{"gene":"GNA13","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2013,"finding":"GNA13 knockdown in highly invasive PC3 prostate cancer cells inhibits invasion, migration, and Rho activation, establishing GNA13 as a required mediator of RhoA activity downstream of GPCRs in these cells. miR-182 and miR-141/200a directly target the 3'-UTR of GNA13, post-transcriptionally suppressing its expression and reducing invasion; restoration of GNA13 blocks this effect.","method":"siRNA knockdown, 3'-UTR luciferase reporter assay, Boyden chamber invasion assay, miRNA inhibitors, ectopic miRNA expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal miRNA/target validation with luciferase reporter and rescue experiment, single lab, multiple orthogonal methods","pmids":["23329838"],"is_preprint":false},{"year":2014,"finding":"GNA13 is a direct target of miR-29c; miR-29c suppresses GNA13 expression and consequently inhibits EMT in colorectal cancer cells through the ERK/GSK3β/β-catenin pathway.","method":"qRT-PCR, in vitro invasion/migration assays, in vivo metastasis assay, miRNA target validation, pathway analysis","journal":"Annals of oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter and functional rescue implied but pathway placement in ERK/GSK3β/β-catenin established by correlative and knockdown approaches; single lab","pmids":["25193986"],"is_preprint":false},{"year":2015,"finding":"GNA13 expression in breast cancer cells is post-transcriptionally controlled by miR-31, which directly targets the GNA13 3'-UTR. Overexpression of GNA13 in MCF-10a cells induces invasion; knockdown in MDA-MB-231 cells inhibits invasion. Rescue of GNA13 in miR-31-expressing cells partially restores invasion.","method":"3'-UTR luciferase reporter assay, RT-PCR, Western blotting, Boyden chamber invasion assay, ectopic miR-31 expression, miR-31 inhibitors","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with luciferase reporter and rescue experiment, single lab, multiple orthogonal methods","pmids":["25889182"],"is_preprint":false},{"year":2015,"finding":"Cancer-specific GNA13 mutations identified in Burkitt's lymphoma and DLBCL are inhibitory (loss-of-function) in nature. Re-expression of wild-type Gα13 in B-cell lymphoma cells bearing mutant GNA13 causes remarkable growth inhibition in vivo, but has limited impact in vitro, supporting a tumor suppressor role for the Gα13/RhoA axis in B cells.","method":"Multiple complementary functional approaches (in vitro and in vivo), mutant characterization, re-expression of wild-type GNA13","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary in vitro and in vivo approaches in a single study; single lab","pmids":["26616858"],"is_preprint":false},{"year":2016,"finding":"Conditional knockout of GNA13 in germinal center B cells (AID-Cre model) leads to disordered GC architecture, altered migration, decreased filamentous actin, attenuated RhoA activity, impaired caspase-mediated apoptosis, and increased somatic hypermutation. Combined with MYC transgene, GNA13 deficiency promotes lymphomagenesis, establishing a tumor suppressor role for GNA13 in GC B cells.","method":"Conditional knockout mouse model (AID-Cre × Gna13 flox), in vivo GC architecture analysis, in vitro migration assay, RhoA activity assay, caspase activity assay, immunoglobulin VH somatic hypermutation analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with multiple orthogonal phenotypic readouts (migration, actin, RhoA, apoptosis, SHM) in vivo and in vitro, genetic epistasis with MYC","pmids":["26989201"],"is_preprint":false},{"year":2016,"finding":"Enhanced GNA13 signaling in MCF-10a breast cells suppresses transcription of tumor-protective Kallikrein genes (KLK5, KLK6, KLK7, KLK8, KLK10) via negative regulation of RhoA/ROCK signaling. Rhotekin pulldown confirmed that GNA13 overexpression reduces active RhoA; blocking RhoA with C3-toxin or ROCK inhibitor phenocopies