Affinage

Showing GPSM1 — AGS3 is a alias.

GPSM1

G-protein-signaling modulator 1 · UniProt Q86YR5

Length
675 aa
Mass
74.5 kDa
Annotated
2026-06-10
35 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPSM1 (AGS3) is a receptor-independent activator of G-protein signaling that uses its GoLoco/GPR motifs to bind Gαi/o-GDP, thereby partitioning heterotrimeric G-protein subunits and tuning both Gαi-dependent and Gβγ-dependent outputs across many cell types (PMID:20716524, PMID:30404823). In intact cells GPSM1 assembles with Gαi1 and dynamically dissociates from a cortical signaling complex upon GPCR activation in a pertussis-toxin- and RGS4-sensitive manner (PMID:20716524), and its subcellular distribution is governed by phosphorylation of a single GPR-domain threonine (T602), with Gαi or Gαo co-expression—but not Gαs or Gαq—redirecting its localization (PMID:30404823). Through the released Gβγ arm, GPSM1 acts as a positive regulator of chemokine-receptor signaling, supporting leukocyte chemotaxis, calcium mobilization, and ERK/Akt activation (PMID:24573680), potentiates polycystin-1/polycystin-2 channel activity to restrain renal cyst progression (PMID:23236168), and drives compulsive ethanol-seeking behavior (PMID:18719114). A recurrent mechanistic theme is GPSM1 control of the cAMP/PKA/CREB axis: in myeloid cells GPSM1 sustains TLR4-induced NF-κB inflammation via Gαi3/cAMP/PKA/CREB-mediated suppression of TNFAIP3, promoting diet-induced metabolic disease (PMID:36434066), and drives monocyte activation and atherosclerosis through a cAMP/PKA/KLF4/PMP22–p38/ERK MAPK cascade (PMID:41296728). GPSM1 also localizes to and organizes trans-Golgi network membranes, where it directs TMED7/E-cadherin cargo trafficking required for early embryonic cell contacts (PMID:33148610), and it antagonizes its paralog LGN/GPSM2 at the apical cortex to bias epidermal spindle orientation and cell fate (PMID:37017303). In immunometabolic and oncogenic settings, GPSM1 modulates PI3K/AKT/mTOR signaling and autophagy in POMC neurons and colorectal cancer cells (PMID:37979657, PMID:36758790), shapes Treg homeostasis via a RHOA–cell-stiffness–TAZ axis (PMID:42185270), and—when stabilized by the deubiquitinase USP9X—promotes MEIS3-driven CSF1 expression and tumor immunosuppression (PMID:40010765).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2008 High

    Established that GPSM1 acts upstream of Gβγ signaling in a behavioral context, defining its pathway position rather than merely correlating its expression with a phenotype.

    Evidence Viral siRNA knockdown in rat nucleus accumbens with operant ethanol self-administration and Gβγ-sequestration epistasis

    PMID:18719114

    Open questions at the time
    • Does not resolve which GPCR engages the GPSM1·Gαi module in this circuit
    • Molecular partners of the released Gβγ in NAcore neurons not identified
  2. 2010 High

    Showed that a seven-transmembrane receptor directly regulates the GPSM1·Gαi module, answering whether this 'receptor-independent' modulator is itself responsive to GPCR activation in living cells.

    Evidence BRET in mammalian cells with α2-adrenergic/μ-opioid receptor activation, pertussis toxin, RGS4, and GRK2-ct controls

    PMID:20716524

    Open questions at the time
    • Mechanism by which receptor activation triggers cortical complex dissociation not defined
    • Stoichiometry of the GPSM1·Gαi·receptor assembly unknown
  3. 2012 High

    Demonstrated a physiological output for GPSM1-released Gβγ on an ion channel, linking the modulator to organ-level disease progression.

