Affinage

GPSM1

G-protein-signaling modulator 1 · UniProt Q86YR5

Length
675 aa
Mass
74.5 kDa
Annotated
2026-04-28
51 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPSM1 (AGS3) is a modular scaffold protein that functions as a receptor-independent guanine nucleotide dissociation inhibitor (GDI) for Gαi/o subunits, thereby liberating free Gβγ for downstream signaling and regulating diverse cellular processes including spindle orientation, autophagy, membrane trafficking, and inflammatory signaling. Its C-terminal GPR (GoLoco) motifs selectively bind GDP-bound Gαi with nanomolar affinity, inhibit GDP release, and compete with Gβγ for Gαi binding, while its N-terminal TPR repeats mediate interactions with partners such as mInsc and NuMA; unlike the paralog LGN, AGS3 cannot form stable higher-order NuMA oligomeric complexes required for cortical force generation, and instead antagonizes LGN-dependent perpendicular divisions in epithelia to promote symmetric cell fates (PMID:11042168, PMID:14530282, PMID:37017303, PMID:39580365). AGS3's GDI activity is counteracted by the GEF Ric-8A, which forms a transient ternary complex to catalyze unidirectional Gα activation, and is regulated by LKB1-mediated phosphorylation of the GPR domain and USP9X-mediated deubiquitination that stabilizes AGS3 protein levels (PMID:18541531, PMID:12719437, PMID:36434066). In macrophages, GPSM1 stabilization promotes metabolic inflammation through the Gαi3/cAMP/PKA/CREB axis controlling NF-κB signaling, and drives M2 polarization via MEIS3-dependent CSF1 expression; in neurons, AGS3 upregulation during drug withdrawal underlies cAMP superactivation and drug-seeking behavior (PMID:36434066, PMID:30, PMID:19549762, PMID:18719114).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    The fundamental question of how AGS3 acts on G proteins was resolved: GPR motifs stabilize Gαi in the GDP-bound state by inhibiting nucleotide exchange, establishing AGS3 as a GDI rather than a GEF or GAP, and showing that GPR-bound Gαi·GDP is not recognized by GPCRs.

    Evidence In vitro GTP γS binding, GDP release kinetics, and receptor-G protein coupling assays with purified proteins and synthetic peptides

    PMID:10969064 PMID:11024022

    Open questions at the time
    • Structural basis of GPR–Gαi interaction at atomic resolution not yet determined
    • Relative contribution of individual GPR motifs to GDI activity in vivo unknown
  2. 2001 High

    The selectivity and cellular context of AGS3–Gα interaction was established: four GPR motifs selectively bind GDP-Gαi (not GTP-bound), compete with Gβγ, and co-immunoprecipitate with Gαi3 from tissues; a brain-enriched long isoform and heart-enriched short isoform with distinct distributions were identified.

    Evidence Co-IP from cell/tissue lysates, GST pulldown, GTPγS binding assays, cDNA cloning, RNase protection assays

    PMID:11042168 PMID:11278352

    Open questions at the time
    • Functional distinction between long and short isoforms in vivo not established
    • Tissue-specific regulation of isoform expression unknown
  3. 2003 High

    Multiple regulatory inputs on AGS3 were discovered simultaneously: LKB1 phosphorylates GPR domains to reduce Gα binding, the GPR domain contains two high-affinity and two low-affinity Gαi binding sites, and cytosolic AGS3 can extract Gαi from membranes to disrupt receptor coupling.

    Evidence ITC with purified proteins, yeast two-hybrid, co-IP, in vitro phosphorylation assays, Sf9 membrane reconstitution

    PMID:12719437 PMID:12834360 PMID:14530282

    Open questions at the time
    • Identity of kinase(s) phosphorylating T602 in vivo not determined
    • Whether LKB1 phosphorylation is the physiologically dominant regulatory mechanism unclear
  4. 2003 Medium

    A direct link between AGS3 and autophagy was established: the GPR domain (Gαi3-binding) promotes macroautophagy while the TPR domain inhibits it, placing AGS3 at an early step before autophagosome formation.

    Evidence Domain truncation mutants, morphometric autophagy analysis, immunofluorescence in HT-29 cells

    PMID:12642577

    Open questions at the time
    • Mechanism by which AGS3 promotes early autophagosome formation not defined
    • Role of specific Gαi subunit selectivity in autophagy not tested
  5. 2005 High

    AGS3 was shown to regulate spindle orientation and cell fate in mammalian neural progenitors, establishing its first in vivo developmental function: AGS3 silencing shifts divisions from apical-basal to planar, causing premature neuronal differentiation.