GNA13-mediated KLK suppression.","method":"Microarray, real-time PCR, promoter luciferase assay, Rhotekin pulldown (RhoA activity assay), C3-toxin and ROCK inhibitor treatment, GNA13 knockdown in MDA-MB-157 cells","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Rhotekin pulldown for RhoA activity plus pharmacological epistasis and KD rescue, single lab, multiple methods","pmids":["27424208"],"is_preprint":false},{"year":2018,"finding":"GNA13 overexpression in colorectal cancer cells activates the NF-κB/p65 signaling pathway, leading to upregulation of chemokines CXCL1, CXCL2, and CXCL4, which promote proliferation and angiogenesis. NF-κB/p65 inhibition abrogates GNA13-induced migration, invasion, and chemokine upregulation.","method":"GNA13 overexpression/knockdown, Western blotting, NF-κB inhibitor treatment, ELISA/chemokine measurement, cell growth and invasion assays","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological epistasis with NF-κB inhibitor and gain/loss-of-function, single lab, limited mechanistic depth","pmids":["30267476"],"is_preprint":false},{"year":2021,"finding":"GNA13 undergoes palmitoylation that is essential for its plasma membrane localization and stability in GCB-DLBCL cells. Palmitoylation-dependent membrane localization is required for GNA13's tumor suppressor function. GNA13 negatively regulates BCL2 expression in a palmitoylation-dependent manner; loss of palmitoylation abrogates GNA13-mediated BCL2 suppression.","method":"Palmitoylation assay, subcellular fractionation, GNA13 mutant overexpression (palmitoylation-deficient), Western blotting for BCL2, cell viability assay with BCL2 inhibitor","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation-deficient mutants used to establish causality, multiple cell-based readouts, single lab","pmids":["33423045"],"is_preprint":false},{"year":2021,"finding":"GNA13 overexpression in glioma cells downregulates PRKACA (a PKA subunit), leading to reduced phosphorylation of RELA and decreased MGMT expression, sensitizing glioma cells to temozolomide through the GNA13/PRKACA/p-RELA and GNA13/PRKACA/MGMT signaling axes.","method":"GNA13 overexpression, Western blotting for PRKACA, p-RELA, MGMT, bioinformatic analysis (GSE80729, GSE43452), cell viability assay with TMZ","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily Western blotting and bioinformatics without direct rescue or in vitro kinase assays","pmids":["34786068"],"is_preprint":false},{"year":2023,"finding":"GNA13 acts upstream of the ERK signaling pathway in glioblastoma cells; GNA13 knockdown increases ERK phosphorylation and promotes migration/invasion, while GNA13 overexpression inhibits ERK phosphorylation and suppresses metastasis. GNA13 regulates FOXO3 as a downstream effector of ERK, and the ERK inhibitor U0126 rescues the pro-metastatic phenotype induced by GNA13 knockdown.","method":"GNA13 knockdown/overexpression, Western blotting for p-ERK, pharmacological epistasis with U0126 (ERK inhibitor), qRT-PCR for FOXO3, migration/invasion assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with ERK inhibitor rescuing GNA13-KD phenotype, gain and loss of function, single lab","pmids":["37392861"],"is_preprint":false},{"year":2024,"finding":"GNA13 suppresses proliferation in ER+ breast cancer cells via an ERα-dependent mechanism that regulates MYC expression at both transcript and protein levels. Loss of GNA13 upregulates MYC signaling pathways; simultaneous silencing of MYC reverses the proliferative effect caused by GNA13 loss, demonstrating epistasis between GNA13 and MYC downstream of ERα.","method":"GNA13 knockdown/overexpression, RNA-sequencing, MYC co-silencing (genetic epistasis), orthotopic xenograft model, soft-agar colony formation assay, Western blotting","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (GNA13 KD + MYC co-KD rescue) and in vivo xenograft, single lab, multiple orthogonal