{"gene":"GNAZ","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1988,"finding":"GNAZ was chromosomally mapped to human chromosome 22 using hybridization of cDNA clones with DNA from human-mouse somatic cell hybrids, establishing its genomic locus.","method":"Somatic cell hybrid panel hybridization with cDNA clones","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping by two orthogonal hybridization methods, single study","pmids":["2902634"],"is_preprint":false},{"year":1995,"finding":"GNAZ is expressed in human fetal cochlea, localized to neural structures, and was proposed to play a role in maintaining ionic balance of perilymphatic and endolymphatic cochlear fluids, based on expression characterization by Northern blot, in-situ hybridization, and immunohistochemistry.","method":"Northern blot, in-situ hybridization, immunohistochemistry","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal localization methods in a single study; functional role inferred from localization, not directly tested","pmids":["8975005"],"is_preprint":false},{"year":2014,"finding":"Gnaz (Gαz) is localized to enteric axonal growth cones and mediates the axon-repulsive response to Sonic hedgehog (Shh) signaling; knockdown or dominant-negative inhibition of Gnaz dampens Shh-induced axon repulsion, and Gnaz mutant intestines contain centrally projected enteric axons, placing Gnaz downstream of Shh/Smo in axon guidance.","method":"In vitro neurosphere-derived enteric neuron axon turning assay, shRNA knockdown, dominant-negative inhibition, Gnaz knockout mouse intestinal phenotyping, subcellular localization imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, dominant-negative, genetic KO, in vitro turning assay, localization) all converging on the same mechanistic conclusion in a single rigorous study","pmids":["25535338"],"is_preprint":false},{"year":2013,"finding":"Gαz (encoded by GNAZ) is localized to axonal growth cones of cortical neurons and inhibits BDNF-stimulated axon growth; this was established using Gz knockout mouse cortical neurons cultured ex vivo, demonstrating an endogenous role for Gαz in regulating neurotrophin (BDNF) signaling in the CNS.","method":"Gz knockout mouse cortical neuron culture, ex vivo manipulation, axon growth measurement, subcellular localization imaging","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined cellular phenotype and localization data, multiple orthogonal approaches in one study","pmids":["24321455"],"is_preprint":false},{"year":2017,"finding":"Gnaz is expressed in mouse photoreceptors and its protein product Gαz shows a daily rhythm in subcellular localization; Gnaz expression rhythmicity persists under constant darkness but is abolished in retinas deficient for Clock or dopamine D4 receptors, placing Gnaz downstream of the circadian clock via D4 receptor-mediated dopamine signaling.","method":"Microdissected photoreceptor RNA analysis, whole retina preparations, constant-darkness experiments, Clock-KO and dopamine D4 receptor-KO mouse retinas, subcellular localization assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Clock KO, D4R KO) combined with localization rhythm data and persistent-darkness experiments across multiple conditions in one study","pmids":["29088301"],"is_preprint":false},{"year":2023,"finding":"GNAZ (Gαz) physically sequesters ADAM17 under basal conditions, preventing ADAM17-mediated degradation of claudin-5 (CLDN5) at the inner blood-retinal barrier; blue light exposure disrupts the GNAZ-ADAM17 interaction, allowing ADAM17 activation, CLDN5 degradation, and paracellular barrier leakage. GNAZ knockdown in vitro caused ADAM17 hyperactivation, CLDN5 downregulation, and increased permeability, while in vivo GNAZ knockdown mimicked blue-light-induced retinal damage.","method":"Co-immunoprecipitation (GNAZ-ADAM17 interaction), pharmacological and genetic inhibition of ADAM17, GNAZ siRNA knockdown in endothelial cells (in vitro), in vivo mouse GNAZ knockdown, electroretinogram, paracellular permeability assay, western blot","journal":"Fluids and barriers of the CNS","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct protein-protein interaction (Co-IP), genetic loss-of-function (knockdown), pharmacological rescue, in vitro and in vivo validation with multiple orthogonal functional readouts in a single study","pmids":["37095509"],"is_preprint":false},{"year":2021,"finding":"A somatic variant in GNAZ found in a plexiform neurofibroma caused increased ERK1/2 activation in cells expressing mutant GNAZ compared to wild-type GNAZ, implicating GNAZ in MAPK pathway regulation.","method":"Whole-exome sequencing of tumor, functional cell-based assay measuring ERK1/2 phosphorylation in mutant vs. wild-type GNAZ-expressing cells","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single functional assay comparing mutant vs. wild-type in cells, single case study","pmids":["34913528"],"is_preprint":false},{"year":2023,"finding":"The lncRNA CDKN2B-AS1 recruits the transcription factor E2F1 to the GNAZ promoter to facilitate GNAZ transcription; depletion of CDKN2B-AS1 inhibited E2F1 binding to the GNAZ promoter and suppressed HCC cell proliferation, establishing a CDKN2B-AS1/E2F1/GNAZ transcriptional