    Evidence In utero RNAi in mouse neocortex, spindle angle measurements, cell fate immunofluorescence

    PMID:16009138

    Open questions at the time
    • Whether AGS3 acts through cortical Gαi or through antagonism of LGN in this context was unresolved
    • Mechanism of cortical recruitment of AGS3 in neural progenitors unclear
  6. 2007 Medium

    AGS3 was linked to membrane trafficking: both overexpression and knockdown disrupt trans-Golgi network organization and alter plasma membrane receptor surface expression, without affecting cis/medial Golgi.

    Evidence siRNA knockdown, immunofluorescence of Golgi markers, biotin internalization assay, flow cytometry

    PMID:17991770

    Open questions at the time
    • Whether AGS3 acts directly at the TGN or indirectly via Gαi/Gβγ signaling not distinguished
    • Cargo specificity of AGS3-dependent trafficking unknown
  7. 2008 High

    The mechanism by which AGS3's GDI activity is reversed was established: Ric-8A (a GEF) forms a transient ternary complex with AGS3·Gαi·GDP, catalyzes GDP release to produce a stable nucleotide-free Ric-8A·Gαi complex, and AGS3 cannot reverse this, ensuring unidirectional Gα activation.

    Evidence Pulldown, gel filtration, ITC, stopped-flow fluorescence with purified proteins

    PMID:18541531

    Open questions at the time
    • Whether Ric-8A acts on AGS3·Gαi complexes in specific cellular compartments not shown
    • Structural basis of ternary complex not determined
  8. 2008 Medium

    The in vivo relevance of AGS3-mediated Gβγ liberation was demonstrated in addiction circuitry: AGS3 upregulation in nucleus accumbens during ethanol abstinence drives ethanol-seeking through Gβγ signaling.

    Evidence Lentiviral shRNA knockdown in rat brain, operant self-administration, pharmacological Gβγ sequestration

    PMID:18719114

    Open questions at the time
    • Mechanism triggering AGS3 upregulation during withdrawal not identified
    • Specificity of the behavioral phenotype to Gβγ vs other AGS3-dependent pathways not fully resolved
  9. 2010 Medium

    The autophagy mechanism was refined: AGS3 recruits Gαi3 to LC3-positive membranes to promote autophagy, and the GEF GIV disrupts this complex upon growth factor stimulation, establishing a GDI-GEF toggle controlling autophagy initiation. Separately, USP9X was identified as a deubiquitinase stabilizing AGS3 protein levels, and phosphorylation/Gαi binding were shown to bidirectionally control AGS3 subcellular distribution.

    Evidence Co-IP, pulldown, autophagy morphometry, USP9X knockdown/overexpression, BRET in live cells, immunofluorescence with site-directed mutants

    PMID:20065032 PMID:20305814 PMID:20716524 PMID:21209316

    Open questions at the time
    • Whether LC3 interaction is direct or via Gαi3 not resolved
    • Ubiquitination sites on AGS3 not mapped
  10. 2014 Medium

    Global knockout revealed AGS3's role in immune cell chemotaxis: Gpsm1−/− lymphocytes and dendritic cells show impaired chemokine-stimulated migration, calcium flux, and ERK/Akt signaling.

    Evidence Gpsm1−/− mice, chemotaxis assays, calcium flux, phospho-immunoblots in primary cells

    PMID:24573680

    Open questions at the time
    • Whether chemotaxis defect reflects Gβγ liberation or Gαi sequestration not distinguished
    • Redundancy with LGN in immune cells not assessed
  11. 2017 Medium

    The apparent paradox of AGS3 in spindle orientation was addressed: unlike LGN, AGS3 is not recruited to the cortex in mouse neural progenitors and cannot rescue LGN loss, despite conserved in vitro binding to NuMA and Gαi, indicating species- and context-specific functional divergence.

    Evidence In utero electroporation, LGN rescue experiments, in vitro binding, spindle angle measurement in mouse cortex

    PMID:28684399

    Open questions at the time
    • Whether earlier in utero RNAi results reflect off-target effects or context differences not resolved
    • Mechanism preventing AGS3 cortical recruitment unclear
  12. 2020 Medium

    AGS3's TGN trafficking function was validated in early embryogenesis: AGS3 knockout arrests mouse embryos after the 4-cell stage with impaired E-cadherin delivery to the plasma membrane and dispersed TGN markers, rescued by Gαi1 overexpression.

    Evidence CRISPR/Cas9 knockout in mouse embryos, live imaging of TGN markers, Gαi1 rescue

    PMID:33148610

    Open questions at the time
    • Direct mechanism by which AGS3/Gαi1 regulates TGN vesicle budding or sorting not established
    • Whether Gβγ or Gαi is the operative downstream effector in TGN trafficking unknown
  13. 2022 High

    A complete signaling axis was defined in macrophages: USP9X stabilizes GPSM1 via K63-deubiquitination; GPSM1 sequesters Gαi3·GDP, elevating cAMP/PKA/CREB signaling that transcribes TNFAIP3, thereby inhibiting TLR4-induced NF-κB and promoting metabolic inflammation.