    Evidence Electrophysiology of polycystin-1/2 channels plus Gpsm1-knockout × Pkd1 hypomorph mouse cross

    PMID:23236168

    Open questions at the time
    • Direct Gβγ–polycystin interaction not structurally defined
    • Whether GPSM1 acts at the channel locale or upstream is unresolved
  4. 2013 High

    Defined GPSM1 as a positive regulator of immune-cell chemokine receptor signaling, clarifying the direction of its effect on G-protein output.

    Evidence AGS3-knockout B/T lymphocytes and dendritic cells with chemotaxis, calcium flux, and ERK/Akt assays

    PMID:24573680

    Open questions at the time
    • Which chemokine receptors physically couple to GPSM1 not mapped
    • Relative contribution of Gαi vs Gβγ arms not separated in these cells
  5. 2013 Medium

    Connected GPSM1 to cAMP/PKA/CREB anti-apoptotic and adhesion signaling in a cancer context, beginning a recurring pathway theme.

    Evidence siRNA knockdown in multiple myeloma cells with p-CREB, apoptosis, and fibronectin/HS-5 adhesion assays

    PMID:24307516

    Open questions at the time
    • Direct link from GPSM1/Gαi to adenylyl cyclase not established
    • Single cell-line system without in vivo validation
  6. 2013 Medium

    Provided a negative control on the autophagy hypothesis, showing the Gαi3/AGS3/RGS19 module is dispensable for macrophage autophagy under the conditions tested.

    Evidence LC3 processing, puncta, and long-lived protein degradation assays in Gpsm1-/-, Gnai3-/-, Rgs19-/- macrophages with pertussis toxin

    PMID:24312373

    Open questions at the time
    • Negative result is context-specific to macrophages and may not generalize to other cell types
    • Does not exclude autophagy roles in non-myeloid cells
  7. 2015 Medium

    Extended the cAMP/PKA/CREB axis to differentiation control, showing GPSM1 suppresses osteogenic gene programs.

    Evidence siRNA knockdown and overexpression in TNF-α-treated dental pulp stem cells with p-CREB and osteogenic marker readouts

    PMID:26143356

    Open questions at the time
    • G-protein step linking GPSM1 to CREB not biochemically dissected
    • In vivo relevance not tested
  8. 2018 High

    Identified a single phosphorylation switch (T602) and Gαi/o binding as the determinants of GPSM1 subcellular distribution, providing a mechanistic basis for its dynamic localization.

    Evidence Site-directed mutagenesis (T602A/E/D and reversion), fluorescence microscopy, alkaline phosphatase gel shift, and Gα-subunit co-expression rescue

    PMID:30404823

    Open questions at the time
    • Kinase responsible for T602 phosphorylation not identified
    • Functional consequence of punctate vs cortical distribution for signaling not directly measured
  9. 2020 High

    Placed GPSM1 at the trans-Golgi network controlling E-cadherin cargo trafficking, expanding its role beyond plasma-membrane G-protein signaling to membrane logistics.

    Evidence CRISPR/Cas9 knockout in mouse embryos with TGN46/TMED7 live imaging and Gαi1 rescue

    PMID:33148610

    Open questions at the time
    • Molecular machinery linking GPSM1·Gαi to TMED7 cargo selection not defined
    • Whether Gβγ release participates in TGN trafficking unresolved
  10. 2020 Medium

    Linked GPSM1's inhibition of Gαi3 to Bcl-2 phosphorylation at TGN-associated membranes, suggesting a route to autophagic signaling regulation.

    Evidence Phospho-Bcl-2 immunoblotting with AGS3 overexpression/loss in an RGS4-KO background and adrenal autophagic flux

    PMID:32501280

    Open questions at the time
    • GPSM1 effect inferred indirectly through RGS4 manipulation
    • Causal chain from phospho-Bcl-2 to autophagy outcome not established
  11. 2020 Medium

    Connected GPSM1 to WNT/β-catenin signaling through a phosphorylation- and GPCR-regulated interaction with DVL2.

