{"gene":"GNA14","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2016,"finding":"Somatic activating GNA14 c.614A>T (p.Gln205Leu) mutation upregulates the MAPK pathway in primary human endothelial cells and melanocytes, inducing changes in cellular morphology and rendering cells growth-factor independent.","method":"Expression of mutant GNA14 in primary human endothelial cells and melanocytes; assessment of MAPK pathway activation, cellular morphology, and growth-factor independence","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assay with defined phenotypic readout (MAPK activation, morphology, growth-factor independence) in two cell types; single lab","pmids":["27476652"],"is_preprint":false},{"year":2021,"finding":"GNA14 directly binds RACK1 (receptor for activated C kinase 1), as shown by co-immunoprecipitation, mass spectrometry, and GST pull-down assay. Through RACK1, GNA14 reduces MAPK/JNK and PI3K/AKT signaling pathway activity, at least in part by competing with PKC for RACK1 binding and thereby reducing PKC stability.","method":"Co-immunoprecipitation, mass spectrometry, GST pull-down, RNA-Seq, loss- and gain-of-function assays, PLC inhibitor (U73122) co-treatment","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus GST pull-down plus RNA-Seq functional confirmation; single lab, multiple orthogonal methods","pmids":["34657150"],"is_preprint":false},{"year":2021,"finding":"GNA14 stimulates expression of KLF7 in endometrial carcinoma cells, which in turn upregulates HAS2, forming a GNA14/KLF7/HAS2 signaling cascade that promotes tumor cell proliferation, migration, and xenograft tumor growth.","method":"Lentiviral knockdown and overexpression, RNA sequencing, qRT-PCR, Western blot, CCK8/colony formation/apoptosis/cell cycle/transwell assays, xenograft mouse model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods; single lab","pmids":["33892667"],"is_preprint":false},{"year":2021,"finding":"GNA14 promotes Notch1 cleavage to activate the RB pathway, thereby inhibiting hepatocellular carcinoma cell proliferation; GNA14 also inhibits tumor metastasis by suppressing JMJD6 expression. HBV X protein (HBx) silences GNA14 by methylating its promoter.","method":"Gain- and loss-of-function assays in vitro; subcutaneous tumorigenesis, lung colonization, and orthotopic liver tumor models in vivo; methyl-target sequencing; co-treatment experiments","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo functional assays with pathway readouts; single lab","pmids":["33500727"],"is_preprint":false},{"year":2018,"finding":"GNA14 silencing in endometrial carcinoma cells suppresses proliferation, induces apoptosis (upregulation of caspase-3 and Fas), and causes G2/M cell cycle arrest, demonstrating a pro-proliferative role for GNA14 in this cancer type.","method":"Lentivirus-mediated knockdown, caspase 3/7 activity assay, apoptosis array, cell cycle analysis","journal":"Bioscience reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with phenotypic readouts but limited mechanistic pathway placement beyond identifying caspase-3/Fas","pmids":["30054423"],"is_preprint":false},{"year":2023,"finding":"GNA14 promotes colorectal cancer cell proliferation and malignant tumor progression via ERK phosphorylation and β-catenin phosphorylation at S675. Gna14 knockout mice showed significantly fewer and smaller intestinal polyps in an APC mouse model, with decreased proliferation and increased apoptosis in polyps.","method":"siRNA knockdown in CRC cell lines, Gna14 knockout mice crossed with Apc mice, Western blot for p-ERK and p-β-catenin (S675), histological analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic in vivo model (knockout × APC) with defined pathway readouts plus in vitro knockdown; single lab","pmids":["37760541"],"is_preprint":false},{"year":2024,"finding":"The GNA14 c.614A>T (p.Gln205Leu) mutation upregulates MAPK and angiogenesis-related pathways (by transcriptomic analysis), and causes enlarged vessels in a mouse xenograft model.","method":"Whole-exome sequencing, targeted deep sequencing, transcriptomic analysis, mouse xenograft model","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft model plus transcriptomic pathway analysis; single lab, corroborates earlier findings","pmids":["38917801"],"is_preprint":false},{"year":2013,"finding":"Gna14 is induced in gastric tumor epithelial cells by TNF-α/TNFR1 signaling and contributes to tumorigenicity and tumor-initiating cell properties of gastric cancer cells, as shown by colony formation assay following