axis.","method":"RNA immunoprecipitation (CDKN2B-AS1–E2F1 interaction), luciferase reporter assay, chromatin immunoprecipitation (E2F1 binding to GNAZ promoter), siRNA knockdown, western blot, CCK-8/EdU/flow cytometry","journal":"World journal of gastrointestinal oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP and RIP confirming interaction and promoter binding, plus functional rescue; single lab, multiple methods","pmids":["38077646"],"is_preprint":false},{"year":2025,"finding":"GNAZ (Gαz) promotes vasculogenic mimicry (VM) in HCC by phosphorylating components of the ERK pathway; GNAZ is a direct target of miR-20a-3p, and the IF1/ESR1/miR-20a-3p/GNAZ axis regulates VM and lung metastasis. Mechanistically, IF1-induced mitochondrial ROS inhibit ESR1 via DNA methylation, reducing miR-20a-3p and thus de-repressing GNAZ, which then activates ERK signaling.","method":"Dual-luciferase reporter assay (miR-20a-3p targeting GNAZ 3'UTR), lentiviral miR-20a-3p overexpression, transcriptome sequencing, in vitro tube formation assay, in vivo VM and metastasis models, western blot for ERK phosphorylation","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase validation of miRNA-target relationship, in vitro and in vivo functional data, multiple methods; single lab","pmids":["41306771"],"is_preprint":false},{"year":2025,"finding":"In mouse islets, Gαz (Gnaz) mediates FFAR4 agonist-induced inhibition of somatostatin (SST) secretion from δ cells by reducing Ca2+ transients; Gnaz deletion prevented Cpd A-induced inhibition of SST secretion and abolishment of Ca2+ suppression in δ cells, but did not block insulin potentiation. In human islets, FFAR4 stimulates insulin secretion via a direct, Gαz-independent mechanism.","method":"Gnaz knockout mouse islets, δ-cell ablation, SST-deficient mice, purified β and δ cell preparations, Ca2+ imaging, insulin and SST secretion assays, human EndoC-βH5 cell experiments","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — clean genetic KO with defined cellular phenotype, multiple complementary mouse models, Ca2+ imaging, species comparison; comprehensive mechanistic dissection","pmids":["40894772"],"is_preprint":true}],"current_model":"GNAZ encodes Gαz, a pertussis-toxin-insensitive inhibitory G protein subunit expressed predominantly in neural and retinal tissues; it localizes to axonal growth cones where it inhibits BDNF-driven axon elongation and mediates Shh-dependent axon repulsion in the enteric nervous system, undergoes circadian-regulated subcellular redistribution in photoreceptors downstream of dopamine D4 receptor signaling, sequesters and inhibits ADAM17 at the inner blood-retinal barrier to protect claudin-5, couples FFAR4 activation to Gαz-dependent suppression of somatostatin secretion from pancreatic δ cells, and can be transcriptionally induced by the CDKN2B-AS1/E2F1 axis or post-transcriptionally repressed by miR-20a-3p to modulate ERK pathway activity."},"narrative":{"mechanistic_narrative":"GNAZ encodes Gαz, an inhibitory G protein α subunit that transduces receptor signals into restraint of cellular growth, secretion, and barrier dynamics across neural, retinal, and endocrine tissues [PMID:25535338, PMID:37095509, PMID:40894772]. In the nervous system, Gαz localizes to axonal growth cones, where it inhibits BDNF-stimulated cortical axon elongation [PMID:24321455] and acts downstream of Shh/Smo to mediate axon-repulsive guidance of enteric neurons [PMID:25535338]. At the inner blood-retinal barrier, Gαz physically sequesters ADAM17 under basal conditions, blocking ADAM17-mediated degradation of claudin-5 and thereby preserving paracellular barrier integrity; this protective interaction is disrupted by blue light, and loss of Gαz produces ADAM17 hyperactivation, claudin-5 loss, and increased permeability [PMID:37095509]. In pancreatic δ cells, Gαz couples FFAR4 activation to suppression of somatostatin secretion by reducing Ca2+ transients [PMID:40894772]. Gαz expression itself is dynamically controlled: it undergoes circadian-regulated subcellular redistribution in photoreceptors downstream of CLOCK and dopamine D4 receptor signaling [PMID:29088301], is transcriptionally induced via a CDKN2B-AS1/E2F1 promoter axis [PMID:38077646], and is post-transcriptionally repressed by miR-20a-3p [PMID:41306771]. In hepatocellular carcinoma and a neurofibroma context, Gαz activity feeds into ERK/MAPK signaling to promote proliferation, vasculogenic mimicry, and metastasis [PMID:34913528, PMID:38077646, PMID:41306771].","teleology":[{"year":1988,"claim":"Establishing the genomic locus of GNAZ provided the foundation for studying it as a discrete gene rather than an undefined G protein activity.","evidence":"Somatic cell hybrid panel hybridization with cDNA clones mapping to human chromosome 22","pmids":["2902634"],"confidence":"Medium","gaps":["No functional role assigned","No tissue expression or protein activity characterized"]},{"year":1995,"claim":"Tissue expression profiling localized GNAZ to neural structures of the fetal cochlea, first linking the gene to neural and ion-homeostasis contexts.","evidence":"Northern blot, in-situ hybridization, and immunohistochemistry in human fetal