    Evidence Co-immunoprecipitation, phosphorylation manipulation, and β-catenin transcription reporter assay

    PMID:32737219

    Open questions at the time
    • Single Co-IP without reciprocal structural validation
    • Direct effect of GPSM1 on Frizzled–Dishevelled assembly not shown
  12. 2020 Medium

    Established GPSM1 as a pro-survival regulator in granulosa cells operating through cAMP-PKA-CREB and Bcl-2/Bax balance.

    Evidence siRNA knockdown in rat granulosa cells with cAMP measurement, proliferation, apoptosis, and pathway immunoblots

    PMID:33220708

    Open questions at the time
    • G-protein step coupling GPSM1 to cAMP not dissected
    • Single-species, single-cell-type model
  13. 2021 Medium

    Tied GPSM1 to a cAMP-generating ADCY6-RAPGEF3-JNK survival pathway in leukemia cells.

    Evidence siRNA knockdown in B-ALL cells with proliferation, apoptosis, cell-cycle, and ADCY6/RAPGEF3/JNK immunoblots

    PMID:34257610

    Open questions at the time
    • Mechanism by which GPSM1 controls ADCY6 expression unknown
    • No in vivo confirmation
  14. 2022 High

    Defined a complete myeloid signaling cascade by which GPSM1 sustains inflammation, answering how it drives metabolic disease at the molecular level.

    Evidence Myeloid-specific conditional knockout mice on HFD with Gαi3/cAMP/PKA/CREB/TNFAIP3/NF-κB biochemistry and small-molecule inhibitor

    PMID:36434066

    Open questions at the time
    • Upstream receptor coupling GPSM1 to Gαi3 in macrophages not identified
    • Transcriptional mechanism of CREB-mediated TNFAIP3 repression not fully mapped
  15. 2023 High

    Showed GPSM1 antagonizes its paralog LGN/GPSM2 at the apical cortex to set spindle orientation and cell fate, defining a paralog-competition mechanism.

    Evidence Conditional knockout/overexpression in mouse epidermis with live imaging, double-mutant epistasis, and clonal lineage tracing

    PMID:37017303

    Open questions at the time
    • Molecular basis of cortical LGN displacement by GPSM1 not resolved
    • Role of Gαi in this cortical competition not directly tested
  16. 2023 High

    Established a neuronal role for GPSM1 in energy balance via PI3K/AKT/mTOR-dependent autophagy and leptin sensitivity in POMC neurons.

    Evidence POMC-specific conditional knockout mice with HFD phenotyping, autophagy assays, and sympathetic innervation/BAT thermogenesis analysis

    PMID:37979657

    Open questions at the time
    • How GPSM1 G-protein activity feeds into PI3K/AKT/mTOR not defined
    • Direct substrate or effector connecting GPSM1 to autophagy machinery unknown
  17. 2023 Medium

    Showed GPSM1 suppresses autophagic flux and promotes metastasis in colorectal cancer through PI3K/AKT/mTOR activation.

    Evidence Gain/loss-of-function with GFP-LC3B imaging, autophagic vesicle electron microscopy, pathway immunoblots, and a metastasis mouse model

    PMID:36758790

    Open questions at the time
    • Mechanistic link from GPSM1 to PI3K activation not defined
    • Whether autophagy suppression is causal for metastasis not separated
  18. 2024 Medium

    Revealed that GPSM1 forms stress-induced biomolecular condensates distinct from stress granules and P-bodies, adding a phase-separation behavior regulated by Gαi3.

    Evidence Fluorescence microscopy, FRAP, lysate fractionation, and G αi3/DVL2 co-expression under oxidative/pH/thermal stress

    PMID:38264908

    Open questions at the time
    • Functional role of GPSM1 condensates in signaling or stress response unknown
    • Composition of the condensates not characterized
  19. 2025 High

    Defined a deubiquitination-driven oncogenic axis in which USP9X stabilizes GPSM1 to promote MEIS3/CSF1-mediated tumor immunosuppression and immunotherapy resistance.