microarray-guided identification.","method":"Microarray analysis, colony formation assay, TNF-α/TNFR1 knockout mouse crossed with Gan gastric cancer mouse model, bone marrow transplantation","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — colony formation assay as primary functional readout for Gna14 specifically; broader study context; single lab","pmids":["23975421"],"is_preprint":false},{"year":2014,"finding":"GNA14 protein localizes to both the nucleus and cytoplasm of human pulmonary arterial endothelial cells (HPAECs) and smooth muscle cells (HPASMCs), as determined by immunocytochemistry and laser scanning confocal microscopy; bioinformatic analysis identified a nuclear localization signal consistent with this distribution.","method":"Immunocytochemistry, laser scanning confocal microscopy, bioinformatic nuclear localization signal analysis","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by immunocytochemistry without direct functional consequence established for GNA14 specifically; single study","pmids":["24797109"],"is_preprint":false}],"current_model":"GNA14 encodes a Gαq-family heterotrimeric G protein subunit that, when activated by somatic gain-of-function mutations (most commonly p.Gln205Leu), drives MAPK/ERK pathway upregulation to promote vascular tumor formation; in non-vascular cancers it can act as either an oncogene (endometrial, colorectal cancer via ERK and β-catenin) or a tumor suppressor (hepatocellular carcinoma), where it directly binds RACK1 to suppress MAPK/JNK and PI3K/AKT signaling by competing with PKC for RACK1, and also promotes Notch1 cleavage to activate the RB pathway; its expression can be silenced by HBx-induced promoter methylation."},"narrative":{"mechanistic_narrative":"GNA14 encodes a Gαq-family heterotrimeric G protein subunit that couples receptor signaling to growth-controlling pathways, and which becomes oncogenic through a somatic activating mutation. The recurrent c.614A>T (p.Gln205Leu) substitution upregulates MAPK signaling in primary endothelial cells and melanocytes, conferring growth-factor independence and altered morphology [PMID:27476652], and in vivo drives MAPK and angiogenesis-related transcriptional programs to produce enlarged vessels in xenografts [PMID:38917801], consistent with a role in vascular tumor formation. In non-vascular epithelial cancers, GNA14 acts as a pro-proliferative effector: it promotes colorectal cancer growth through ERK phosphorylation and β-catenin phosphorylation at S675, and Gna14 loss reduces intestinal polyp burden in APC mice [PMID:37760541], while in endometrial carcinoma it engages a KLF7→HAS2 cascade to drive proliferation, migration, and xenograft growth [PMID:33892667]. Conversely, in hepatocellular carcinoma GNA14 is tumor-suppressive, directly binding RACK1 to compete with PKC and thereby dampen MAPK/JNK and PI3K/AKT signaling [PMID:34657150], and promoting Notch1 cleavage to activate the RB pathway while suppressing JMJD6-driven metastasis; its expression in this context is silenced by HBx-induced promoter methylation [PMID:33500727]. This context-dependent oncogene/tumor-suppressor duality is the central feature of GNA14 biology in the available corpus.","teleology":[{"year":2013,"claim":"Established that Gna14 is a downstream transcriptional target of inflammatory signaling and contributes to tumor-initiating properties, linking it to cancer before its mutational role was known.","evidence":"Microarray-guided identification plus colony formation assay in a TNF-α/TNFR1 knockout × Gan gastric cancer mouse model","pmids":["23975421"],"confidence":"Low","gaps":["Colony formation as the primary functional readout; no pathway mechanism placed for Gna14 specifically","Does not establish whether the effect is via G-protein signaling"]},{"year":2014,"claim":"Addressed where GNA14 protein resides, finding both nuclear and cytoplasmic localization in vascular cell types.","evidence":"Immunocytochemistry, confocal microscopy, and bioinformatic NLS prediction in HPAECs and HPASMCs","pmids":["24797109"],"confidence":"Low","gaps":["No functional consequence tied to nuclear localization","Single study, no validation of the predicted NLS"]},{"year":2016,"claim":"Identified the somatic gain-of-function p.Gln205Leu mutation as the driver of constitutive MAPK activation, defining GNA14 as an oncogene in vascular/melanocytic lineages.","evidence":"Expression of mutant GNA14 in primary human endothelial cells and melanocytes with MAPK, morphology, and growth-factor independence