cochlea","pmids":["8975005"],"confidence":"Medium","gaps":["Functional role inferred from localization, not tested","No signaling partner or receptor identified"]},{"year":2013,"claim":"Genetic loss-of-function established an endogenous neuronal role for Gαz, showing it restrains neurotrophin-driven axon growth at the growth cone.","evidence":"Gz knockout mouse cortical neuron culture with axon growth measurement and localization imaging","pmids":["24321455"],"confidence":"High","gaps":["Receptor coupling Gαz to BDNF signaling not defined","Downstream effectors of growth inhibition not identified"]},{"year":2014,"claim":"Convergent genetic and pharmacologic approaches placed Gαz in the Shh/Smo axon-guidance pathway, defining it as a transducer of a repulsive guidance cue in the enteric nervous system.","evidence":"Enteric neuron axon turning assay, shRNA knockdown, dominant-negative inhibition, Gnaz KO mouse intestinal phenotyping","pmids":["25535338"],"confidence":"High","gaps":["Direct biochemical link between Smo and Gαz not shown","Effector mechanism of repulsion downstream of Gαz unknown"]},{"year":2017,"claim":"Genetic epistasis revealed that Gαz subcellular distribution is under circadian and dopaminergic control, connecting the protein to rhythmic photoreceptor physiology.","evidence":"Photoreceptor RNA analysis, constant-darkness experiments, and Clock-KO / D4 receptor-KO mouse retinas with localization assays","pmids":["29088301"],"confidence":"High","gaps":["Functional consequence of Gαz redistribution in photoreceptors not defined","Signaling output downstream of redistributed Gαz unknown"]},{"year":2021,"claim":"A tumor-derived variant assay first implicated GNAZ in MAPK pathway control, showing mutant Gαz elevates ERK1/2 activation.","evidence":"Whole-exome sequencing of a plexiform neurofibroma and cell-based ERK1/2 phosphorylation assay comparing mutant vs. wild-type GNAZ","pmids":["34913528"],"confidence":"Medium","gaps":["Single case variant, not validated across tumors","Mechanism linking Gαz to ERK not resolved"]},{"year":2023,"claim":"Co-IP and loss-of-function defined a non-canonical role for Gαz as a physical sequester of ADAM17 that protects claudin-5 and blood-retinal barrier integrity, and identified blue light as the disrupting stimulus.","evidence":"GNAZ-ADAM17 co-immunoprecipitation, siRNA knockdown in endothelial cells, ADAM17 inhibition, in vivo knockdown, ERG and permeability assays","pmids":["37095509"],"confidence":"High","gaps":["Structural basis of the GNAZ-ADAM17 interaction not resolved","How blue light mechanistically disrupts the interaction unknown"]},{"year":2023,"claim":"Promoter-level dissection established that GNAZ transcription is driven by a CDKN2B-AS1/E2F1 axis that supports HCC proliferation.","evidence":"RIP, ChIP of E2F1 at the GNAZ promoter, luciferase reporter, siRNA knockdown, and proliferation assays in HCC cells","pmids":["38077646"],"confidence":"Medium","gaps":["Single lab; not independently replicated","Whether elevated GNAZ alone is sufficient for proliferation not isolated"]},{"year":2025,"claim":"Genetic KO and species comparison defined Gαz as the obligate transducer coupling FFAR4 to suppression of somatostatin secretion in mouse δ cells via Ca2+ reduction, distinguishing it from a Gαz-independent insulin pathway.","evidence":"Gnaz knockout mouse islets, δ-cell ablation, SST-deficient mice, purified cell preparations, Ca2+ imaging, secretion assays, human EndoC-βH5 cells","pmids":["40894772"],"confidence":"High","gaps":["Preprint, not peer-reviewed","Human δ-cell role of GNAZ not directly tested"]},{"year":2025,"claim":"An upstream regulatory cascade was mapped showing miR-20a-3p directly represses GNAZ, and de-repression activates ERK signaling to drive vasculogenic mimicry and metastasis in HCC.","evidence":"Dual-luciferase reporter of miR-20a-3p targeting GNAZ 3'UTR, miRNA overexpression, tube formation and in vivo VM/metastasis models, ERK phosphorylation western blot","pmids":["41306771"],"confidence":"Medium","gaps":["Single lab; not independently replicated","Direct biochemical step from Gαz to ERK phosphorylation not isolated"]},{"year":null,"claim":"The receptors and downstream effectors that link Gαz to its diverse tissue-specific outputs remain incompletely mapped, and the structural basis of its protein-protein sequestration functions is undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified effector pathway defined across neural, retinal, and endocrine contexts","No structural model of Gαz-effector or Gαz-ADAM17 complexes","GPCR partners coupling to Gαz in each tissue not systematically identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,3,9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["ADAM17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19086","full_name":"Guanine nucleotide-binding protein G(z) subunit alpha","aliases":["G(x) alpha chain","Gz-alpha"],"length_aa":355,"mass_kda":40.9,"function":"Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P19086/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GNAZ","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GNAZ","total_profiled":1310},"omim":[{"mim_id":"611240","title":"GPRIN FAMILY, MEMBER 