    Evidence Myeloid-specific GPSM1 KO mice, HFD metabolic phenotyping, ChIP-PCR, mass spectrometry, co-IP

    PMID:36434066

    Open questions at the time
    • Whether Gβγ liberation contributes to the inflammatory phenotype not tested
    • Ubiquitin ligase targeting GPSM1 for K63 ubiquitination not identified
  14. 2023 High

    The long-standing question of AGS3 vs LGN in spindle orientation was definitively resolved in epidermis: AGS3 antagonizes LGN by displacing it from the apical cortex, promoting planar/symmetric divisions, while LGN promotes perpendicular/asymmetric divisions; genetic epistasis confirms AGS3 acts through LGN.

    Evidence In vivo mouse epidermal manipulation, live imaging, double-mutant epistasis, clonal lineage tracing

    PMID:37017303

    Open questions at the time
    • Molecular mechanism by which AGS3 displaces LGN from cortex not defined
    • Whether AGS3 competes directly with LGN for Gαi or acts indirectly unclear
  15. 2025 Medium

    The molecular basis for AGS3/LGN functional divergence in spindle orientation was identified: AGS3 cannot form stable hetero-hexameric complexes with NuMA due to differences in ~20 N-terminal residues preceding the TPR domain, and Insc selectively disrupts AGS3/NuMA but not LGN/NuMA complexes.

    Evidence Biochemical reconstitution, gel filtration, pulldown with domain truncations

    PMID:39580365

    Open questions at the time
    • Structural determination of AGS3 TPR domain vs LGN TPR domain not achieved
    • Whether this oligomerization difference fully explains all in vivo context-dependent phenotypes unknown
  16. 2025 Medium

    Direct demonstration that AGS3's GDI activity is sufficient to liberate Gβγ signaling was achieved using an optogenetic GPR-based tool (OptoGDI) at the plasma membrane, producing localized PIP3 and triggering macrophage migration without GPCR activation.

    Evidence Optogenetic plasma membrane recruitment, PIP3 biosensor imaging, macrophage migration assay

    PMID:39904370

    Open questions at the time
    • Whether endogenous AGS3 produces comparable spatially restricted Gβγ signals not shown
    • OptoGDI may not recapitulate TPR-domain-dependent regulation of endogenous AGS3