    Evidence Mass spectrometry, co-immunoprecipitation, ChIP-PCR, single-cell RNA-seq, and orthotopic CRC xenografts with mass/flow cytometry

    PMID:40010765

    Open questions at the time
    • How GPSM1 promotes MEIS3 nuclear translocation mechanistically not resolved
    • Whether G-protein modulator activity is required for the MEIS3/CSF1 output unclear
  20. 2025 High

    Identified a complete myeloid cAMP/PKA/KLF4/PMP22–MAPK cascade through which GPSM1 drives atherosclerosis, and validated it pharmacologically and by rescue.

    Evidence Myeloid conditional KO and overexpression in Apoe-/- and AAV-PCSK9 mice with chemotaxis/adhesion assays, pathway biochemistry, PMP22 siRNA-liposome rescue, and a small-molecule GPSM1 inhibitor

    PMID:41296728

    Open questions at the time
    • Upstream receptor/Gα coupling in monocytes not defined
    • Relationship between this KLF4/PMP22 cascade and the TNFAIP3/NF-κB cascade in myeloid cells not reconciled
  21. 2026 High

    Established GPSM1 as a restrictor of adipose Treg homeostasis acting through a RHOA–cell-stiffness–TAZ mechanotransduction axis, with metabolic consequences confirmed by adoptive transfer.

    Evidence CD4/Treg-specific conditional KO and overexpression with HFD phenotyping, Treg subset flow cytometry, RHOA/TAZ biochemistry, and adoptive transfer into Rag1-/- mice

    PMID:42185270

    Open questions at the time
    • How GPSM1 G-protein activity engages RHOA/cell stiffness not defined
    • Direct GPSM1 effectors in Treg cells not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The unifying question remains how a single GoLoco/GPR Gαi/o modulator selects among its many divergent outputs—Gβγ-driven chemotaxis and channel modulation, cAMP/PKA/CREB inflammation, PI3K/AKT/mTOR autophagy, TGN cargo trafficking, cortical LGN antagonism, and ubiquitin-stabilized transcriptional programs—and which upstream receptors and cell-type-specific cofactors dictate this choice.
  • No structural model reconciling Gαi-binding with the diverse downstream cascades
  • Upstream GPCRs coupling GPSM1 in most contexts unidentified
  • Determinants of context-specific pathway selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 2 R-HSA-9612973 Autophagy 2 R-HSA-9609507 Protein localization 1
Partners
DVL2GNAI1GNAI3GNAO1GPSM2RGS4USP9X