2; GPRIN2","url":"https://www.omim.org/entry/611240"},{"mim_id":"611239","title":"GPRIN FAMILY, MEMBER 1; GPRIN1","url":"https://www.omim.org/entry/611239"},{"mim_id":"607193","title":"REGULATOR OF G PROTEIN SIGNALING 20; RGS20","url":"https://www.omim.org/entry/607193"},{"mim_id":"139160","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA Z POLYPEPTIDE; GNAZ","url":"https://www.omim.org/entry/139160"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":45.1}],"url":"https://www.proteinatlas.org/search/GNAZ"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P19086","domains":[{"cath_id":"1.10.400.10","chopping":"62-176","consensus_level":"high","plddt":96.8352,"start":62,"end":176},{"cath_id":"3.40.50.300","chopping":"216-340","consensus_level":"high","plddt":96.3978,"start":216,"end":340}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19086","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19086-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19086-F1-predicted_aligned_error_v6.png","plddt_mean":93.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GNAZ","jax_strain_url":"https://www.jax.org/strain/search?query=GNAZ"},"sequence":{"accession":"P19086","fasta_url":"https://rest.uniprot.org/uniprotkb/P19086.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19086/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19086"}},"corpus_meta":[{"pmid":"21398039","id":"PMC_21398039","title":"Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients.","date":"2011","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/21398039","citation_count":153,"is_preprint":false},{"pmid":"2902634","id":"PMC_2902634","title":"Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human.","date":"1988","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2902634","citation_count":118,"is_preprint":false},{"pmid":"28421530","id":"PMC_28421530","title":"Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT.","date":"2017","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/28421530","citation_count":82,"is_preprint":false},{"pmid":"17239488","id":"PMC_17239488","title":"Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: implications for oligodendrocyte viability.","date":"2007","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/17239488","citation_count":73,"is_preprint":false},{"pmid":"9599735","id":"PMC_9599735","title":"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.","date":"1998","source":"European urology","url":"https://pubmed.ncbi.nlm.nih.gov/9599735","citation_count":44,"is_preprint":false},{"pmid":"34049561","id":"PMC_34049561","title":"Identification of circRNA-miRNA-mRNA networks contributes to explore underlying pathogenesis and therapy strategy of gastric cancer.","date":"2021","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34049561","citation_count":42,"is_preprint":false},{"pmid":"28813466","id":"PMC_28813466","title":"Comprehensive comparison of neonate and adult human platelet transcriptomes.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28813466","citation_count":41,"is_preprint":false},{"pmid":"25535338","id":"PMC_25535338","title":"Gas1 is a receptor for sonic hedgehog to repel enteric axons.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25535338","citation_count":40,"is_preprint":false},{"pmid":"35879796","id":"PMC_35879796","title":"RGS1 and related genes as potential targets for immunotherapy in cervical cancer: computational biology and experimental validation.","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35879796","citation_count":32,"is_preprint":false},{"pmid":"22065927","id":"PMC_22065927","title":"The human Müller cell line MIO-M1 expresses opsins.","date":"2011","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/22065927","citation_count":31,"is_preprint":false},{"pmid":"20424519","id":"PMC_20424519","title":"Novel somatic mutations in heterotrimeric G proteins in melanoma.","date":"2010","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20424519","citation_count":19,"is_preprint":false},{"pmid":"18474292","id":"PMC_18474292","title":"BCR expression is decreased in meningiomas showing loss of heterozygosity of 22q within a new minimal deletion region.","date":"2008","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/18474292","citation_count":18,"is_preprint":false},{"pmid":"30218739","id":"PMC_30218739","title":"Differentially expressed gene (DEG) based protein-protein interaction (PPI) network identifies a spectrum of gene interactome, transcriptome and correlated miRNA in nondisjunction Down syndrome.","date":"2018","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/30218739","citation_count":18,"is_preprint":false},{"pmid":"10402497","id":"PMC_10402497","title":"Analysis of GNAZ gene polymorphism in bipolar affective disorder.","date":"1999","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10402497","citation_count":16,"is_preprint":false},{"pmid":"33960436","id":"PMC_33960436","title":"Screening of tumor grade-related mRNAs and lncRNAs for Esophagus Squamous Cell Carcinoma.","date":"2021","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/33960436","citation_count":16,"is_preprint":false},{"pmid":"10607907","id":"PMC_10607907","title":"Isolation of genes from the rhabdoid tumor deletion region in chromosome band 22q11.2.