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase targeting GPSM1, the structural basis for differential GPR motif affinities and their regulation by phosphorylation, the mechanism by which AGS3 displaces LGN from the cortex in epithelia, and whether AGS3 functions primarily through Gαi sequestration or Gβγ liberation in each specific biological context.
  • No E3 ligase for GPSM1 identified
  • No high-resolution structure of full-length AGS3 or AGS3–Gαi complex
  • Gαi vs Gβγ effector identity in specific tissues not systematically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 3
Localization
GO:0005829 cytosol 3 GO:0005794 Golgi apparatus 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-9612973 Autophagy 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
GNAI1GNAI3GPSM2INSCNUMA1RIC8ASTK11USP9X
Complex memberships
AGS3·Gαi·GDP complexmInsc–AGS3–Par3 complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 AGS3's C-terminal domain contains four GPR (G-protein regulatory) motifs that selectively bind the GDP-bound conformation of Gαi (not GTPγS-bound), compete with Gβγ for Gαi(GDP) binding, and act as a guanine nucleotide dissociation inhibitor (GDI), blocking GTPγS binding to Gαi. AGS3 co-immunoprecipitates with Gαi3 from cell and tissue lysates. Co-immunoprecipitation, GST pulldown with purified Gα subunits, GTPγS binding assays, immunofluorescence/confocal imaging The Journal of biological chemistry High 11042168
2000 A consensus GPR peptide from AGS3 stabilizes the GDP-bound conformation of Gαi (functions as GDI), inhibits GTPγS binding to Gαi1/2, and blocks receptor coupling to Gαiβγ, indicating that AGS3-GPR-stabilized Gαi(GDP) is not recognized by GPCRs. In vitro GTPγS binding assays, receptor-G protein coupling assays with purified proteins and peptides The Journal of biological chemistry High 10969064
2000 The AGS3 GPR domain inhibits GDP dissociation from Gαi and rhodopsin-stimulated GDP release from Gαt, acting as a GDP dissociation inhibitor. The full-length GPR domain (residues 463–650) is ~30-fold more potent than a two-GPR-motif fragment, and does not alter the catalytic rate of GTP hydrolysis by Gαt. In vitro kinetic assays of GTPγS binding, GDP release (stopped-flow/fluorescence), steady-state GTP hydrolysis with purified Gα subunits The Journal of biological chemistry High 11024022
2001 AGS3 exists in two forms: a full-length brain-enriched form (AGS3-LONG, 650 aa) and a heart-enriched truncated form (AGS3-SHORT, starting at Met495) that lacks TPR domains but retains GPR motifs. Both forms selectively bind Gαi1/2/3 in GDP-bound conformation and inhibit GTPγS binding, but they differ in subcellular distribution. cDNA library screening, RNase protection, GST pulldown with purified Gα, GTPγS binding assay, immunofluorescence, subcellular fractionation The Journal of biological chemistry High 11278352
2002 LGN (but not AGS3) translocates from the nucleus to the midbody during cytokinesis in PC12 and COS7 cells, suggesting a role for LGN/G-proteins in cytokinesis; AGS3 and LGN have distinct subcellular distributions regulated by cell cycle and external stimuli. Immunocytochemistry, confocal microscopy, cell cycle analysis in dividing cells The Journal of biological chemistry Medium 11832491
2003 AGS3 localizes to compartments compatible with autophagosome formation and its C-terminal GPR domain (which binds Gαi3) promotes macroautophagy, while its N-terminal domain (non-Gαi3-interacting) inhibits autophagy; AGS3 acts at an early event in the autophagic pathway prior to autophagosome formation. Immunofluorescence localization, expression of domain truncation mutants, biochemical and morphometric analysis of autophagic flux in HT-29 cells The Journal of biological chemistry Medium 12642577
2003 AGS3 interacts with the serine/threonine kinase LKB1; LKB1 immunoprecipitates phosphorylate the GPR domains of AGS3, and phosphorylation within the GPR motif reduces binding to Gα, suggesting that LKB1-mediated phosphorylation of GPR domains is a regulatory mechanism for AGS3–G-protein interactions. Yeast two-hybrid screen, co-immunoprecipitation from mammalian cells/brain lysate, in vitro phosphorylation assay, GPR peptide competition The Journal of biological chemistry Medium 12719437
2003 AGS3-C (C-terminal domain) possesses two high-affinity (Kd ~20 nM) and two low-affinity (Kd ~300 nM) binding sites for Gαi1; individual GPR motif peptides bind with Kd 1–8 µM. Residues flanking the GPR core strongly potentiate binding affinity and GDI activity. GPR3 alone lacks GDI activity but gains it with flanking residues. Isothermal titration calorimetry (ITC), fluorescent GTP analog binding assay with purified proteins and peptides The Journal of biological chemistry High 14530282
2003 Cytosolic (not membrane-associated) AGS3 can interact with Gαi subunits and disrupt receptor-G protein coupling; cytosolic AGS3 removes Gαi subunits from the membrane and sequesters them in the cytosol, as shown in an Sf9 membrane reconstitution system. Sf9 membrane-based receptor-G protein coupling reconstitution, GST pulldown, immunoblotting of membrane/cytosolic fractions Biochemistry Medium 12834360
2004 AGS3-SHORT blocks adenylyl cyclase sensitization that normally follows prolonged Gαi-coupled receptor activation; this effect requires intact G-protein binding by AGS3, and is correlated with AGS3 stabilizing Gαi3 in the membrane and slowing Gαi3 decay. cAMP measurement in CHO cells, immunoblot of membrane Gαi3, G-protein binding mutant controls The Journal of biological chemistry Medium 14726514