readouts","pmids":["27476652"],"confidence":"Medium","gaps":["Single lab cell-based assay; no in vivo tumor formation in this study","Effector mechanism downstream of Gαq not dissected"]},{"year":2018,"claim":"Demonstrated a pro-proliferative, anti-apoptotic role for GNA14 in endometrial carcinoma, supporting an oncogenic function in this epithelial context.","evidence":"Lentiviral knockdown with caspase 3/7, apoptosis array, and cell cycle analysis","pmids":["30054423"],"confidence":"Low","gaps":["Limited mechanistic placement beyond caspase-3/Fas and G2/M arrest","No upstream signaling pathway defined"]},{"year":2021,"claim":"Resolved a downstream transcriptional cascade for the oncogenic role in endometrial cancer, placing GNA14 upstream of a KLF7→HAS2 axis.","evidence":"Lentiviral knockdown/overexpression, RNA-seq, qRT-PCR, proliferation/migration assays, and xenograft model","pmids":["33892667"],"confidence":"Medium","gaps":["Mechanism linking GNA14 G-protein activity to KLF7 induction not defined","Single lab"]},{"year":2021,"claim":"Revealed a tumor-suppressive mechanism in a different tissue, showing GNA14 directly binds RACK1 to compete with PKC and downregulate MAPK/JNK and PI3K/AKT signaling.","evidence":"Reciprocal co-IP, mass spectrometry, GST pull-down, RNA-Seq, and gain/loss-of-function assays with PLC inhibitor co-treatment","pmids":["34657150"],"confidence":"Medium","gaps":["Structural basis of GNA14–RACK1 competition with PKC not resolved","Single lab"]},{"year":2021,"claim":"Established GNA14 as a tumor suppressor in hepatocellular carcinoma acting through Notch1/RB activation and JMJD6 suppression, and identified its epigenetic silencing by HBx.","evidence":"In vitro gain/loss-of-function, subcutaneous/lung colonization/orthotopic liver tumor models, methyl-target sequencing","pmids":["33500727"],"confidence":"Medium","gaps":["Direct mechanism by which GNA14 promotes Notch1 cleavage unclear","Single lab"]},{"year":2023,"claim":"Provided genetic in vivo evidence for an oncogenic role in colorectal cancer via ERK and β-catenin S675 phosphorylation.","evidence":"siRNA knockdown in CRC lines, Gna14 knockout × Apc mice, and Western blot for p-ERK and p-β-catenin","pmids":["37760541"],"confidence":"Medium","gaps":["Whether wild-type GNA14 signaling or a mutant drives the effect not separated","Single lab"]},{"year":2024,"claim":"Confirmed in vivo that the p.Gln205Leu mutation drives MAPK and angiogenic programs and produces vascular phenotypes, reinforcing the original oncogenic mechanism.","evidence":"Whole-exome/targeted deep sequencing, transcriptomic analysis, and mouse xenograft model","pmids":["38917801"],"confidence":"Medium","gaps":["Effectors bridging mutant Gαq to angiogenic transcription not enumerated","Single lab"]},{"year":null,"claim":"It remains unresolved what determines GNA14's context-dependent switch between oncogene (endometrial, colorectal, vascular) and tumor suppressor (hepatocellular), and how its receptor coupling and effector selection differ across these tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling pro- and anti-tumorigenic functions","Upstream GPCRs coupling to GNA14 in each tissue not identified","Structural consequences of p.Gln205Leu on effector binding not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,5]}],"complexes":[],"partners":["RACK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95837","full_name":"Guanine nucleotide-binding protein subunit alpha-14","aliases":[],"length_aa":355,"mass_kda":41.6,"function":"Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O95837/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GNA14","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GNA14","total_profiled":1310},"omim":[{"mim_id":"605978","title":"VACUOLAR PROTEIN SORTING 13 HOMOLOG A; VPS13A","url":"https://www.omim.org/entry/605978"},{"mim_id":"604397","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-14; GNA14","url":"https://www.omim.org/entry/604397"},{"mim_id":"603349","title":"ENDOTHELIAL PAS DOMAIN PROTEIN 1; EPAS1","url":"https://www.omim.org/entry/603349"},{"mim_id":"600446","title":"ADENOSINE A2B RECEPTOR; ADORA2B","url":"https://www.omim.org/entry/600446"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GNA14"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O95837","domains":[{"cath_id":"3.40.50.300","chopping":"40-64_183-344","consensus_level":"medium","plddt":95.2904,"start":40,"end":344},{"cath_id":"1.10.400.10","chopping":"66-178","consensus_level":"medium","plddt":97.5204,"start":66,"end":178}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95837","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95837-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95837-F1-predicted_aligned_error_v6.png","plddt_mean":93.