Affinage

GNAZ

Guanine nucleotide-binding protein G(z) subunit alpha · UniProt P19086

Length
355 aa
Mass
40.9 kDa
Annotated
2026-04-28
32 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GNAZ encodes Gαz, a pertussis toxin-insensitive inhibitory heterotrimeric G protein alpha subunit that transduces signals from diverse receptors to regulate axon guidance, photoreceptor physiology, barrier integrity, and endocrine secretion. Gαz localizes to axonal growth cones where it inhibits BDNF-stimulated axon growth and couples Smoothened signaling downstream of Sonic Hedgehog to mediate enteric axon repulsion (PMID:24321455, PMID:25535338). In the retina, Gαz undergoes circadian- and dopamine D4 receptor-dependent rhythmic redistribution in photoreceptors and sequesters the sheddase ADAM17 in retinal endothelial cells, preventing claudin-5 cleavage and preserving inner blood-retinal barrier integrity (PMID:29088301, PMID:37095509). GNAZ transcription is driven by a CDKN2B-AS1/E2F1 axis and post-transcriptionally suppressed by miR-20a-3p, and in hepatocellular carcinoma its overexpression activates ERK/MAPK signaling to promote vasculogenic mimicry (PMID:38077646, PMID:41306771).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1988 High

    The chromosomal position of GNAZ was unknown among the expanding G protein alpha-subunit family; somatic cell hybrid mapping placed it on human chromosome 22, anchoring it genomically.

    Evidence cDNA hybridization to human-mouse somatic cell hybrid DNA panel

    PMID:2902634

    Open questions at the time
    • No functional data at this stage
    • Expression pattern undefined
  2. 1995 Medium

    Whether GNAZ was expressed outside the brain was unclear; detection of Gαz mRNA and protein in human fetal cochlea expanded the tissue repertoire and suggested involvement in ionic homeostasis of cochlear fluids.

    Evidence Northern blot, in situ hybridization, and immunohistochemistry on human fetal cochlea

    PMID:8975005

    Open questions at the time
    • Functional role in cochlea remains inferred from localization only
    • No loss-of-function data in this tissue
  3. 2013 High

    It was not known whether Gαz had a cell-autonomous role in CNS axon development; Gnaz knockout cortical neurons showed enhanced BDNF-stimulated axon growth, establishing Gαz as an endogenous brake on neurotrophin-driven axon extension.

    Evidence Gnaz knockout mouse cortical neurons, immunolocalization to growth cones, axon length assays

    PMID:24321455

    Open questions at the time
    • Receptor upstream of Gαz in cortical neurons not identified
    • Downstream effector linking Gαz to growth cone cytoskeleton unknown
  4. 2014 High

    How Sonic Hedgehog repels enteric axons was unresolved; this work showed that Gαz couples the Smoothened receptor to an axon-repulsive output, and Gnaz-mutant intestines exhibit misprojected enteric axons.

    Evidence Gnaz knockdown and dominant-negative inhibition in enteric neurons, axon turning assay, Gnaz mutant mouse intestines

    PMID:25535338

    Open questions at the time
    • Effector between Gαz and cytoskeletal rearrangement in enteric growth cones uncharacterized
    • Whether Gαz-Smo coupling is direct or requires an intermediate is unresolved
  5. 2017 High

    How circadian and dopaminergic signals converge on photoreceptor G protein signaling was unknown; Gαz was shown to undergo daily rhythmic subcellular redistribution in photoreceptors dependent on Clock and dopamine D4 receptors.

    Evidence Microdissected photoreceptors from Clock KO and D4R KO mice, subcellular fractionation, constant-darkness paradigm

    PMID:29088301

    Open questions at the time
    • Downstream effector of Gαz in photoreceptor signaling not identified
    • Mechanism driving Gαz subcellular translocation unclear
  6. 2021 Low

    Whether GNAZ variants could activate oncogenic signaling was untested; a somatic GNAZ variant in a plexiform neurofibroma increased ERK1/2 phosphorylation relative to wild-type, linking mutant Gαz to MAPK pathway activation.

