Affinage

GNB4

Guanine nucleotide-binding protein subunit beta-4 · UniProt Q9HAV0

Length
340 aa
Mass
37.6 kDa
Annotated
2026-06-10
11 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 2/3 claims corpus-supported (67%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GNB4 encodes Gβ4, a guanine nucleotide-binding protein β-subunit that positively facilitates G-protein-coupled receptor signaling, demonstrated for bradykinin-induced GPCR signaling in peripheral nerve, where Gβ4 localizes to axons and Schwann cells (PMID:23434117). Disease-associated missense mutations (p.Gly53Asp, p.Lys89Glu) impair this signaling activity, and pathogenic variants cluster spatially within the WD40 repeat region required for Gβ function, providing a structural rationale for loss of function that underlies dominant intermediate Charcot-Marie-Tooth disease (PMID:23434117, PMID:41164122). Beyond its canonical signaling role, GNB4 expression is regulated in disease contexts: it is epigenetically upregulated in gastric cancer when H. pylori-driven NF-κB induces TET1, which demethylates the GNB4 promoter, and the resulting elevated GNB4 activates Hippo-YAP1 oncogenic signaling (PMID:37016382), while it is repressed by miR-133b during osteoblast differentiation (PMID:33687637).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2013 Medium

    Established that GNB4 functions as a positive regulator of GPCR signaling and that disease mutations disrupt this activity, linking the gene to peripheral nerve function.

    Evidence In vitro bradykinin GPCR signaling assays comparing mutant and wild-type GNB4, with immunohistochemistry of peripheral nerve

    PMID:23434117

    Open questions at the time
    • Specific GPCRs and downstream effectors engaged by Gβ4 in nerve not enumerated
    • Mechanism by which mutations alter Gβ4-Gγ or receptor coupling not resolved
    • Single lab, not independently replicated
  2. 2021 Low

    Placed GNB4 downstream of a microRNA regulatory axis in bone, showing its expression is repressed by miR-133b during osteoblast differentiation.

    Evidence miR-133b target validation, GNB4 overexpression rescue, and osteoblast differentiation marker assays in cultured cells

    PMID:33687637

    Open questions at the time
    • Direct luciferase target confirmation not fully detailed
    • Signaling pathway through which GNB4 affects osteoblast fate unspecified
    • No in vivo validation
  3. 2023 Medium

    Defined an epigenetic regulatory cascade upregulating GNB4 in cancer and connected elevated GNB4 to Hippo-YAP1 oncogenic signaling.

    Evidence ChIP, methylation-specific PCR/pyrosequencing, Co-IP, gain/loss-of-function and xenograft assays in gastric cancer cells

    PMID:37016382

    Open questions at the time
    • Molecular link between Gβ4 and YAP1 activation not mechanistically dissected
    • Whether GNB4's GPCR-subunit activity mediates the Hippo effect unknown
    • Single lab, not independently replicated
  4. 2024 Low

    Positioned GNB4 upstream of the cGAS-STING/pyroptosis axis in glioma, indicating its silencing restrains tumor cell behavior.

    Evidence siRNA silencing with pharmacological cGAS-STING inhibitor rescue and proliferation/migration/invasion assays in glioma cells

    PMID:38814382

    Open questions at the time
    • No direct binding or reconstitution linking GNB4 to cGAS-STING
    • Mechanism by which GNB4 represses the pathway unknown
    • Pharmacological rescue only, single lab
  5. 2025 Low

    Provided a structural framework for GNB4 loss of function by showing pathogenic CMT variants cluster within the WD40 repeat region.

    Evidence 3D structural mapping of pathogenic variants, ACMG reclassification, and segregation analysis

    PMID:41164122

    Open questions at the time
    • Structural clustering not validated by direct in vitro functional assays
    • Effect of clustering on Gβ4 protein interactions not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Gβ4's canonical GPCR-coupled signaling activity relates mechanistically to its context-dependent roles in Hippo-YAP1, cGAS-STING, and osteoblast pathways remains unresolved.
  • No unifying mechanism connecting Gβ4 signaling subunit function to its downstream cancer and differentiation effects
  • Direct effectors and binding partners of Gβ4 in non-neuronal contexts not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 1
Pathway
R-HSA-162582 Signal Transduction 1