2005 AGS3 (and Gβγ) regulate mitotic spindle orientation in neural progenitors of the developing neocortex; silencing AGS3 shifts spindle orientation from apical-basal to planar divisions, causing hyperdifferentiation of progenitors due to both daughter cells adopting a neuronal fate. In utero RNA interference in mouse neocortex, spindle angle measurements, cell fate analysis by immunofluorescence Cell High 16009138
2006 Human Inscuteable (mInsc) proteins bind to both LGN and AGS3 through their TPR domains, and to Par3/Par3β; coexpression of mInsc bridges LGN and Par3 (which do not interact directly), indicating mInsc is an adaptor linking Pins homologs to the Par polarity complex. Co-immunoprecipitation from transfected mammalian cells Biochemical and biophysical research communications Medium 16458856
2007 AGS3 overexpression alters surface expression of a subset of plasma membrane receptors/channels and disrupts trans-Golgi network (TGN)-associated cargo localization without affecting cis- or medial-Golgi; AGS3 knockdown similarly disperses TGN markers, implicating AGS3 in protein trafficking along the TGN/plasma membrane/endosome loop. Biotin-based internalization assay, immunofluorescence of Golgi markers, siRNA knockdown, flow cytometry of surface proteins Proceedings of the National Academy of Sciences of the United States of America Medium 17991770
2008 Ric-8A (a GEF) catalyzes rapid GDP release from the AGS3-C:Gαi1·GDP complex by forming a transient ternary complex; subsequent dissociation of AGS3 and GDP yields a stable nucleotide-free Ric-8A·Gαi1 complex that proceeds to Gαi1·GTP upon GTP addition. AGS3 cannot reverse the Ric-8A·Gαi1 complex, ensuring unidirectional Gα activation. Pulldown assays, gel filtration, isothermal titration calorimetry, stopped-flow fluorescence spectroscopy with purified proteins The Journal of biological chemistry High 18541531
2008 AGS3 upregulation in rat nucleus accumbens core during ethanol abstinence drives ethanol-seeking behavior through Gβγ signaling; AGS3 knockdown or Gβγ sequestration (but not Gαi knockdown) reduced ethanol seeking, placing AGS3 upstream of Gβγ in this behavioral circuit. Lentiviral shRNA knockdown in rat brain, operant ethanol self-administration model, pharmacological Gβγ sequestration, Gαi knockdown Proceedings of the National Academy of Sciences of the United States of America Medium 18719114
2010 AGS3 interacts with LC3 (autophagosome marker), recruits Gαi3 to LC3-positive membranes upon starvation, and promotes autophagy by acting as GDI for Gαi3. Upon growth factor stimulation, GIV (a GEF for Gαi3) disrupts the Gαi3–AGS3 complex, releasing Gαi3 from LC3-positive membranes and inhibiting autophagy. Protein-protein interaction assays (co-IP, pulldown), G protein enzymology, morphological analysis of autophagy (LC3 puncta), starvation/growth factor conditions Molecular biology of the cell High 21209316
2010 α2-adrenergic and μ-opioid receptor activation reduces AGS3–Gαi1 BRET signal by >30% (pertussis toxin- and RGS4-sensitive), indicating that GPCR activation dissociates the AGS3·Gαi complex at the cell cortex. AGS3 also shows BRET with GPCRs, suggesting it is part of a larger receptor signaling complex. Bioluminescence resonance energy transfer (BRET) in live mammalian cells, pharmacological and genetic controls (pertussis toxin, RGS4, GRK2-ct) The Journal of biological chemistry Medium 20716524
2010 AGS3 enters the aggresome pathway; Gαi rescues AGS3 from the aggresome, whereas mInsc augments aggresome-like distribution. TPR domain integrity and a specific nonsynonymous SNP regulate AGS3 aggresome entry, revealing that Gαi and mInsc bidirectionally control AGS3 subcellular distribution under cellular stress. Immunofluorescence, confocal microscopy, co-expression with Gαi/mInsc, TPR domain mutant and SNP analysis in COS7 cells Molecular and cellular biology Medium 20065032
2010 AGS3 interacts with the deubiquitinating enzyme USP9x (interaction mediated through AGS3's C-terminal GPR domain); USP9x knockdown reduces AGS3 levels, while USP9x or its deubiquitinating domain UCH overexpression increases AGS3, indicating USP9x stabilizes a subpopulation of AGS3 through deubiquitination. Co-immunoprecipitation, USP9x knockdown, overexpression of catalytic domain mutants, immunofluorescence of Golgi markers PloS one Medium 20305814
2009 Morphine withdrawal-induced cAMP superactivation requires AGS3 upregulation; elevated AGS3 binds Gαi and prevents its inhibition of adenylyl cyclase, while withdrawal-induced cAMP/PKA activates phospholipase C and εPKC to further stimulate AC5 and AC7. cAMP measurement in nucleus accumbens/striatal neurons, AGS3 knockdown, pharmacological dissection of Gβγ vs Gαi involvement, AC5/AC7 identification Molecular pharmacology Medium 19549762
2011 In C. elegans, AGS-3 (GPSM1 ortholog) activates Gαo signaling in ASH chemosensory neurons in response to food deprivation; genetic epistasis shows AGS-3 and the GEF RIC-8 act in ASH in a mutually dependent fashion to activate Gαo, requiring the GPR domain–Gαo interaction, and Gαo-GTP is the downstream signaling molecule. Genetic epistasis analysis in C. elegans (double mutants, tissue-specific rescue), behavioral assays (octanol aversion delay), biochemical fractionation The Journal of neuroscience High 21832186