methods","pmids":["38965558"],"is_preprint":false},{"year":2025,"finding":"A gain-of-function R200K missense mutation in GNA13 hyperactivates the RHOA/ROCK signaling pathway, increasing actin polymerization and myosin light chain phosphorylation, promoting melanocyte rounding and impairing cell migration/adhesion without affecting proliferation. R200K Gα13 also hyperactivates the YAP signaling pathway. The resulting defect in melanosome transfer to keratinocytes causes hypopigmentation.","method":"In-depth functional investigations in patient-derived cells, actin polymerization assay, myosin light chain phosphorylation Western blot, cell morphology and migration assay, YAP pathway analysis, comparison to wild-type GNA13","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in patient-derived cells with a defined GOF mutation; single study but multiple readouts","pmids":["39966435"],"is_preprint":false},{"year":2025,"finding":"DHHC13 (zinc finger DHHC-type palmitoyltransferase 13) catalyzes S-palmitoylation of GNA13 at Cys14 and Cys18 residues in Sertoli cells, which is required for GNA13 plasma membrane localization and its selective enrichment in Sertoli cell-derived extracellular vesicles. Palmitoylated GNA13 delivered via EVs to spermatogonial stem cells suppresses autophagy through interaction with ARHGEF12, promoting RhoA activity; inhibition of GNA13 palmitoylation reduces ARHGEF12 interaction, diminishes RhoA activity, and elevates autophagy.","method":"Site-directed mutagenesis of palmitoylation sites (Cys14/Cys18), palmitoylation assay, subcellular fractionation, EV isolation, Co-immunoprecipitation (GNA13–ARHGEF12 interaction), RhoA activity assay, autophagy assay","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of palmitoylation sites, Co-IP for binding partner, and functional autophagy/RhoA readouts; single lab, multiple orthogonal methods","pmids":["40205436"],"is_preprint":false},{"year":2022,"finding":"GNA13 knockdown in lung squamous cell carcinoma cells reduces phosphorylation of PI3K and AKT, while GNA13 overexpression increases PI3K/AKT phosphorylation, placing GNA13 upstream of the PI3K/AKT pathway in regulating LUSC cell growth and migration.","method":"GNA13 siRNA knockdown and overexpression, Western blotting for p-PI3K and p-AKT, MTT assay, wound healing, Transwell invasion assay, in vivo LUSC mouse model","journal":"Tissue & cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily Western blotting without direct enzymatic or epistasis rescue validation","pmids":["35413491"],"is_preprint":false}],"current_model":"GNA13 encodes Gα13, the α-subunit of a heterotrimeric G12/13 family G-protein that transduces GPCR signals primarily through RhoA activation (via ARHGEF12/LARG-type GEFs) and downstream ROCK/actin remodeling; its plasma membrane localization and stability require S-palmitoylation at Cys14/Cys18 (catalyzed by DHHC13), and it regulates diverse downstream pathways—including RhoA/ROCK, ERK, NF-κB, PI3K/AKT, Wnt/β-catenin, and YAP—in a context-dependent manner that can be either oncogenic (promoting invasion and EMT in epithelial cancers) or tumor-suppressive (in germinal center B-cell lymphomas and ER+ breast cancer), with its expression post-transcriptionally controlled by multiple miRNAs (miR-182, miR-200a/141, miR-31, miR-29c, miR-30d)."},"narrative":{"mechanistic_narrative":"GNA13 encodes Gα13, the α-subunit of a G12/13-family heterotrimeric G-protein that transduces signals into RhoA activation and downstream actin remodeling, governing cell migration, invasion, and survival in a strongly context-dependent manner [PMID:23329838, PMID:26989201]. Its membrane targeting and stability depend on S-palmitoylation at Cys14/Cys18, catalyzed by DHHC13; this lipid modification is required both for Gα13 plasma-membrane localization and for engagement of the RhoGEF ARHGEF12 to drive RhoA activity, and loss of palmitoylation abolishes Gα13 function [PMID:33423045, PMID:40205436]. In epithelial cancers (prostate, colorectal, breast, lung), GNA13 acts as a pro-invasive/oncogenic mediator, promoting migration, EMT, and invasion through RhoA and additional effector arms including ERK/GSK3β/β-catenin, NF-κB/p65-driven chemokine induction, and PI3K/AKT signaling [PMID:23329838, PMID:25193986, PMID:30267476, PMID:35413491]. In sharp contrast, GNA13 is tumor-suppressive in germinal-center B cells, where inhibitory lymphoma-associated mutations and conditional knockout disrupt the Gα13/RhoA axis, derange GC architecture, impair apoptosis, increase somatic hypermutation, and cooperate with MYC to drive lymphomagenesis; this suppressor role requires palmitoylation-dependent negative regulation of BCL2 [PMID:26616858, PMID:26989201, PMID:33423045]. A similar growth-restraining function operates in ER+ breast cancer, where GNA13 limits MYC expression downstream of ERα [PMID:38965558]. Across these settings GNA13 expression is post-transcriptionally repressed by multiple miRNAs that directly target its 3'-UTR, including miR-182, miR-141/200a, miR-29c, and miR-31 [PMID:23329838, PMID:25193986, PMID:25889182]. A gain-of-function R200K missense mutation in GNA13 hyperactivates RHOA/ROCK and YAP signaling, increasing actin polymerization and myosin light-chain phosphorylation; the resulting defect in melanosome transfer from melanocytes to keratinocytes causes a hypopigmentation disorder [PMID:39966435].","teleology":[{"year":2013,"claim":"Established GNA13 as a required transducer of RhoA activation driving cancer cell invasion, and identified miRNA-mediated 3'-UTR repression as a control point over this activity.","evidence":"siRNA knockdown, Rho activity and invasion assays, and 3'-UTR luciferase reporters with miR-182 and miR-141/200a in prostate cancer cells","pmids":["23329838"],"confidence":"Medium","gaps":["GEF and GPCR receptor identity upstream of GNA13 not defined here","Single cell-type context"]},{"year":2014,"claim":"Extended GNA13 effector reach beyond RhoA by placing it upstream of the ERK/GSK3β/β-catenin axis controlling EMT, under repression by miR-29c.","evidence":"miRNA target validation, pathway analysis, and in vitro/in vivo metastasis assays in colorectal cancer cells","pmids":["25193986"],"confidence":"Medium","gaps":["Direct molecular link from GNA13 to ERK not mechanistically resolved","Pathway placement partly correlative"]},{"year":2015,"claim":"Confirmed pro-invasive, oncogenic GNA13 function in breast epithelium via miR-31 control, while parallel lymphoma work revealed the opposite — that GNA13 mutations are loss-of-function and GNA13/RhoA is tumor-suppressive in B cells.","evidence":"Reciprocal gain/loss-of-function with 3'-UTR reporters in breast cells; mutant characterization and wild-type re-expression with in vivo growth assays in B-cell lymphoma","pmids":["25889182","26616858"],"confidence":"Medium","gaps":["Mechanistic basis for opposite directionality between epithelial and B cells unresolved","In vitro vs in vivo discordance in lymphoma cells unexplained"]},{"year":2016,"claim":"Provided genetic in vivo proof of GNA13 tumor suppression in germinal-center B cells and linked it to RhoA-dependent actin, migration, apoptosis, and somatic hypermutation control.","evidence":"AID-Cre conditional knockout mouse with RhoA, actin, caspase and SHM readouts and MYC genetic cooperation; plus RhoA/ROCK-dependent kallikrein suppression in breast cells","pmids":["26989201","27424208"],"confidence":"High","gaps":["Upstream GPCR/GEF driving GC B-cell RhoA signaling not identified","How attenuated RhoA increases SHM mechanistically unclear"]},{"year":2018,"claim":"Identified an NF-κB/p65 effector arm by which GNA13 induces chemokines to promote proliferation and angiogenesis in colorectal cancer.","evidence":"Gain/loss-of-function with NF-κB inhibitor epistasis and chemokine measurement in colorectal cancer