Affinage

GAB3

GRB2-associated-binding protein 3 · UniProt Q8WWW8

Length
586 aa
Mass
65.6 kDa
Annotated
2026-04-28
12 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GAB3 is a scaffolding adaptor protein of the Grb2-associated binder family that couples cytokine and growth factor receptor signaling to PI3K/Akt and MAPK/Erk pathways in hematopoietic cells. It contains an N-terminal pleckstrin homology domain, multiple tyrosine phosphorylation sites, and proline-rich motifs; upon receptor activation (e.g., M-CSFR, IL-2R/IL-15R), GAB3 is tyrosine phosphorylated and recruits p85 (PI3K), SHP2, and the adaptor Mona/Gads to assemble signaling complexes that drive macrophage differentiation and NK cell expansion (PMID:11739737, PMID:11997510, PMID:31375526). GAB3-deficient mice are viable with grossly normal hematopoiesis, but show selective impairment of IL-2/IL-15-driven MAPK signaling in NK cells, resulting in defective missing-self recognition, impaired tumor clearance, and aberrant uterine NK cell-mediated spiral artery remodeling; combined loss of GAB2 and GAB3 unmasks redundant roles in suppressing colitis through PI3K/Akt/mTORC1 signaling in macrophages and T cells (PMID:12640125, PMID:31375526, PMID:30936879). In cancer contexts, GAB3 promotes Akt and Erk activation and tumor cell proliferation in colorectal cancer and glioma, while in lung adenocarcinoma it interacts with LYN kinase to inhibit MAPK signaling and enhance anti-tumor immunity (PMID:28115166, PMID:28291820, PMID:42031161).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2002 High

    Identification of GAB3 as a tyrosine-phosphorylated docking protein that assembles p85/SHP2 complexes downstream of M-CSFR and accelerates macrophage differentiation established its basic molecular architecture and initial function.

    Evidence Co-immunoprecipitation and overexpression in FD-Fms cells with M-CSF stimulation

    PMID:11739737

    Open questions at the time
    • Upstream kinase(s) responsible for GAB3 tyrosine phosphorylation not identified
    • Whether GAB3 acts through PI3K, SHP2, or both to promote differentiation was not resolved
    • No in vivo loss-of-function data at this stage
  2. 2002 High

    Mapping of the GAB3–Mona/Gads interaction via an atypical proline-rich motif and demonstration that specific M-CSFR tyrosines (Y697, Y807) are required for GAB3 phosphorylation defined how receptor signals are transmitted through GAB3.

    Evidence GST pull-down domain mapping, site-directed receptor mutagenesis, Co-IP in bone marrow-derived cells

    PMID:11997510

    Open questions at the time
    • Functional consequence of the Mona/Gads–GAB3 complex for downstream signaling not tested
    • Whether GAB3 is recruited directly to the receptor or via an intermediary adaptor (e.g., Grb2) was not resolved
  3. 2003 High

    Gab3 knockout mice revealed that GAB3 is dispensable for normal hematopoiesis and macrophage development, raising the possibility of functional redundancy with GAB1/GAB2 or context-specific roles.

    Evidence Homologous recombination knockout with comprehensive hematopoietic and immune phenotyping

    PMID:12640125

    Open questions at the time
    • Redundancy with GAB1/GAB2 was not formally tested by combinatorial knockouts
    • Specialized immune challenges (infection, tumor rejection) were not examined
    • NK cell-specific phenotypes were not assessed
  4. 2017 Medium

    Extension of GAB3 function to cancer showed that GAB3 promotes Akt and Erk activation and tumor cell proliferation in colorectal cancer and glioma, confirming its scaffolding role for PI3K/MAPK signaling outside normal hematopoiesis.

    Evidence shRNA knockdown and overexpression in CRC and glioma cells with xenograft models; Co-IP confirmed p85/SHP2 association in CRC

    PMID:28115166 PMID:28291820

    Open questions at the time
    • Whether GAB3 is amplified, mutated, or transcriptionally upregulated in these cancers was not established
    • Receptor inputs activating GAB3 in cancer cells not identified
    • Single-lab findings without independent replication
  5. 2019 High

    Discovery that GAB3 is selectively required for IL-2/IL-15-driven MAPK (but not STAT5) signaling in NK cells resolved the long-standing question of GAB3's non-redundant physiological function, linking it to missing-self recognition, tumor clearance, and uterine vascular remodeling.