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 AGS3 (GPSM1) forms a complex with Gαi1 in intact mammalian cells, as detected by BRET. Activation of α2-adrenergic receptors or μ-opioid receptors reduces this AGS3·Gαi1 complex by >30% in a pertussis-toxin- and RGS4-sensitive manner, but not by Gβγ sequestration. Upon receptor activation, AGS3 reversibly dissociates from the cortical signaling complex, demonstrating that a seven-transmembrane receptor directly regulates the AGS3·Gαi signaling module. Bioluminescence resonance energy transfer (BRET) in mammalian cells; pertussis toxin inhibition; RGS4 co-expression; GRK2-ct Gβγ sequestration The Journal of biological chemistry High 20716524
2008 AGS3 (GPSM1) is upregulated in the rat nucleus accumbens core during abstinence from ethanol self-administration. Knockdown of NAcore AGS3 reduces ethanol seeking to pre-abstinence levels. The effect is mediated through Gβγ: sequestration of Gβγ (but not Gαi knockdown) similarly reduces ethanol seeking, placing GPSM1 upstream of Gβγ-mediated signaling in compulsive ethanol seeking. Viral knockdown (siRNA) in vivo; operant ethanol self-administration behavioral model; Gβγ sequestration with GRK2-ct; Gαi knockdown Proceedings of the National Academy of Sciences of the United States of America High 18719114
2012 GPSM1 increases heteromeric polycystin-1/polycystin-2 ion channel activity via Gβγ subunits in renal epithelial cells. Loss of GPSM1 in a Pkd1 hypomorphic mouse model accelerates cyst progression and reduces renal function, establishing GPSM1 as a modulator of polycystin channel activity and cyst progression via Gβγ. Electrophysiology (ion channel activity assay); genetic cross of Gpsm1 knockout with Pkd1^V/V mice; renal function assessment Proceedings of the National Academy of Sciences of the United States of America High 23236168
2014 AGS3 (GPSM1) is required for normal chemokine receptor signaling in leukocytes. AGS3-null B and T lymphocytes and bone marrow-derived dendritic cells exhibit significant chemotactic defects, reduced chemokine-stimulated calcium mobilization, and altered ERK and Akt activation, indicating AGS3 is a positive regulator of G-protein signaling downstream of chemokine receptors in immune cells. AGS3 knockout mice; chemotaxis assays; calcium mobilization assays; ERK and Akt western blotting The Journal of biological chemistry High 24573680
2018 Phosphorylation of a single threonine residue (T602) in the GPR domain of AGS3 (GPSM1) controls its subcellular distribution. Non-phosphorylatable AGS3-T602A localizes to cytosolic puncta rather than the cortical/diffuse distribution of wild-type AGS3. Co-expression of Gαi or Gαo (but not Gαs or Gαq) rescues the punctate localization. Alkaline phosphatase treatment confirms phosphorylation-dependent gel shifts, and the T602E/D phosphomimetics maintain punctate distribution, while T602A→T602 reversion restores normal localization. Site-directed mutagenesis; fluorescence microscopy; alkaline phosphatase treatment; SDS-PAGE gel shift; co-expression with Gα subunit variants Journal of cell science High 30404823
2022 Myeloid GPSM1 promotes metabolic inflammation via the Gαi3/cAMP/PKA/CREB axis, which suppresses TNFAIP3 transcription and thereby sustains TLR4-induced NF-κB signaling in macrophages. Myeloid-specific GPSM1 ablation increases TNFAIP3 (A20) expression and inhibits NF-κB, protecting mice against high-fat-diet-induced insulin resistance, glucose dysregulation, and liver steatosis. Myeloid-specific conditional knockout mice; HFD metabolic phenotyping; cAMP/PKA/CREB pathway biochemistry; TNFAIP3 transcription assay; NF-κB signaling assays; small-molecule inhibitor (AN-465/42243987) Nature communications High 36434066
2020 AGS3 (GPSM1) regulates trans-Golgi network (TGN) dynamics and the transport of TMED7-positive cargo containing E-cadherin (Cdh1) to the cell-contact surface during early mouse embryo development. CRISPR/Cas9-mediated AGS3 knockout causes developmental arrest, fragmentation after the four-cell stage, and decreased Cdh1 at cell-contact membranes, along with dispersal of TGN46- and TMED7-positive vesicles. Increased Gαi1 expression rescues AGS3-overexpression phenotypes, linking AGS3's GoLoco/Gαi interaction to TGN-dependent membrane trafficking. CRISPR/Cas9 knockout in mouse embryos; fluorescent protein tagging of TGN46 and TMED7; confocal live imaging; Gαi1 rescue overexpression Journal of cell science High 33148610