    Evidence Whole-exome sequencing of tumor, ERK phosphorylation assay comparing mutant and wild-type GNAZ in cell lines

    PMID:34913528

    Open questions at the time
    • Single case with limited controls
    • Mechanism by which mutant Gαz activates ERK unknown
    • Not independently confirmed in additional tumors
  7. 2023 High

    The mechanism protecting the inner blood-retinal barrier from sheddase activity was unclear; Gαz was shown to sequester ADAM17, and disruption of this interaction (by blue light or GNAZ knockdown) hyperactivates ADAM17, cleaves claudin-5, and increases paracellular permeability.

    Evidence Co-immunoprecipitation of GNAZ-ADAM17, GNAZ knockdown in vitro and in vivo, tight junction permeability assays, mouse blue-light model

    PMID:37095509

    Open questions at the time
    • Structural basis of the GNAZ-ADAM17 interaction unknown
    • Whether Gαz GTPase activity is required for ADAM17 sequestration untested
  8. 2023 Medium

    Transcriptional control of GNAZ was undefined; the CDKN2B-AS1 lncRNA was found to recruit E2F1 to the GNAZ promoter, driving transcription, and miR-20a-3p was identified as a direct post-transcriptional suppressor, with GNAZ overexpression promoting ERK-dependent vasculogenic mimicry in hepatocellular carcinoma.

    Evidence RNA immunoprecipitation, ChIP, dual-luciferase reporters, miR-20a-3p overexpression, in vivo VM/metastasis assays in HCC models

    PMID:38077646 PMID:41306771

    Open questions at the time
    • Findings from a single group; independent replication needed
    • Whether ERK activation by wild-type Gαz in HCC uses the same mechanism as the tumor-derived mutant is unknown
    • Role of GTPase cycle in ERK activation not dissected
  9. 2025 High

    How FFAR4 agonists stimulate insulin secretion was incompletely understood; Gnaz deletion in mouse δ cells abolished FFAR4-mediated inhibition of somatostatin secretion and the associated Ca²⁺ transient reduction, demonstrating Gαz as the coupling G protein in δ cells for paracrine regulation of insulin release.

    Evidence (preprint) Gnaz knockout mouse islets, δ-cell ablation, SST-deficient mice, Ca²⁺ imaging, insulin/SST secretion assays

    PMID:40894772

    Open questions at the time
    • Preprint; not yet peer-reviewed
    • Mechanism differs between mouse and human islets — human δ-cell coupling not fully resolved
    • Direct Gαz–FFAR4 physical interaction not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The immediate downstream effectors of Gαz in most contexts (growth cones, photoreceptors, enteric axons) remain unidentified, and no structural model of Gαz interaction with ADAM17 or Smoothened exists.
  • No effector identified for Gαz in axon growth or retinal signaling
  • Structural basis of GNAZ-ADAM17 and GNAZ-Smo coupling unknown
  • In vivo relevance of GNAZ-ERK axis in human cancer not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0060089 molecular transducer activity 3 GO:0140313 molecular sequestering activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-112316 Neuronal System 2 R-HSA-1266738 Developmental Biology 1 R-HSA-9709957 Sensory Perception 1
Partners
ADAM17DRD4E2F1FFAR4SMO