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GNA14","jax_strain_url":"https://www.jax.org/strain/search?query=GNA14"},"sequence":{"accession":"O95837","fasta_url":"https://rest.uniprot.org/uniprotkb/O95837.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95837/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95837"}},"corpus_meta":[{"pmid":"27476652","id":"PMC_27476652","title":"GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27476652","citation_count":119,"is_preprint":false},{"pmid":"23975421","id":"PMC_23975421","title":"TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23975421","citation_count":116,"is_preprint":false},{"pmid":"29975248","id":"PMC_29975248","title":"Frequent GNAQ and GNA14 Mutations in Hepatic Small Vessel Neoplasm.","date":"2018","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29975248","citation_count":60,"is_preprint":false},{"pmid":"31189994","id":"PMC_31189994","title":"High frequency of GNA14, GNAQ, and GNA11 mutations in cherry hemangioma: a histopathological and molecular study of 85 cases indicating GNA14 as the most commonly mutated gene in vascular neoplasms.","date":"2019","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/31189994","citation_count":39,"is_preprint":false},{"pmid":"33500727","id":"PMC_33500727","title":"Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33500727","citation_count":33,"is_preprint":false},{"pmid":"31707589","id":"PMC_31707589","title":"GNA11 joins GNAQ and GNA14 as a recurrently mutated gene in anastomosing hemangioma.","date":"2019","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31707589","citation_count":28,"is_preprint":false},{"pmid":"34040639","id":"PMC_34040639","title":"GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34040639","citation_count":23,"is_preprint":false},{"pmid":"34657150","id":"PMC_34657150","title":"GNA14's interaction with RACK1 inhibits hepatocellular carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway.","date":"2021","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34657150","citation_count":14,"is_preprint":false},{"pmid":"33892667","id":"PMC_33892667","title":"GNA14 stimulation of KLF7 promotes malignant growth of endometrial cancer through upregulation of HAS2.","date":"2021","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33892667","citation_count":12,"is_preprint":false},{"pmid":"31423605","id":"PMC_31423605","title":"Tufted angioma with associated Kasabach-Merritt phenomenon caused by somatic mutation in GNA14.","date":"2019","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31423605","citation_count":11,"is_preprint":false},{"pmid":"18330691","id":"PMC_18330691","title":"Cloning, expression pattern, chromosomal localization, and evolution analysis of Porcine gnaq, gna11, and gna14.","date":"2008","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18330691","citation_count":10,"is_preprint":false},{"pmid":"30054423","id":"PMC_30054423","title":"GNA14 silencing suppresses the proliferation of endometrial carcinoma cells through inducing apoptosis and G2/M cell cycle arrest.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/30054423","citation_count":9,"is_preprint":false},{"pmid":"31310691","id":"PMC_31310691","title":"Oral pyogenic granulomas show MAPK/ERK signaling pathway activation, which occurs independently of BRAF, KRAS, HRAS, NRAS, GNA11, and GNA14 mutations.","date":"2019","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31310691","citation_count":9,"is_preprint":false},{"pmid":"38917801","id":"PMC_38917801","title":"GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.","date":"2024","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38917801","citation_count":6,"is_preprint":false},{"pmid":"24797109","id":"PMC_24797109","title":"Subcellular distribution patterns and elevated expression of GNA11 and GNA14 proteins in the lungs of humans with pulmonary arterial hypertension.","date":"2014","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/24797109","citation_count":6,"is_preprint":false},{"pmid":"37760541","id":"PMC_37760541","title":"Tumor-Promoting Role of GNA14 in Colon Cancer Development.