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10607907","citation_count":16,"is_preprint":false},{"pmid":"37095509","id":"PMC_37095509","title":"Blue light exposure collapses the inner blood-retinal barrier by accelerating endothelial CLDN5 degradation through the disturbance of GNAZ and the activation of ADAM17.","date":"2023","source":"Fluids and barriers of the CNS","url":"https://pubmed.ncbi.nlm.nih.gov/37095509","citation_count":15,"is_preprint":false},{"pmid":"22997493","id":"PMC_22997493","title":"Activated PTHLH coupling feedback phosphoinositide to G-protein receptor signal-induced cell adhesion network in human hepatocellular carcinoma by systems-theoretic analysis.","date":"2012","source":"TheScientificWorldJournal","url":"https://pubmed.ncbi.nlm.nih.gov/22997493","citation_count":15,"is_preprint":false},{"pmid":"24321455","id":"PMC_24321455","title":"Gαz regulates BDNF-induction of axon growth in cortical neurons.","date":"2013","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/24321455","citation_count":15,"is_preprint":false},{"pmid":"29088301","id":"PMC_29088301","title":"Gnaz couples the circadian and dopaminergic system to G protein-mediated signaling in mouse photoreceptors.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29088301","citation_count":12,"is_preprint":false},{"pmid":"8973916","id":"PMC_8973916","title":"G protein alpha subunit multigene family in the Japanese puffer fish Fugu rubripes: PCR from a compact vertebrate genome.","date":"1996","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8973916","citation_count":12,"is_preprint":false},{"pmid":"30627818","id":"PMC_30627818","title":"Downregulation of genes outside the deleted region in individuals with 22q11.2 deletion syndrome.","date":"2019","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30627818","citation_count":9,"is_preprint":false},{"pmid":"8975005","id":"PMC_8975005","title":"GNAZ in human fetal cochlea: expression, localization, and potential role in inner ear function.","date":"1995","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/8975005","citation_count":7,"is_preprint":false},{"pmid":"9653653","id":"PMC_9653653","title":"Fine genetic and comparative mapping of the deafness mutation Ames waltzer on mouse chromosome 10.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9653653","citation_count":6,"is_preprint":false},{"pmid":"16264227","id":"PMC_16264227","title":"Differentially expressed genes associated with hepatitis B virus HBx and MHBs protein function in hepatocellular carcinoma.","date":"2006","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/16264227","citation_count":5,"is_preprint":false},{"pmid":"30788840","id":"PMC_30788840","title":"Expression of GNAZ, encoding the Gαz protein, predicts survival in mantle cell lymphoma.","date":"2019","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/30788840","citation_count":4,"is_preprint":false},{"pmid":"38077646","id":"PMC_38077646","title":"Long non-coding RNA CDKN2B-AS1 promotes hepatocellular carcinoma progression via E2F transcription factor 1/G protein subunit alpha Z axis.","date":"2023","source":"World journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38077646","citation_count":4,"is_preprint":false},{"pmid":"34913528","id":"PMC_34913528","title":"Concomitant variants in NF1, LZTR1 and GNAZ genes probably contribute to the aggressiveness of plexiform neurofibroma and warrant treatment with MEK inhibitor.","date":"2021","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/34913528","citation_count":3,"is_preprint":false},{"pmid":"34768523","id":"PMC_34768523","title":"Differential Expression of the Sphingolipid Pathway Is Associated with Sensitivity to the PP2A Activator FTY720 in Colorectal Cancer Cell Lines.","date":"2021","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34768523","citation_count":1,"is_preprint":false},{"pmid":"41306771","id":"PMC_41306771","title":"ATPase Inhibitory Factor 1 Drives Mitochondrial Energy Metabolic Reprogramming to Promote HCC Vasculogenic Mimicry via the ESR1/miR-20a-3p/GNAZ Pathway.","date":"2025","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/41306771","citation_count":0,"is_preprint":false},{"pmid":"40894772","id":"PMC_40894772","title":"Free fatty acid receptor 4 agonists stimulate insulin secretion via different mechanisms in mouse versus human islets.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40894772","citation_count":0,"is_preprint":false},{"pmid":"41025546","id":"PMC_41025546","title":"LAG3 as a Tumor Suppressor and Immune Regulator in Cervical Cancer: From Functional Validation to Therapeutic Strategy.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41025546","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18275,"output_tokens":2832,"usd":0.048653,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10246,"output_tokens":3333,"usd":0.067278,"stage2_stop_reason":"end_turn"},"total_usd":0.115931,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"GNAZ was chromosomally mapped to human chromosome 22 using hybridization of cDNA clones with DNA from human-mouse somatic cell hybrids, establishing its genomic locus.