2014 AGS3 is required for proper chemokine receptor signaling in leukocytes; AGS3-null B and T lymphocytes and dendritic cells show defects in chemotaxis, reduced chemokine-stimulated calcium mobilization, and altered ERK and Akt activation. Characterization of Gpsm1-/- mice: chemotaxis assays, calcium flux measurements, ERK/Akt phosphorylation immunoblots in primary immune cells The Journal of biological chemistry Medium 24573680
2017 AGS3 is not recruited to the cell cortex in mouse neural progenitors and does not rescue LGN loss of function in oriented divisions; despite conserved in vitro interactions with NuMA and Gαi, AGS3 lacks spindle orientation function in vivo, revealing that species-specific modulation of interactions distinguishes LGN and AGS3 function. In utero electroporation (mouse neocortex), LGN rescue experiments, in vitro binding assays, spindle angle measurements EMBO reports Medium 28684399
2018 Phosphorylation of AGS3 at a single threonine (T602) in the GPR domain regulates its subcellular distribution: AGS3-T602A localizes to cytosolic puncta instead of cortical/diffuse distribution, and this punctate localization is rescued by co-expression of Gαi or Gαo but not Gαs or Gαq, indicating that GPR phosphorylation controls G-protein-dependent subcellular positioning of AGS3. Site-directed mutagenesis, immunofluorescence in COS7 cells, alkaline phosphatase treatment + SDS-PAGE gel shift, co-expression with Gα subunits Journal of cell science Medium 30404823
2020 AGS3 regulates E-cadherin (Cdh1) transport to the plasma membrane via the trans-Golgi network in early mouse embryos; AGS3 knockout arrests embryo development after the 4-cell stage with decreased membrane Cdh1 accumulation and dispersal of TGN markers; Gαi1 overexpression rescues AGS3-overexpression phenotype, indicating Gαi1 acts downstream of AGS3 in TGN-to-membrane trafficking. CRISPR/Cas9 knockout in mouse embryos, fluorescent protein tagging of TGN markers (TGN46, TMED7), live imaging, Gαi1 rescue experiment Journal of cell science Medium 33148610
2020 AGS3 and Gαi3 are co-upregulated as part of the spindle orientation complex during human neural progenitor cell differentiation; co-immunoprecipitation shows AGS3 preferentially interacts with Gαi3 (not Gαi1/2) in differentiated cells, and this interaction is suppressed by GTPγS and pertussis toxin, indicating AGS3 recognizes the same Gα binding site as GPCRs. Co-immunoprecipitation, western blot from differentiating neural progenitor cell lines, GTPγS and pertussis toxin treatments Molecules Medium 33172018
2022 Myeloid GPSM1 promotes metabolic inflammation; GPSM1 deficiency in macrophages mainly promotes TNFAIP3 transcription via the Gαi3/cAMP/PKA/CREB axis, thereby inhibiting TLR4-induced NF-κB signaling. USP9X prevents GPSM1 degradation through K63-polyubiquitination stabilization. Myeloid-specific GPSM1 knockout mice, high-fat diet metabolic phenotyping, ChIP-PCR, mass spectrometry, co-immunoprecipitation, macrophage signaling assays Nature communications High 36434066
2023 AGS3 negatively regulates LGN to balance spindle orientation in mammalian epidermis; AGS3 overexpression displaces LGN from the apical cortex and increases planar divisions, AGS3 loss prolongs cortical LGN localization and biases toward perpendicular divisions; genetic epistasis in double mutants confirms AGS3 acts through LGN. Clonal lineage tracing shows AGS3 promotes symmetric fates and LGN promotes asymmetric fates. In vivo mouse epidermal genetic manipulation, static and ex vivo live imaging, genetic epistasis (double mutant analysis), clonal lineage tracing eLife High 37017303
2023 GPSM1 deficiency in POMC neurons protects against diet-induced obesity by enhancing autophagy and improving leptin sensitivity through PI3K/AKT/mTOR signaling, increasing POMC/α-MSH production and sympathetic innervation of brown adipose tissue. POMC-neuron-specific GPSM1 knockout mice, high-fat diet metabolic phenotyping, immunofluorescence, immunohistochemistry, molecular pathway analysis (PI3K/AKT/mTOR) Molecular metabolism Medium 37979657
2025 AGS3 binds NuMA and Gαi3·GDP in vitro similarly to LGN, but cannot form stable hetero-hexamers or higher-order oligomeric complexes with NuMA that are required for spindle orientation. The ~20 N-terminal residues preceding the conserved TPR motifs account for this difference. Insc disrupts the AGS3/NuMA oligomeric complex but not the LGN/NuMA complex, further distinguishing their spindle orientation functions. Biochemical reconstitution, gel filtration, pulldown assays, structural characterization of AGS3 vs LGN domain truncations Journal of molecular cell biology Medium 39580365
2025 GPSM1 is stabilized by USP9X via prevention of K63-polyubiquitination-dependent degradation; GPSM1 stabilization leads to MEIS3 nuclear translocation, activating CSF1 (macrophage colony-stimulating factor) expression, driving M2 macrophage polarization and anti-PD-1 resistance in colorectal cancer. ChIP-PCR, mass spectrometry, co-immunoprecipitation, single-cell RNA sequencing, orthotopic CRC model, macrophage polarization assays Journal for immunotherapy of cancer Medium 40010765
2025 Plasma membrane recruitment of an optogenetic tool based on AGS3's GPR motif (OptoGDI) releases Gβγ in living cells in a GPCR-independent manner, generating localized PIP3 and triggering macrophage migration, directly demonstrating that AGS3-mediated GDI activity on Gαi is sufficient to produce free Gβγ signaling. Optogenetics in living cells, PIP3 biosensor imaging, macrophage migration assay Open biology Medium 39904370

