progenitor kinase-1 to the activated TCR. Journal of immunology (Baltimore, Md. : 1950) 56 10903746
2004 What makes Mona Lisa smile? Vision research 52 15126060
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