\",\n      \"method\": \"Somatic cell hybrid panel hybridization with cDNA clones\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping by two orthogonal hybridization methods, single study\",\n      \"pmids\": [\"2902634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"GNAZ is expressed in human fetal cochlea, localized to neural structures, and was proposed to play a role in maintaining ionic balance of perilymphatic and endolymphatic cochlear fluids, based on expression characterization by Northern blot, in-situ hybridization, and immunohistochemistry.\",\n      \"method\": \"Northern blot, in-situ hybridization, immunohistochemistry\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal localization methods in a single study; functional role inferred from localization, not directly tested\",\n      \"pmids\": [\"8975005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Gnaz (Gαz) is localized to enteric axonal growth cones and mediates the axon-repulsive response to Sonic hedgehog (Shh) signaling; knockdown or dominant-negative inhibition of Gnaz dampens Shh-induced axon repulsion, and Gnaz mutant intestines contain centrally projected enteric axons, placing Gnaz downstream of Shh/Smo in axon guidance.\",\n      \"method\": \"In vitro neurosphere-derived enteric neuron axon turning assay, shRNA knockdown, dominant-negative inhibition, Gnaz knockout mouse intestinal phenotyping, subcellular localization imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, dominant-negative, genetic KO, in vitro turning assay, localization) all converging on the same mechanistic conclusion in a single rigorous study\",\n      \"pmids\": [\"25535338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Gαz (encoded by GNAZ) is localized to axonal growth cones of cortical neurons and inhibits BDNF-stimulated axon growth; this was established using Gz knockout mouse cortical neurons cultured ex vivo, demonstrating an endogenous role for Gαz in regulating neurotrophin (BDNF) signaling in the CNS.\",\n      \"method\": \"Gz knockout mouse cortical neuron culture, ex vivo manipulation, axon growth measurement, subcellular localization imaging\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined cellular phenotype and localization data, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"24321455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Gnaz is expressed in mouse photoreceptors and its protein product Gαz shows a daily rhythm in subcellular localization; Gnaz expression rhythmicity persists under constant darkness but is abolished in retinas deficient for Clock or dopamine D4 receptors, placing Gnaz downstream of the circadian clock via D4 receptor-mediated dopamine signaling.\",\n      \"method\": \"Microdissected photoreceptor RNA analysis, whole retina preparations, constant-darkness experiments, Clock-KO and dopamine D4 receptor-KO mouse retinas, subcellular localization assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Clock KO, D4R KO) combined with localization rhythm data and persistent-darkness experiments across multiple conditions in one study\",\n      \"pmids\": [\"29088301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GNAZ (Gαz) physically sequesters ADAM17 under basal conditions, preventing ADAM17-mediated degradation of claudin-5 (CLDN5) at the inner blood-retinal barrier; blue light exposure disrupts the GNAZ-ADAM17 interaction, allowing ADAM17 activation, CLDN5 degradation, and paracellular barrier leakage. GNAZ knockdown in vitro caused ADAM17 hyperactivation, CLDN5 downregulation, and increased permeability, while in vivo GNAZ knockdown mimicked blue-light-induced retinal damage.\",\n      \"method\": \"Co-immunoprecipitation (GNAZ-ADAM17 interaction), pharmacological and genetic inhibition of ADAM17, GNAZ siRNA knockdown in endothelial cells (in vitro), in vivo mouse GNAZ knockdown, electroretinogram, paracellular permeability assay, western blot\",\n      \"journal\": \"Fluids and barriers of the CNS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct protein-protein interaction (Co-IP), genetic loss-of-function (knockdown), pharmacological rescue, in vitro and in vivo validation with multiple orthogonal functional readouts in a single study\",\n      \"pmids\": [\"37095509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A somatic variant in GNAZ found in a plexiform neurofibroma caused increased ERK1/2 activation in cells expressing mutant GNAZ compared to wild-type GNAZ, implicating GNAZ in MAPK pathway regulation.\",\n      \"method\": \"Whole-exome sequencing of tumor, functional cell-based assay measuring ERK1/2 phosphorylation in mutant vs. wild-type GNAZ-expressing cells\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional assay comparing mutant vs. wild-type in cells, single case study\",\n      \"pmids\": [\"34913528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lncRNA CDKN2B-AS1 recruits the transcription factor E2F1 to the GNAZ promoter to facilitate GNAZ transcription; depletion of CDKN2B-AS1 inhibited E2F1 binding to the GNAZ promoter and suppressed HCC cell proliferation, establishing a CDKN2B-AS1/E2F1/GNAZ transcriptional axis.