    Evidence Gab3-deficient mice with cytokine stimulation, adoptive transfer, and NK cell functional assays in vivo

    PMID:31375526

    Open questions at the time
    • Mechanism by which GAB3 selectively channels to MAPK rather than STAT5 is unknown
    • Whether GAB3 directly scaffolds a Ras-activating complex in NK cells was not shown
    • Human NK cell relevance not demonstrated
  6. 2019 Medium

    Combined GAB2/GAB3 knockout revealed redundant suppression of colitis through PI3K/Akt/mTORC1 signaling in macrophages and T cells, demonstrating that GAB family members cooperatively restrain inflammatory responses.

    Evidence Double knockout mice, bone marrow transplantation, intracellular signaling analysis

    PMID:30936879

    Open questions at the time
    • GAB3-specific contribution versus GAB2-specific contribution not dissected
    • Whether the colitis phenotype is driven primarily by macrophage or T cell dysfunction remains unclear
    • Downstream transcriptional targets of GAB3-dependent mTORC1 signaling not identified
  7. 2026 Medium

    Identification of LYN kinase as a GAB3 interaction partner in lung adenocarcinoma, where GAB3 inhibits MAPK/EMT and promotes CD8+ T cell infiltration via CXCL10, revealed a context-dependent tumor-suppressive role contrasting with its oncogenic function in other cancers.

    Evidence Co-immunoprecipitation of GAB3–LYN, overexpression/knockdown with MAPK/EMT and immune profiling readouts in vitro and in vivo

    PMID:42031161

    Open questions at the time
    • Whether LYN phosphorylates GAB3 or vice versa is unknown
    • Mechanism by which GAB3 switches from pro-MAPK to anti-MAPK signaling in different tumor types not resolved
    • Single-lab study without independent validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of GAB3's context-dependent signaling — how it activates MAPK/Akt in some settings but inhibits MAPK in others — and the functional significance of its interaction with RSK kinases remain to be established.
  • No crystal or cryo-EM structure of GAB3 or its complexes exists
  • RSK interaction confirmed only by single Co-IP in a preprint; functional consequence for GAB3 not demonstrated
  • Human genetic studies linking GAB3 variants to disease are absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 2
Partners
GRAP2GRB2LYNPIK3R1PTPN11