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 GNAZ was chromosomally localized to human chromosome 22 by hybridization of cDNA clones with DNA from human-mouse somatic cell hybrids, establishing its genomic position within the G protein alpha-subunit gene family. Somatic cell hybrid panel + cDNA hybridization Proceedings of the National Academy of Sciences of the United States of America High 2902634
1995 GNAZ is expressed in human fetal cochlea, specifically localized by in situ hybridization and immunohistochemistry, suggesting a role in maintaining ionic balance of perilymphatic and endolymphatic cochlear fluids. Northern blot, tissue in situ hybridization, immunohistochemistry Hearing research Medium 8975005
2013 Gαz (GNAZ) is localized to axonal growth cones in cortical neurons and inhibits BDNF-stimulated axon growth, establishing an endogenous role in regulating neurotrophin signaling in the CNS. Gz knockout mouse cortical neurons (ex vivo and cultured), immunolocalization, axon growth assays Molecular and cellular neurosciences High 24321455
2014 Gnaz is expressed in enteric axons and couples Smoothened (Smo) signaling downstream of Sonic Hedgehog (Shh) to mediate axon repulsion; knockdown or dominant-negative inhibition of Gnaz dampens the axon-repulsive response to Shh, and Gnaz mutant intestines contain centrally projected enteric axons. Enteric neuron knockdown, dominant-negative inhibition, Gnaz mutant mouse intestines, in vitro axon turning assay Proceedings of the National Academy of Sciences of the United States of America High 25535338
2017 Gnaz is expressed in photoreceptors and its protein product Gαz shows a daily rhythm in subcellular localization; Gnaz expression rhythm is dependent on the circadian Clock gene and dopamine D4 receptors, linking the circadian clockwork via dopamine to G protein-mediated signaling in retinal photoreceptors. Microdissected photoreceptors, whole retina preparations, Clock and D4 receptor knockout mice, subcellular fractionation/immunolocalization, constant darkness experiments PloS one High 29088301
2023 GNAZ sequesters ADAM17 under normal conditions; blue light illumination disrupts the GNAZ-ADAM17 interaction, allowing ADAM17 to hyperactivate and cleave claudin-5 (CLDN5), collapsing the inner blood-retinal barrier. GNAZ knockdown phenocopies blue light exposure by causing ADAM17 hyperactivation, CLDN5 downregulation, and paracellular permeability. GNAZ knockdown (in vitro and in vivo), pharmacological and genetic ADAM17 inhibition, co-immunoprecipitation (GNAZ-ADAM17 interaction), tight junction permeability assays, electroretinogram, mouse blue-light exposure model Fluids and barriers of the CNS High 37095509
2025 In mouse pancreatic islets, FFAR4 activation stimulates insulin secretion indirectly through Gαz-coupled inhibition of somatostatin (SST) secretion from δ cells; Gnaz deletion prevents FFAR4 agonist inhibition of SST secretion and abolishes the reduction in Ca2+ transients in δ cells, but does not prevent direct insulin potentiation in human islets. Gnaz knockout mouse islets, δ-cell ablation, SST-deficient mice, purified β and δ cells, Ca2+ imaging, insulin/SST secretion assays bioRxivpreprint High 40894772
2023 GNAZ promotes hepatocellular carcinoma vasculogenic mimicry by phosphorylating components of the ERK pathway; it is a direct target of miR-20a-3p, and its expression is transcriptionally regulated by E2F1 via the CDKN2B-AS1/E2F1/GNAZ axis. Dual-luciferase reporter assay, chromatin immunoprecipitation, lentivirus-mediated miR-20a-3p overexpression, transcriptome sequencing, in vitro tube formation and in vivo VM/metastasis assays Research (Washington, D.C.) Medium 41306771
2023 CDKN2B-AS1 lncRNA recruits E2F1 to the GNAZ promoter region to facilitate GNAZ transcription, promoting HCC cell proliferation and survival; RNA immunoprecipitation confirmed CDKN2B-AS1-E2F1 interaction and ChIP verified E2F1 binding to the GNAZ promoter. RNA immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, CDKN2B-AS1 knockdown with GNAZ/E2F1 rescue experiments World journal of gastrointestinal oncology Medium 38077646
2021 A somatic variant in GNAZ found in a plexiform neurofibroma leads to increased ERK1/2 activation compared to wild-type GNAZ, suggesting GNAZ can activate the MAPK pathway when mutated. Whole-exome sequencing, ERK1/2 phosphorylation assay in cells expressing mutant vs. wild-type GNAZ Experimental dermatology Low 34913528