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37760541","citation_count":1,"is_preprint":false},{"pmid":"40765578","id":"PMC_40765578","title":"FilaggrinHigh melanomas exhibit active FGFR and allergic signatures with impaired GNA14 and Th1 signatures.","date":"2025","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40765578","citation_count":1,"is_preprint":false},{"pmid":"40946929","id":"PMC_40946929","title":"GNAQ-/GNA14-mutated hepatic vascular malformation with capillary proliferation in adults and children.","date":"2025","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40946929","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11028,"output_tokens":2206,"usd":0.033087,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9271,"output_tokens":3020,"usd":0.060928,"stage2_stop_reason":"end_turn"},"total_usd":0.094015,"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\": 2016,\n      \"finding\": \"Somatic activating GNA14 c.614A>T (p.Gln205Leu) mutation upregulates the MAPK pathway in primary human endothelial cells and melanocytes, inducing changes in cellular morphology and rendering cells growth-factor independent.\",\n      \"method\": \"Expression of mutant GNA14 in primary human endothelial cells and melanocytes; assessment of MAPK pathway activation, cellular morphology, and growth-factor independence\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assay with defined phenotypic readout (MAPK activation, morphology, growth-factor independence) in two cell types; single lab\",\n      \"pmids\": [\"27476652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GNA14 directly binds RACK1 (receptor for activated C kinase 1), as shown by co-immunoprecipitation, mass spectrometry, and GST pull-down assay. Through RACK1, GNA14 reduces MAPK/JNK and PI3K/AKT signaling pathway activity, at least in part by competing with PKC for RACK1 binding and thereby reducing PKC stability.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, GST pull-down, RNA-Seq, loss- and gain-of-function assays, PLC inhibitor (U73122) co-treatment\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus GST pull-down plus RNA-Seq functional confirmation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34657150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GNA14 stimulates expression of KLF7 in endometrial carcinoma cells, which in turn upregulates HAS2, forming a GNA14/KLF7/HAS2 signaling cascade that promotes tumor cell proliferation, migration, and xenograft tumor growth.\",\n      \"method\": \"Lentiviral knockdown and overexpression, RNA sequencing, qRT-PCR, Western blot, CCK8/colony formation/apoptosis/cell cycle/transwell assays, xenograft mouse model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods; single lab\",\n      \"pmids\": [\"33892667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GNA14 promotes Notch1 cleavage to activate the RB pathway, thereby inhibiting hepatocellular carcinoma cell proliferation; GNA14 also inhibits tumor metastasis by suppressing JMJD6 expression. HBV X protein (HBx) silences GNA14 by methylating its promoter.\",\n      \"method\": \"Gain- and loss-of-function assays in vitro; subcutaneous tumorigenesis, lung colonization, and orthotopic liver tumor models in vivo; methyl-target sequencing; co-treatment experiments\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo functional assays with pathway readouts; single lab\",\n      \"pmids\": [\"33500727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GNA14 silencing in endometrial carcinoma cells suppresses proliferation, induces apoptosis (upregulation of caspase-3 and Fas), and causes G2/M cell cycle arrest, demonstrating a pro-proliferative role for GNA14 in this cancer type.\",\n      \"method\": \"Lentivirus-mediated knockdown, caspase 3/7 activity assay, apoptosis array, cell cycle analysis\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with phenotypic readouts but limited mechanistic pathway placement beyond identifying caspase-3/Fas\",\n      \"pmids\": [\"30054423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GNA14 promotes colorectal cancer cell proliferation and malignant tumor progression via ERK phosphorylation and β-catenin phosphorylation at S675. Gna14 knockout mice showed significantly fewer and smaller intestinal polyps in an APC mouse model, with decreased proliferation and increased apoptosis in polyps.\",\n      \"method\": \"siRNA knockdown in CRC cell lines, Gna14 knockout mice crossed with Apc mice, Western blot for p-ERK and p-β-catenin (S675), histological analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic in vivo model (knockout × APC) with defined pathway readouts plus in vitro knockdown; single lab\",\n      \"pmids\": [\"37760541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The GNA14 c.614A>T (p.Gln205Leu) mutation upregulates MAPK and angiogenesis-related pathways (by transcriptomic analysis), and causes enlarged vessels in a mouse xenograft model.