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 G protein betagamma subunits and AGS3 control spindle orientation and asymmetric cell fate of cerebral cortical progenitors. Cell 229 16009138
2003 Asymmetrically distributed C. elegans homologs of AGS3/PINS control spindle position in the early embryo. Current biology : CB 198 12814548
2001 Selective interaction of AGS3 with G-proteins and the influence of AGS3 on the activation state of G-proteins. The Journal of biological chemistry 132 11042168
2000 Stabilization of the GDP-bound conformation of Gialpha by a peptide derived from the G-protein regulatory motif of AGS3. The Journal of biological chemistry 121 10969064
2002 Expression analysis and subcellular distribution of the two G-protein regulators AGS3 and LGN indicate distinct functionality. Localization of LGN to the midbody during cytokinesis. The Journal of biological chemistry 100 11832491
2000 AGS3 inhibits GDP dissociation from galpha subunits of the Gi family and rhodopsin-dependent activation of transducin. The Journal of biological chemistry 98 11024022
2006 AGS3, an alpha(1-3)glucan synthase gene family member of Aspergillus fumigatus, modulates mycelium growth in the lung of experimentally infected mice. Fungal genetics and biology : FG & B 88 16531086
2011 A GDI (AGS3) and a GEF (GIV) regulate autophagy by balancing G protein activity and growth factor signals. Molecular biology of the cell 87 21209316
2008 Nucleus accumbens AGS3 expression drives ethanol seeking through G betagamma. Proceedings of the National Academy of Sciences of the United States of America 69 18719114
2003 The G-protein regulator AGS3 controls an early event during macroautophagy in human intestinal HT-29 cells. The Journal of biological chemistry 64 12642577
2008 Ric-8A catalyzes guanine nucleotide exchange on G alphai1 bound to the GPR/GoLoco exchange inhibitor AGS3. The Journal of biological chemistry 58 18541531
2003 Interaction of activator of G-protein signaling 3 (AGS3) with LKB1, a serine/threonine kinase involved in cell polarity and cell cycle progression: phosphorylation of the G-protein regulatory (GPR) motif as a regulatory mechanism for the interaction of GPR motifs with Gi alpha. The Journal of biological chemistry 54 12719437
2001 Identification of a truncated form of the G-protein regulator AGS3 in heart that lacks the tetratricopeptide repeat domains. The Journal of biological chemistry 54 11278352
2009 Up-regulation of AGS3 during morphine withdrawal promotes cAMP superactivation via adenylyl cyclase 5 and 7 in rat nucleus accumbens/striatal neurons. Molecular pharmacology 48 19549762
2010 Regulation of the AGS3·G{alpha}i signaling complex by a seven-transmembrane span receptor. The Journal of biological chemistry 45 20716524
2003 Thermodynamic characterization of the binding of activator of G protein signaling 3 (AGS3) and peptides derived from AGS3 with G alpha i1. The Journal of biological chemistry 44 14530282
2004 AGS3 and signal integration by Galpha(s)- and Galpha(i)-coupled receptors: AGS3 blocks the sensitization of adenylyl cyclase following prolonged stimulation of a Galpha(i)-coupled receptor by influencing processing of Galpha(i). The Journal of biological chemistry 42 14726514
2007 A specific role of AGS3 in the surface expression of plasma membrane proteins. Proceedings of the National Academy of Sciences of the United States of America 37 17991770
2022 GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages. Nature communications 36 36434066
2006 Two forms of human Inscuteable-related protein that links Par3 to the Pins homologues LGN and AGS3. Biochemical and biophysical research communications 28 16458856
2011 AGS-3 alters Caenorhabditis elegans behavior after food deprivation via RIC-8 activation of the neural G protein G αo. The Journal of neuroscience : the official journal of the Society for Neuroscience 26 21832186
2010 Distribution of activator of G-protein signaling 3 within the aggresomal pathway: role of specific residues in the tetratricopeptide repeat domain and differential regulation by the AGS3 binding partners Gi(alpha) and mammalian inscuteable. Molecular and cellular biology 25 20065032