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 GNB4 mutations (p.Gly53Asp and p.Lys89Glu) impair bradykinin-induced G-protein-coupled receptor (GPCR) signaling that is normally facilitated by wild-type Gβ4, establishing GNB4 as a positive regulator of GPCR signaling in peripheral nerve function. In vitro GPCR signaling assays with mutant vs. wild-type GNB4 constructs; immunohistochemistry showing Gβ4 localization in axons and Schwann cells of peripheral nerves and reduced expression in sural nerve of mutation carriers American journal of human genetics Medium 23434117
2023 H. pylori infection activates NF-κB, which upregulates TET1; TET1 binds the GNB4 promoter and demethylates it (particularly at CpG#5), increasing GNB4 expression; elevated GNB4 then drives oncogenic behavior via activation of the Hippo-YAP1 pathway (promoting YAP1 activity) in gastric cancer cells. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), methylation-specific PCR, pyrosequencing, mass spectrometry, western blotting, gain/loss-of-function assays (CCK-8, EdU, colony formation, transwell, xenograft), immunofluorescence BMC medicine Medium 37016382
2024 Silencing GNB4 in glioma cells activates the cGAS-STING pathway, which in turn induces pyroptosis (evidenced by increased pyroptosis-related protein expression and elevated inflammatory factors), thereby inhibiting glioma cell proliferation, migration, and invasion. A cGAS-STING inhibitor reversed these effects, placing GNB4 upstream of cGAS-STING-mediated pyroptosis. siRNA-mediated GNB4 silencing, western blotting, ELISA, cell viability/wound-healing/transwell assays, pathway inhibitor rescue experiments Molecular biotechnology Low 38814382
2021 miR-133b targets GNB4 mRNA (confirmed as a direct downstream target), suppressing its expression; overexpression of GNB4 reverses the pro-viability and pro-differentiation effects of miR-133b on osteoblasts, placing GNB4 downstream of miR-133b in the regulation of osteoblast differentiation. qRT-PCR, western blot, CCK-8 cell viability, flow cytometry apoptosis, osteoblast differentiation markers (ALP, Runx2, Osterix, OPN); luciferase target validation implied by 'identified and confirmed as a downstream target gene' Biochemical genetics Low 33687637
2025 Pathogenic GNB4 variants in CMT patients cluster in 3D space on the GNB4 protein structure, suggesting a structural basis for loss of function; affected residues map to the WD40 domain repeat region critical for Gβ function. 3D structural mapping of known pathogenic variants, variant reclassification per ACMG guidelines, segregation analysis Neurology. Genetics Low 41164122

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease. American journal of human genetics 43 23434117
2023 Helicobacter pylori-induced aberrant demethylation and expression of GNB4 promotes gastric carcinogenesis via the Hippo-YAP1 pathway. BMC medicine 31 37016382
2023 Plasma methylated GNB4 and Riplet as a novel dual-marker panel for the detection of hepatocellular carcinoma. Epigenetics 22 38154055
2017 A novel missense variant (Gln220Arg) of GNB4 encoding guanine nucleotide-binding protein, subunit beta-4 in a Japanese family with autosomal dominant motor and sensory neuropathy. European journal of medical genetics 12 28642160
2024 CircRNA circRREB1 promotes tumorigenesis and progression of breast cancer by activating Erk1/2 signaling through interacting with GNB4. Heliyon 11 38617926
2016 Confirmation of the GNB4 gene as causal for Charcot-Marie-Tooth disease by a novel de novo mutation in a Czech patient. Neuromuscular disorders : NMD 11 27908631
2021 Clinical and Neuroimaging Features in Charcot-Marie-Tooth Patients with GNB4 Mutations. Life (Basel, Switzerland) 10 34071515
2021 MiR-133b Modulates the Osteoblast Differentiation to Prevent Osteoporosis Via Targeting GNB4. Biochemical genetics 8 33687637
2024 GNB4 Silencing Promotes Pyroptosis to Inhibit the Development of Glioma by Activating cGAS-STING Pathway. Molecular biotechnology 7 38814382
2022 Disrupting circ-GNB4 mitigates high glucose-induced human mesangial cells injury by regulating the proliferation, ECM accumulation, inflammation and oxidative stress through circ-GNB4/miR-23c/EGR1 pathway [RETRACTED]. Journal of cardiovascular pharmacology 6 35170486
2025 Novel GNB4 Gene Variant and the Spectrum of GNB4 Variants in Patients With Charcot-Marie-Tooth Disease. Neurology. Genetics 0 41164122

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