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain 151 21398039
1988 Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human. Proceedings of the National Academy of Sciences of the United States of America 118 2902634
2017 Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT. Molecular neurobiology 80 28421530
2007 Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: implications for oligodendrocyte viability. Neurochemistry international 72 17239488
1998 Total genome scan analysis in a single extended family for primary nocturnal enuresis: evidence for a new locus (ENUR3) for primary nocturnal enuresis on chromosome 22q11. European urology 44 9599735
2021 Identification of circRNA-miRNA-mRNA networks contributes to explore underlying pathogenesis and therapy strategy of gastric cancer. Journal of translational medicine 41 34049561
2017 Comprehensive comparison of neonate and adult human platelet transcriptomes. PloS one 40 28813466
2014 Gas1 is a receptor for sonic hedgehog to repel enteric axons. Proceedings of the National Academy of Sciences of the United States of America 40 25535338
2022 RGS1 and related genes as potential targets for immunotherapy in cervical cancer: computational biology and experimental validation. Journal of translational medicine 32 35879796
2011 The human Müller cell line MIO-M1 expresses opsins. Molecular vision 30 22065927
2010 Novel somatic mutations in heterotrimeric G proteins in melanoma. Cancer biology & therapy 19 20424519
2018 Differentially expressed gene (DEG) based protein-protein interaction (PPI) network identifies a spectrum of gene interactome, transcriptome and correlated miRNA in nondisjunction Down syndrome. International journal of biological macromolecules 18 30218739
2008 BCR expression is decreased in meningiomas showing loss of heterozygosity of 22q within a new minimal deletion region. Cancer genetics and cytogenetics 18 18474292
2021 Screening of tumor grade-related mRNAs and lncRNAs for Esophagus Squamous Cell Carcinoma. Journal of clinical laboratory analysis 16 33960436
2000 Isolation of genes from the rhabdoid tumor deletion region in chromosome band 22q11.2. Gene 16 10607907
1999 Analysis of GNAZ gene polymorphism in bipolar affective disorder. American journal of medical genetics 16 10402497
2012 Activated PTHLH coupling feedback phosphoinositide to G-protein receptor signal-induced cell adhesion network in human hepatocellular carcinoma by systems-theoretic analysis. TheScientificWorldJournal 15 22997493
2013 Gαz regulates BDNF-induction of axon growth in cortical neurons. Molecular and cellular neurosciences 14 24321455
2023 Blue light exposure collapses the inner blood-retinal barrier by accelerating endothelial CLDN5 degradation through the disturbance of GNAZ and the activation of ADAM17. Fluids and barriers of the CNS 13 37095509
2017 Gnaz couples the circadian and dopaminergic system to G protein-mediated signaling in mouse photoreceptors. PloS one 12 29088301
1996 G protein alpha subunit multigene family in the Japanese puffer fish Fugu rubripes: PCR from a compact vertebrate genome. Genome research 12 8973916
2019 Downregulation of genes outside the deleted region in individuals with 22q11.2 deletion syndrome. Human genetics 9 30627818
1995 GNAZ in human fetal cochlea: expression, localization, and potential role in inner ear function. Hearing research 7 8975005
1998 Fine genetic and comparative mapping of the deafness mutation Ames waltzer on mouse chromosome 10. Genomics 6 9653653
2006 Differentially expressed genes associated with hepatitis B virus HBx and MHBs protein function in hepatocellular carcinoma. Methods in molecular biology (Clifton, N.J.) 5 16264227
2023 Long non-coding RNA CDKN2B-AS1 promotes hepatocellular carcinoma progression via E2F transcription factor 1/G protein subunit alpha Z axis. World journal of gastrointestinal oncology 4 38077646
2019 Expression of GNAZ, encoding the Gαz protein, predicts survival in mantle cell lymphoma. British journal of haematology 4 30788840
2021 Concomitant variants in NF1, LZTR1 and GNAZ genes probably contribute to the aggressiveness of plexiform neurofibroma and warrant treatment with MEK inhibitor. Experimental dermatology 3 34913528
2021 Differential Expression of the Sphingolipid Pathway Is Associated with Sensitivity to the PP2A Activator FTY720 in Colorectal Cancer Cell Lines. Journal of clinical medicine 1 34768523
2025 Free fatty acid receptor 4 agonists stimulate insulin secretion via different mechanisms in mouse versus human islets. bioRxiv : the preprint server for biology 0 40894772
2025 LAG3 as a Tumor Suppressor and Immune Regulator in Cervical Cancer: From Functional Validation to Therapeutic Strategy. Cancer medicine 0 41025546
2025 ATPase Inhibitory Factor 1 Drives Mitochondrial Energy Metabolic Reprogramming to Promote HCC Vasculogenic Mimicry via the ESR1/miR-20a-3p/GNAZ Pathway. Research (Washington, D.C.) 0 41306771