2020 AGS3 (GPSM1) inhibits Gαi3 activity, and this inhibition leads to markedly increased Bcl-2 phosphorylation on TGN38-containing intracellular vesicle pools. Loss of AGS3 (along with RGS4) results in reduced phospho-Bcl-2, whereas overexpression of AGS3 increases phospho-Bcl-2 levels, linking GPSM1 to autophagic signaling regulation via Gαi3-dependent Bcl-2 phosphorylation at TGN-associated membranes. Western blotting for phospho-Bcl-2; manipulation of palmitoylation/intracellular localization of RGS4; macrophage autophagy assays; adrenal gland autophagic flux in RGS4-KO mice Journal of cell science Medium 32501280
2013 AGS3 (GPSM1) enhances phosphorylation of CREB (p-CREB) in multiple myeloma cells. Knockdown of AGS3 reduces p-CREB levels, increases apoptosis, and reverses cell adhesion to fibronectin and HS-5 stromal cells, implicating GPSM1 in anti-apoptotic signaling via cAMP/PKA/CREB in a cell adhesion context. siRNA knockdown; western blotting for p-CREB; apoptosis assay; cell adhesion assay with fibronectin and HS-5 cells; doxorubicin-induced apoptosis model International journal of hematology Medium 24307516
2015 AGS3 (GPSM1) inhibits osteogenic differentiation of dental pulp stem cells exposed to TNF-α via the cAMP/PKA/CREB signaling pathway. Increased AGS3 expression suppresses p-CREB levels and downstream osteogenic gene expression (BMP2, ID2, osteocalcin), while knockdown of AGS3 promotes osteogenic differentiation. AGS3 knockdown (siRNA) and overexpression; osteogenic differentiation assays; western blotting for p-CREB and osteogenic markers; TNF-α stimulation Differentiation; research in biological diversity Medium 26143356
2020 Silencing of Gpsm1 in rat ovarian granulosa cells reduces cAMP levels, PKA catalytic subunit, and p-CREB, decreases the Bcl-2/Bax ratio, and increases Caspase-3/Cleaved Caspase-3, leading to increased apoptosis and decreased proliferation. This establishes GPSM1 as a pro-survival regulator in granulosa cells via the cAMP-PKA-CREB pathway. siRNA knockdown; CCK8 proliferation assay; flow cytometry (apoptosis); cAMP measurement; western blotting for PKAc, p-CREB, Bcl-2, Bax, Caspase-3 Journal of ovarian research Medium 33220708
2023 AGS3 (GPSM1) antagonizes LGN (GPSM2) to regulate spindle orientation and cell fate in mammalian epidermis. AGS3 overexpression displaces LGN from the apical cortex, increasing planar divisions and symmetric fates; AGS3 loss prolongs cortical LGN localization and biases divisions toward perpendicular orientation and asymmetric fates. Genetic epistasis in double mutants confirms AGS3 operates through LGN. Clonal lineage tracing shows that LGN promotes asymmetric fates while AGS3 promotes symmetric fates and influences differentiation via delamination. Static and ex vivo live imaging; conditional knockout and overexpression in mouse epidermis; genetic epistasis (double-mutant analysis); clonal lineage tracing eLife High 37017303
2021 Knockdown of GPSM1 in B-ALL cells inhibits proliferation and promotes apoptosis by suppressing the ADCY6-RAPGEF3-JNK signaling pathway. Reduced GPSM1 decreases expression of ADCY6 and RAPGEF3, with downstream reduction in JNK activity, linking GPSM1 to cAMP production and JNK-mediated survival signaling. siRNA knockdown; cell proliferation and apoptosis assays; western blotting for ADCY6, RAPGEF3, JNK; cell cycle analysis Pathology oncology research : POR Medium 34257610
2023 GPSM1 deficiency in POMC neurons enhances autophagy and leptin sensitivity through the PI3K/AKT/mTOR signaling pathway, increasing POMC expression and α-MSH production, enhancing sympathetic innervation, and increasing brown adipose tissue thermogenesis. POMC-specific GPSM1 knockout mice are protected against diet-induced obesity, glucose dysregulation, and insulin resistance. POMC neuron-specific conditional knockout mice; HFD metabolic phenotyping; molecular/biochemical analysis of PI3K/AKT/mTOR pathway; autophagy assays; immunofluorescence/immunohistochemistry; sympathetic innervation analysis Molecular metabolism High 37979657