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Gab3 contains an amino-terminal pleckstrin homology (PH) domain, multiple tyrosine phosphorylation sites, SH2 domain binding sites, and two polyproline motifs. Upon M-CSF receptor (Fms) stimulation, Gab3 is tyrosine phosphorylated and associates transiently with p85 (PI3K regulatory subunit) and SHP2. Overexpression of Gab3 in FD-Fms cells dramatically accelerates macrophage differentiation upon M-CSF stimulation. Co-immunoprecipitation, overexpression in FDC-P1/FD-Fms cell lines, tyrosine phosphorylation assay, mRNA expression analysis Molecular and cellular biology High 11739737
2002 Gab3 specifically interacts with the adapter protein Mona/Gads during monocyte/macrophage differentiation. This interaction is mediated by the C-terminal SH3 domain of Mona and the atypical proline-rich domain of Gab3. Gab3 does not interact with the related adapter Grb2 via Mona but does form a complex with Grb2. The M-CSF receptor mutation Y697F impairs Gab3 tyrosine phosphorylation and reduces Mona induction, while Y807F (differentiation-defective) also fails to induce Mona expression. GST pull-down, co-immunoprecipitation, site-directed mutagenesis of M-CSF receptor (Y697F, Y807F), immunoblotting Molecular and cellular biology High 11997510
2003 Gab3-deficient mice generated by homologous recombination develop normally with no impairment in macrophage differentiation or numbers, no compensation by Gab1 or Gab2 upregulation, and no major immune deficiency in T- or B-lymphocyte responses, indicating Gab3 is dispensable for normal hematopoiesis in vivo. Homologous recombination knockout, monoclonal antibody generation, immunoblotting, detailed hematopoietic and immune phenotyping Molecular and cellular biology High 12640125
2019 Gab3 is required for IL-2- and IL-15-induced NK cell expansion. Loss of Gab3 causes selective impairment of MAPK signaling but not STAT5 signaling downstream of these cytokines. Gab3-deficient mice show impaired NK cell-mediated elimination of missing-self and tumor targets, and impaired uterine NK cell expansion leading to defective spiral artery remodeling and increased trophoblast invasion. Gab3-deficient mouse model (in vivo and ex vivo), cytokine stimulation with signaling readouts (MAPK, STAT5), adoptive transfer, NK cell functional assays Science immunology High 31375526
2019 Gab2 and Gab3 redundantly suppress colitis by modulating macrophage and CD8+ T-cell activation. Double knockout (Gab2/3-/-) mice develop spontaneous colitis with reduced PI3-kinase/Akt/mTORC1 signaling in macrophages and T-cells, and increased pSTAT5 in IL-2-stimulated T-cells. Reciprocal bone marrow transplantation demonstrated a hematopoietic disease-initiating mechanism. Double knockout mouse generation, bone marrow transplantation, adoptive transfer, intracellular signaling analysis (PI3K/Akt/mTORC1, STAT5) Frontiers in immunology Medium 30936879
2017 In colorectal cancer cells, Gab3 co-precipitates with p85 and SHP2, and is required for downstream Akt and Erk activation. Gab3 knockdown inhibits both Akt and Erk activation, while overexpression augments them, promoting CRC cell proliferation in vitro and tumor growth in vivo. Co-immunoprecipitation, shRNA knockdown, overexpression, xenograft tumor model, Akt/Erk phosphorylation assays Biochemical and biophysical research communications Medium 28115166
2017 In human glioma cells, Gab3 knockdown inhibits Akt activation and cell proliferation, while Gab3 overexpression promotes Akt activation and proliferation both in vitro and in vivo in xenograft models. shRNA/siRNA knockdown, forced overexpression, Akt phosphorylation assay, xenograft tumor model PloS one Medium 28291820
2026 In lung adenocarcinoma, GAB3 interacts with LYN kinase to inhibit the MAPK signaling pathway and reverse epithelial-mesenchymal transition (EMT). GAB3 overexpression also enhances CXCL10 secretion, increases CD8+ T cell infiltration, and sensitizes tumors to anti-PD-1 therapy. Co-immunoprecipitation (GAB3-LYN interaction), overexpression/knockdown with MAPK and EMT readouts, in vitro and in vivo tumor models, immune cell profiling Cancer letters Medium 42031161
2024 GAB3 interacts with RSK kinases (p90 ribosomal S6 kinases) through a DDVF-like short linear motif (SLiM), the same interface used by viral and bacterial proteins to hijack RSKs. This interaction was identified by AlphaFold docking and confirmed by co-immunoprecipitation, suggesting GAB3 participates in negative feedback regulation of the RAS-ERK MAPK pathway via RSK. AlphaFold structural docking, co-immunoprecipitation, SLiM prediction screening of human proteome bioRxivpreprint Low bio_10.1101_2024.08.08.607128

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Gab3, a new DOS/Gab family member, facilitates macrophage differentiation. Molecular and cellular biology 71 11739737
2019 Gab3 is required for IL-2- and IL-15-induced NK cell expansion and limits trophoblast invasion during pregnancy. Science immunology 52 31375526
2003 Gab3-deficient mice exhibit normal development and hematopoiesis and are immunocompetent. Molecular and cellular biology 45 12640125
2002 Induced expression and association of the Mona/Gads adapter and Gab3 scaffolding protein during monocyte/macrophage differentiation. Molecular and cellular biology 34 11997510
2019 Gab2 and Gab3 Redundantly Suppress Colitis by Modulating Macrophage and CD8+ T-Cell Activation. Frontiers in immunology 14 30936879
2017 Gab3 overexpression in human glioma mediates Akt activation and tumor cell proliferation. PloS one 12 28291820
2017 Gab3 is required for human colorectal cancer cell proliferation. Biochemical and biophysical research communications 11 28115166
2022 Silencing Asian Seabass gab3 Inhibits Nervous Necrosis Virus Replication. Marine biotechnology (New York, N.Y.) 6 36227511
2020 Characterization of GAB3 and its association with NNV resistance in the Asian seabass. Fish & shellfish immunology 6 32473363
2024 Association analysis of polymorphisms in SLK, ARHGEF9, WWC2, GAB3, and FSHR genes with reproductive traits in different sheep breeds. Frontiers in genetics 5 38680425
2026 GAB3 suppresses lung adenocarcinoma progression by inhibiting the MAPK signaling and potentiating CD8+ T cell immunity. Cancer letters 0 42031161
2025 Genetic susceptibility to essential hypertension in the Chinese han population: a study on GAB1, GAB2, and GAB3 gene polymorphisms. BMC cardiovascular disorders 0 40140746