\",\n      \"method\": \"Whole-exome sequencing, targeted deep sequencing, transcriptomic analysis, mouse xenograft model\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft model plus transcriptomic pathway analysis; single lab, corroborates earlier findings\",\n      \"pmids\": [\"38917801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Gna14 is induced in gastric tumor epithelial cells by TNF-α/TNFR1 signaling and contributes to tumorigenicity and tumor-initiating cell properties of gastric cancer cells, as shown by colony formation assay following microarray-guided identification.\",\n      \"method\": \"Microarray analysis, colony formation assay, TNF-α/TNFR1 knockout mouse crossed with Gan gastric cancer mouse model, bone marrow transplantation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — colony formation assay as primary functional readout for Gna14 specifically; broader study context; single lab\",\n      \"pmids\": [\"23975421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GNA14 protein localizes to both the nucleus and cytoplasm of human pulmonary arterial endothelial cells (HPAECs) and smooth muscle cells (HPASMCs), as determined by immunocytochemistry and laser scanning confocal microscopy; bioinformatic analysis identified a nuclear localization signal consistent with this distribution.\",\n      \"method\": \"Immunocytochemistry, laser scanning confocal microscopy, bioinformatic nuclear localization signal analysis\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by immunocytochemistry without direct functional consequence established for GNA14 specifically; single study\",\n      \"pmids\": [\"24797109\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GNA14 encodes a Gαq-family heterotrimeric G protein subunit that, when activated by somatic gain-of-function mutations (most commonly p.Gln205Leu), drives MAPK/ERK pathway upregulation to promote vascular tumor formation; in non-vascular cancers it can act as either an oncogene (endometrial, colorectal cancer via ERK and β-catenin) or a tumor suppressor (hepatocellular carcinoma), where it directly binds RACK1 to suppress MAPK/JNK and PI3K/AKT signaling by competing with PKC for RACK1, and also promotes Notch1 cleavage to activate the RB pathway; its expression can be silenced by HBx-induced promoter methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GNA14 encodes a Gαq-family heterotrimeric G protein subunit that couples receptor signaling to growth-controlling pathways, and which becomes oncogenic through a somatic activating mutation. The recurrent c.614A>T (p.Gln205Leu) substitution upregulates MAPK signaling in primary endothelial cells and melanocytes, conferring growth-factor independence and altered morphology [#0], and in vivo drives MAPK and angiogenesis-related transcriptional programs to produce enlarged vessels in xenografts [#6], consistent with a role in vascular tumor formation. In non-vascular epithelial cancers, GNA14 acts as a pro-proliferative effector: it promotes colorectal cancer growth through ERK phosphorylation and β-catenin phosphorylation at S675, and Gna14 loss reduces intestinal polyp burden in APC mice [#5], while in endometrial carcinoma it engages a KLF7→HAS2 cascade to drive proliferation, migration, and xenograft growth [#2]. Conversely, in hepatocellular carcinoma GNA14 is tumor-suppressive, directly binding RACK1 to compete with PKC and thereby dampen MAPK/JNK and PI3K/AKT signaling [#1], and promoting Notch1 cleavage to activate the RB pathway while suppressing JMJD6-driven metastasis; its expression in this context is silenced by HBx-induced promoter methylation [#3]. This context-dependent oncogene/tumor-suppressor duality is the central feature of GNA14 biology in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that Gna14 is a downstream transcriptional target of inflammatory signaling and contributes to tumor-initiating properties, linking it to cancer before its mutational role was known.\",\n      \"evidence\": \"Microarray-guided identification plus colony formation assay in a TNF-α/TNFR1 knockout × Gan gastric cancer mouse model\",\n      \"pmids\": [\"23975421\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Colony formation as the primary functional readout; no pathway mechanism placed for Gna14 specifically\", \"Does not establish whether the effect is via G-protein signaling\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Addressed where GNA14 protein resides, finding both nuclear and cytoplasmic localization in vascular cell types.