2023 GPSM1 promotes colorectal cancer cell migration and invasion and inhibits autophagy by activating the PI3K/AKT/mTOR pathway. GFP-LC3B imaging and autophagic vesicle ultrastructure confirmed that GPSM1 suppresses autophagic flux, while gain- and loss-of-function experiments in vitro and a tumor metastasis mouse model confirmed its role in metastasis. siRNA knockdown and overexpression; GFP-LC3B immunofluorescence; electron microscopy of autophagic vesicles; PI3K/AKT/mTOR western blotting; in vivo metastasis mouse model The international journal of biochemistry & cell biology Medium 36758790
2025 GPSM1 in macrophages promotes anti-PD-1 resistance in colorectal cancer by driving M2 polarization and tumor microenvironment immunosuppression. The deubiquitinase USP9X stabilizes GPSM1 by preventing K63-polyubiquitination-mediated degradation. Stabilized GPSM1 promotes MEIS3 nuclear translocation, which activates macrophage colony-stimulating factor (CSF1) expression. ChIP-PCR; mass spectrometry; co-immunoprecipitation; single-cell RNA sequencing; multiplex immunofluorescence; orthotopic CRC xenograft model; mass cytometry; flow cytometry Journal for immunotherapy of cancer High 40010765
2025 Myeloid GPSM1 promotes atherosclerosis by sustaining monocyte activation, chemotaxis, and adhesion through the cAMP/PKA/KLF4/PMP22 axis, which activates the p38/ERK MAPK pathway. Myeloid-specific GPSM1 ablation protects against atherosclerosis in Apoe-/- and AAV-PCSK9 mice, while myeloid-restricted GPSM1 overexpression accelerates disease. siRNA-loaded liposome blockade of PMP22 rescues GPSM1-overexpression mice, and a small molecule inhibiting GPSM1 suppresses atherosclerosis in vivo. Myeloid-specific conditional knockout and overexpression in Apoe-/- and AAV-PCSK9 mouse models; monocyte chemotaxis and adhesion assays; cAMP/PKA/KLF4/PMP22 pathway biochemistry; p38/ERK MAPK western blotting; siRNA-loaded liposome PMP22 blockade; small-molecule GPSM1 inhibitor Proceedings of the National Academy of Sciences of the United States of America High 41296728
2024 AGS3 (GPSM1) forms biomolecular condensates (BMCs) under cellular stress (oxidative, pH, thermal). Stress-induced AGS3 BMCs are biochemically distinct from G3BP1 stress granules and Dcp1a P-bodies. Co-expression of Gαi3 (but not DVL2) reduces stress-induced BMC formation. FRAP analysis reveals distinct diffusion kinetics and restricted fluidity within AGS3 BMCs, and stress shifts AGS3 to a membrane pellet fraction. Fluorescence microscopy; FRAP; immunoblotting of fractionated cell lysates; co-expression experiments with Gαi3 and DVL2; stress induction (oxidative, pH, thermal) Journal of cell science Medium 38264908
2020 AGS3 (GPSM1) interacts with Dishevelled-2 (DVL2), and this interaction is regulated by protein phosphorylation, subcellular distribution, and a cell-surface GPCR. AGS3 signaling influences β-catenin-regulated transcription through the WNT-Frizzled-Dishevelled axis, suggesting integration between Gαi/GPR signaling and WNT pathway. Co-immunoprecipitation; phosphorylation manipulation; GPCR activation; β-catenin transcription reporter assay; subcellular localization imaging Journal of cell science Medium 32737219
2013 Macrophages lacking Gαi3, AGS3 (GPSM1), or RGS19, or treated with pertussis toxin, show normal levels of basal autophagy, autophagic induction, autophagic flux, autophagic degradation, and anti-autophagic action, indicating that the Gαi3/AGS3/RGS19 pathway does not regulate autophagy in macrophages (negative finding). LC3 processing western blot; LC3 puncta formation assay; long-lived protein degradation assay; Gpsm1-/-, Gnai3-/-, Rgs19-/- bone marrow-derived macrophages; pertussis toxin treatment PloS one Medium 24312373
2026 GPSM1 in CD4+ T cells (especially Treg cells) restricts CD73+CD103+ Treg cell abundance in adipose tissue. GPSM1 deletion in CD4+ T cells or Treg cells increases adipose Treg cells, reduces inflammation, and improves metabolic parameters. Mechanistically, GPSM1 regulates Treg cell abundance via a RHOA-cell stiffness-TAZ axis. Adoptive transfer of GPSM1-deficient Treg cells improves energy expenditure and glucose/lipid metabolism in Rag1-/- mice. Conditional knockout (CD4-Cre and Treg-specific); CD4-T-cell-specific overexpression; flow cytometry (Treg subset analysis); HFD metabolic phenotyping; adoptive transfer into Rag1-/- mice; RHOA/TAZ pathway biochemistry Nature communications High 42185270