\",\n      \"method\": \"RNA immunoprecipitation (CDKN2B-AS1–E2F1 interaction), luciferase reporter assay, chromatin immunoprecipitation (E2F1 binding to GNAZ promoter), siRNA knockdown, western blot, CCK-8/EdU/flow cytometry\",\n      \"journal\": \"World journal of gastrointestinal oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP and RIP confirming interaction and promoter binding, plus functional rescue; single lab, multiple methods\",\n      \"pmids\": [\"38077646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GNAZ (Gαz) promotes vasculogenic mimicry (VM) in HCC by phosphorylating components of the ERK pathway; GNAZ is a direct target of miR-20a-3p, and the IF1/ESR1/miR-20a-3p/GNAZ axis regulates VM and lung metastasis. Mechanistically, IF1-induced mitochondrial ROS inhibit ESR1 via DNA methylation, reducing miR-20a-3p and thus de-repressing GNAZ, which then activates ERK signaling.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-20a-3p targeting GNAZ 3'UTR), lentiviral miR-20a-3p overexpression, transcriptome sequencing, in vitro tube formation assay, in vivo VM and metastasis models, western blot for ERK phosphorylation\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase validation of miRNA-target relationship, in vitro and in vivo functional data, multiple methods; single lab\",\n      \"pmids\": [\"41306771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mouse islets, Gαz (Gnaz) mediates FFAR4 agonist-induced inhibition of somatostatin (SST) secretion from δ cells by reducing Ca2+ transients; Gnaz deletion prevented Cpd A-induced inhibition of SST secretion and abolishment of Ca2+ suppression in δ cells, but did not block insulin potentiation. In human islets, FFAR4 stimulates insulin secretion via a direct, Gαz-independent mechanism.\",\n      \"method\": \"Gnaz knockout mouse islets, δ-cell ablation, SST-deficient mice, purified β and δ cell preparations, Ca2+ imaging, insulin and SST secretion assays, human EndoC-βH5 cell experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — clean genetic KO with defined cellular phenotype, multiple complementary mouse models, Ca2+ imaging, species comparison; comprehensive mechanistic dissection\",\n      \"pmids\": [\"40894772\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GNAZ encodes Gαz, a pertussis-toxin-insensitive inhibitory G protein subunit expressed predominantly in neural and retinal tissues; it localizes to axonal growth cones where it inhibits BDNF-driven axon elongation and mediates Shh-dependent axon repulsion in the enteric nervous system, undergoes circadian-regulated subcellular redistribution in photoreceptors downstream of dopamine D4 receptor signaling, sequesters and inhibits ADAM17 at the inner blood-retinal barrier to protect claudin-5, couples FFAR4 activation to Gαz-dependent suppression of somatostatin secretion from pancreatic δ cells, and can be transcriptionally induced by the CDKN2B-AS1/E2F1 axis or post-transcriptionally repressed by miR-20a-3p to modulate ERK pathway activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GNAZ encodes Gαz, an inhibitory G protein α subunit that transduces receptor signals into restraint of cellular growth, secretion, and barrier dynamics across neural, retinal, and endocrine tissues [#2, #5, #9]. In the nervous system, Gαz localizes to axonal growth cones, where it inhibits BDNF-stimulated cortical axon elongation [#3] and acts downstream of Shh/Smo to mediate axon-repulsive guidance of enteric neurons [#2]. At the inner blood-retinal barrier, Gαz physically sequesters ADAM17 under basal conditions, blocking ADAM17-mediated degradation of claudin-5 and thereby preserving paracellular barrier integrity; this protective interaction is disrupted by blue light, and loss of Gαz produces ADAM17 hyperactivation, claudin-5 loss, and increased permeability [#5]. In pancreatic δ cells, Gαz couples FFAR4 activation to suppression of somatostatin secretion by reducing Ca2+ transients [#9]. Gαz expression itself is dynamically controlled: it undergoes circadian-regulated subcellular redistribution in photoreceptors downstream of CLOCK and dopamine D4 receptor signaling [#4], is transcriptionally induced via a CDKN2B-AS1/E2F1 promoter axis [#7], and is post-transcriptionally repressed by miR-20a-3p [#8]. In hepatocellular carcinoma and a neurofibroma context, Gαz activity feeds into ERK/MAPK signaling to promote proliferation, vasculogenic mimicry, and metastasis [#6, #7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Establishing the genomic locus of GNAZ provided the foundation for studying it as a discrete gene rather than an undefined G protein activity.\",\n      \"evidence\": \"Somatic cell hybrid panel hybridization with cDNA clones mapping to human chromosome 22\",\n      \"pmids\": [\"2902634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional role assigned\", \"No tissue expression or protein activity characterized\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Tissue expression profiling localized GNAZ to neural structures of the fetal cochlea, first linking the gene to neural and ion-homeostasis contexts.