\",\n      \"evidence\": \"Immunocytochemistry, confocal microscopy, and bioinformatic NLS prediction in HPAECs and HPASMCs\",\n      \"pmids\": [\"24797109\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequence tied to nuclear localization\", \"Single study, no validation of the predicted NLS\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the somatic gain-of-function p.Gln205Leu mutation as the driver of constitutive MAPK activation, defining GNA14 as an oncogene in vascular/melanocytic lineages.\",\n      \"evidence\": \"Expression of mutant GNA14 in primary human endothelial cells and melanocytes with MAPK, morphology, and growth-factor independence readouts\",\n      \"pmids\": [\"27476652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab cell-based assay; no in vivo tumor formation in this study\", \"Effector mechanism downstream of Gαq not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a pro-proliferative, anti-apoptotic role for GNA14 in endometrial carcinoma, supporting an oncogenic function in this epithelial context.\",\n      \"evidence\": \"Lentiviral knockdown with caspase 3/7, apoptosis array, and cell cycle analysis\",\n      \"pmids\": [\"30054423\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic placement beyond caspase-3/Fas and G2/M arrest\", \"No upstream signaling pathway defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved a downstream transcriptional cascade for the oncogenic role in endometrial cancer, placing GNA14 upstream of a KLF7→HAS2 axis.\",\n      \"evidence\": \"Lentiviral knockdown/overexpression, RNA-seq, qRT-PCR, proliferation/migration assays, and xenograft model\",\n      \"pmids\": [\"33892667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GNA14 G-protein activity to KLF7 induction not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a tumor-suppressive mechanism in a different tissue, showing GNA14 directly binds RACK1 to compete with PKC and downregulate MAPK/JNK and PI3K/AKT signaling.\",\n      \"evidence\": \"Reciprocal co-IP, mass spectrometry, GST pull-down, RNA-Seq, and gain/loss-of-function assays with PLC inhibitor co-treatment\",\n      \"pmids\": [\"34657150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of GNA14–RACK1 competition with PKC not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established GNA14 as a tumor suppressor in hepatocellular carcinoma acting through Notch1/RB activation and JMJD6 suppression, and identified its epigenetic silencing by HBx.\",\n      \"evidence\": \"In vitro gain/loss-of-function, subcutaneous/lung colonization/orthotopic liver tumor models, methyl-target sequencing\",\n      \"pmids\": [\"33500727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which GNA14 promotes Notch1 cleavage unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided genetic in vivo evidence for an oncogenic role in colorectal cancer via ERK and β-catenin S675 phosphorylation.\",\n      \"evidence\": \"siRNA knockdown in CRC lines, Gna14 knockout × Apc mice, and Western blot for p-ERK and p-β-catenin\",\n      \"pmids\": [\"37760541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether wild-type GNA14 signaling or a mutant drives the effect not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed in vivo that the p.Gln205Leu mutation drives MAPK and angiogenic programs and produces vascular phenotypes, reinforcing the original oncogenic mechanism.\",\n      \"evidence\": \"Whole-exome/targeted deep sequencing, transcriptomic analysis, and mouse xenograft model\",\n      \"pmids\": [\"38917801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effectors bridging mutant Gαq to angiogenic transcription not enumerated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what determines GNA14's context-dependent switch between oncogene (endometrial, colorectal, vascular) and tumor suppressor (hepatocellular), and how its receptor coupling and effector selection differ across these tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling pro- and anti-tumorigenic functions\", \"Upstream GPCRs coupling to GNA14 in each tissue not identified\", \"Structural consequences of p.Gln205Leu on effector binding not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RACK1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}