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Genetic variants of gestational diabetes mellitus: a study of 112 SNPs among 8722 women in two independent populations. Diabetologia 87 29947923
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
2008 Probing neurochemical structure and function of retinal ON bipolar cells with a transgenic mouse. The Journal of comparative neurology 55 18671302
2015 The identification of specific methylation patterns across different cancers. PloS one 47 25774687
2010 Regulation of the AGS3·G{alpha}i signaling complex by a seven-transmembrane span receptor. The Journal of biological chemistry 45 20716524
2022 GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages. Nature communications 42 36434066
2012 G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease. Proceedings of the National Academy of Sciences of the United States of America 35 23236168
2015 Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome. Carcinogenesis 31 25740824
2014 Defective chemokine signal integration in leukocytes lacking activator of G protein signaling 3 (AGS3). The Journal of biological chemistry 24 24573680
2015 AGS3 is involved in TNF-α medicated osteogenic differentiation of human dental pulp stem cells. Differentiation; research in biological diversity 21 26143356
2013 A role for activator of G-protein signaling 3 (AGS3) in multiple myeloma. International journal of hematology 20 24307516
2017 Two novel candidate genes identified in adults from the Newfoundland population with addictive tendencies towards food. Appetite 18 28115213
2018 Presence of aggregates of smooth endoplasmic reticulum in MII oocytes affects oocyte competence: molecular-based evidence. Molecular human reproduction 17 29635518
2013 Normal autophagic activity in macrophages from mice lacking Gαi3, AGS3, or RGS19. PloS one 14 24312373
2023 Three-dimensional genome landscape comprehensively reveals patterns of spatial gene regulation in papillary and anaplastic thyroid cancers: a study using representative cell lines for each cancer type. Cellular & molecular biology letters 13 36609218
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 13 30404823
2013 Group II activators of G-protein signaling: monitoring the interaction of Gα with the G-protein regulatory motif in the intact cell. Methods in enzymology 12 23374185
2023 AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis. eLife 10 37017303
2020 RGS4 controls Gαi3-mediated regulation of Bcl-2 phosphorylation on TGN38-containing intracellular membranes. Journal of cell science 10 32501280
2025 Disruption of GPSM1/CSF1 signaling reprograms tumor-associated macrophages to overcome anti-PD-1 resistance in colorectal cancer. Journal for immunotherapy of cancer 9 40010765
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
2023 G-protein signaling modulator 1 promotes colorectal cancer metastasis by PI3K/AKT/mTOR signaling and autophagy. The international journal of biochemistry & cell biology 8 36758790
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
2015 Overexpression of activator of G-protein signaling 3 decreases the proliferation of esophageal squamous cell carcinoma. Pathology, research and practice 7 25812748
2018 A Residue outside the Binding Site Determines the Gα Binding Specificity of GoLoco Motifs. Biochemistry 4 30406994
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 Intersection of two key signal integrators in the cell: activator of G-protein signaling 3 and dishevelled-2. Journal of cell science 3 32737219
2020 AGS3-dependent trans-Golgi network membrane trafficking is essential for compaction in mouse embryos. Journal of cell science 3 33148610
2024 Properties of biomolecular condensates defined by Activator of G-protein Signaling 3. Journal of cell science 1 38264908
2024 Identification of novel proteins in inflammatory bowel disease based on the gut-brain axis: a multi-omics integrated analysis. Clinical proteomics 1 39407121
2026 GPSM1 restricts CD73+CD103+ Treg cells in adipose tissue, critical for promoting obesity-related metabolic deterioration. Nature communications 0 42185270
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 Genetic causes of primary immunodeficiency in the Jordanian population. Biomedical reports 0 39268404

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