\",\n      \"evidence\": \"Northern blot, in-situ hybridization, and immunohistochemistry in human fetal cochlea\",\n      \"pmids\": [\"8975005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role inferred from localization, not tested\", \"No signaling partner or receptor identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic loss-of-function established an endogenous neuronal role for Gαz, showing it restrains neurotrophin-driven axon growth at the growth cone.\",\n      \"evidence\": \"Gz knockout mouse cortical neuron culture with axon growth measurement and localization imaging\",\n      \"pmids\": [\"24321455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling Gαz to BDNF signaling not defined\", \"Downstream effectors of growth inhibition not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Convergent genetic and pharmacologic approaches placed Gαz in the Shh/Smo axon-guidance pathway, defining it as a transducer of a repulsive guidance cue in the enteric nervous system.\",\n      \"evidence\": \"Enteric neuron axon turning assay, shRNA knockdown, dominant-negative inhibition, Gnaz KO mouse intestinal phenotyping\",\n      \"pmids\": [\"25535338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between Smo and Gαz not shown\", \"Effector mechanism of repulsion downstream of Gαz unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic epistasis revealed that Gαz subcellular distribution is under circadian and dopaminergic control, connecting the protein to rhythmic photoreceptor physiology.\",\n      \"evidence\": \"Photoreceptor RNA analysis, constant-darkness experiments, and Clock-KO / D4 receptor-KO mouse retinas with localization assays\",\n      \"pmids\": [\"29088301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Gαz redistribution in photoreceptors not defined\", \"Signaling output downstream of redistributed Gαz unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A tumor-derived variant assay first implicated GNAZ in MAPK pathway control, showing mutant Gαz elevates ERK1/2 activation.\",\n      \"evidence\": \"Whole-exome sequencing of a plexiform neurofibroma and cell-based ERK1/2 phosphorylation assay comparing mutant vs. wild-type GNAZ\",\n      \"pmids\": [\"34913528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case variant, not validated across tumors\", \"Mechanism linking Gαz to ERK not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Co-IP and loss-of-function defined a non-canonical role for Gαz as a physical sequester of ADAM17 that protects claudin-5 and blood-retinal barrier integrity, and identified blue light as the disrupting stimulus.\",\n      \"evidence\": \"GNAZ-ADAM17 co-immunoprecipitation, siRNA knockdown in endothelial cells, ADAM17 inhibition, in vivo knockdown, ERG and permeability assays\",\n      \"pmids\": [\"37095509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the GNAZ-ADAM17 interaction not resolved\", \"How blue light mechanistically disrupts the interaction unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Promoter-level dissection established that GNAZ transcription is driven by a CDKN2B-AS1/E2F1 axis that supports HCC proliferation.\",\n      \"evidence\": \"RIP, ChIP of E2F1 at the GNAZ promoter, luciferase reporter, siRNA knockdown, and proliferation assays in HCC cells\",\n      \"pmids\": [\"38077646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; not independently replicated\", \"Whether elevated GNAZ alone is sufficient for proliferation not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic KO and species comparison defined Gαz as the obligate transducer coupling FFAR4 to suppression of somatostatin secretion in mouse δ cells via Ca2+ reduction, distinguishing it from a Gαz-independent insulin pathway.\",\n      \"evidence\": \"Gnaz knockout mouse islets, δ-cell ablation, SST-deficient mice, purified cell preparations, Ca2+ imaging, secretion assays, human EndoC-βH5 cells\",\n      \"pmids\": [\"40894772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Human δ-cell role of GNAZ not directly tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An upstream regulatory cascade was mapped showing miR-20a-3p directly represses GNAZ, and de-repression activates ERK signaling to drive vasculogenic mimicry and metastasis in HCC.\",\n      \"evidence\": \"Dual-luciferase reporter of miR-20a-3p targeting GNAZ 3'UTR, miRNA overexpression, tube formation and in vivo VM/metastasis models, ERK phosphorylation western blot\",\n      \"pmids\": [\"41306771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; not independently replicated\", \"Direct biochemical step from Gαz to ERK phosphorylation not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptors and downstream effectors that link Gαz to its diverse tissue-specific outputs remain incompletely mapped, and the structural basis of its protein-protein sequestration functions is undefined.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified effector pathway defined across neural, retinal, and endocrine contexts\", \"No structural model of Gαz-effector or Gαz-ADAM17 complexes\", \"GPCR partners coupling to Gαz in each tissue not systematically identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 3, 9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ADAM17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}