2014 Defective chemokine signal integration in leukocytes lacking activator of G protein signaling 3 (AGS3). The Journal of biological chemistry 24 24573680
2004 Asymmetric localization of LGN but not AGS3, two homologs of Drosophila pins, in dividing human neural progenitor cells. Journal of neuroscience research 22 14994339
2015 AGS3 is involved in TNF-α medicated osteogenic differentiation of human dental pulp stem cells. Differentiation; research in biological diversity 20 26143356
2013 A role for activator of G-protein signaling 3 (AGS3) in multiple myeloma. International journal of hematology 20 24307516
2010 An inhibitory role of the G-protein regulator AGS3 in mTOR-dependent macroautophagy. PloS one 19 20126274
2003 Influence of cytosolic AGS3 on receptor--G protein coupling. Biochemistry 18 12834360
2017 Loss of the canonical spindle orientation function in the Pins/LGN homolog AGS3. EMBO reports 17 28684399
2010 Identification of a deubiquitinating enzyme as a novel AGS3-interacting protein. PloS one 16 20305814
2013 Normal autophagic activity in macrophages from mice lacking Gαi3, AGS3, or RGS19. PloS one 14 24312373
2020 Depletion of GPSM1 enhances ovarian granulosa cell apoptosis via cAMP-PKA-CREB pathway in vitro. Journal of ovarian research 13 33220708
2018 Role of G-proteins and phosphorylation in the distribution of AGS3 to cell puncta. Journal of cell science 12 30404823
2016 Regulation of Airway Inflammation by G-protein Regulatory Motif Peptides of AGS3 protein. Scientific reports 10 27270970
2013 Differential effects of AGS3 expression on D(2L) dopamine receptor-mediated adenylyl cyclase signaling. Cellular and molecular neurobiology 10 23504261
2023 AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis. eLife 9 37017303
2020 Genome-wide meta-analysis associates GPSM1 with type 2 diabetes, a plausible gene involved in skeletal muscle function. Journal of human genetics 9 31959871
2025 Disruption of GPSM1/CSF1 signaling reprograms tumor-associated macrophages to overcome anti-PD-1 resistance in colorectal cancer. Journal for immunotherapy of cancer 8 40010765
2023 GPSM1 in POMC neurons impairs brown adipose tissue thermogenesis and provokes diet-induced obesity. Molecular metabolism 8 37979657
2021 Knockdown of GPSM1 Inhibits the Proliferation and Promotes the Apoptosis of B-Cell Acute Lymphoblastic Leukemia Cells by Suppressing the ADCY6-RAPGEF3-JNK Signaling Pathway. Pathology oncology research : POR 8 34257610
2013 Increased expression of AGS3 in rat brain cortex after traumatic brain injury. Journal of neuroscience research 8 23404409
2022 Investigation of bioactivity of unsaturated oligo‑galacturonic acids produced from apple waste by Alcaligenes faecalis AGS3 and Paenibacillus polymyxa S4 Pectinases. Scientific reports 5 36138114
2025 GPSM1 interacts and cooperates with MMP19 to promote proliferation and EMT in colorectal cancer cells. Biochimica et biophysica acta. Molecular cell research 3 39855604
2020 AGS3-dependent trans-Golgi network membrane trafficking is essential for compaction in mouse embryos. Journal of cell science 3 33148610
2020 AGS3 and Gαi3 Are Concomitantly Upregulated as Part of the Spindle Orientation Complex during Differentiation of Human Neural Progenitor Cells. Molecules (Basel, Switzerland) 3 33172018
2025 AGS3-based optogenetic GDI induces GPCR-independent Gβγ signalling and macrophage migration. Open biology 2 39904370
2012 The G protein regulator AGS-3 allows C. elegans to alter behaviors in response to food deprivation. Worm 1 24058824
2025 Molecular insights into AGS3's role in spindle orientation: a biochemical perspective. Journal of molecular cell biology 0 39580365
2025 Myeloid GPSM1 regulates atherosclerosis progression by governing monocyte and macrophage activation and chemotaxis. Proceedings of the National Academy of Sciences of the United States of America 0 41296728
2024 AGS3-based optogenetic GDI induces GPCR-independent Gβγ signaling and macrophage migration. bioRxiv : the preprint server for biology 0 38895415
2010 [The effect of AGS3 on the I(A) of newborn rat prefrontal cortical neurons pretreated by chronic morphine]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 0 20684276