cells","pmids":["30267476"],"confidence":"Medium","gaps":["Direct molecular link from GNA13 to NF-κB activation not defined","Limited mechanistic depth"]},{"year":2021,"claim":"Demonstrated that palmitoylation is mechanistically required for GNA13 membrane localization, stability, and its tumor-suppressor function through BCL2 repression in lymphoma; separately placed GNA13 upstream of a PRKACA/RELA/MGMT axis in glioma.","evidence":"Palmitoylation-deficient mutants with fractionation and BCL2/cell-viability readouts in GCB-DLBCL; Western blot and bioinformatics for the glioma axis","pmids":["33423045","34786068"],"confidence":"Medium","gaps":["Palmitoyltransferase enzyme not yet identified at this stage","Glioma PRKACA axis lacks direct rescue and is Low confidence"]},{"year":2022,"claim":"Placed GNA13 upstream of PI3K/AKT signaling in lung squamous carcinoma growth and migration.","evidence":"siRNA knockdown and overexpression with p-PI3K/p-AKT Western blots and in vivo LUSC model","pmids":["35413491"],"confidence":"Low","gaps":["No enzymatic or epistasis rescue validation","Direct connection to PI3K/AKT undefined"]},{"year":2023,"claim":"Defined a tumor-suppressive ERK/FOXO3 effector arm in glioblastoma in which GNA13 restrains ERK phosphorylation and metastasis.","evidence":"Gain/loss-of-function with U0126 ERK-inhibitor epistasis rescuing the GNA13-knockdown phenotype in glioblastoma cells","pmids":["37392861"],"confidence":"Medium","gaps":["Mechanism by which GNA13 lowers ERK phosphorylation unresolved","Reconciliation with pro-ERK roles in other cancers not addressed"]},{"year":2024,"claim":"Established GNA13 as a suppressor of ER+ breast cancer proliferation acting through an ERα-dependent restraint of MYC.","evidence":"Knockdown/overexpression with RNA-seq, MYC co-silencing genetic epistasis, and orthotopic xenograft","pmids":["38965558"],"confidence":"Medium","gaps":["Molecular mechanism linking GNA13 to ERα-dependent MYC control undefined","Single lab"]},{"year":2025,"claim":"Identified DHHC13 as the palmitoyltransferase modifying GNA13 at Cys14/Cys18 and linked palmitoylation-dependent ARHGEF12 binding to RhoA-mediated autophagy suppression; and defined a disease-causing GOF R200K mutation that hyperactivates RHOA/ROCK and YAP to impair melanosome transfer and cause hypopigmentation.","evidence":"Cys14/Cys18 mutagenesis with Co-IP, RhoA and autophagy assays in Sertoli cell/EV system; patient-derived cell functional assays of actin, MLC phosphorylation and YAP for R200K","pmids":["40205436","39966435"],"confidence":"Medium","gaps":["Generality of DHHC13 as the GNA13 palmitoyltransferase across other cell types untested","Structural basis of R200K gain-of-function not resolved"]},{"year":null,"claim":"The molecular determinant that switches GNA13/RhoA signaling between oncogenic (epithelial) and tumor-suppressive (B-cell, ER+ breast) outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism explains context-dependent directionality","Upstream GPCRs and tissue-specific effector wiring not mapped","Direct biochemical links to NF-κB, ERK, PI3K/AKT remain indirect"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,11]}],"complexes":[],"partners":["ARHGEF12","ZDHHC13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14344","full_name":"Guanine nucleotide-binding protein subunit alpha-13","aliases":[],"length_aa":377,"mass_kda":44.0,"function":"Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems (PubMed:15240885, PubMed:16705036, PubMed:16787920, PubMed:27084452). Activates effector molecule RhoA by binding and activating RhoGEFs (ARHGEF1/p115RhoGEF, ARHGEF11/PDZ-RhoGEF and ARHGEF12/LARG) (PubMed:12515866, PubMed:15240885). GNA13-dependent Rho signaling subsequently regulates transcription factor AP-1 (activating protein-1) (By similarity). Promotes tumor cell invasion and metastasis by activating RhoA/ROCK signaling pathway (PubMed:16705036, PubMed:16787920, PubMed:27084452). Inhibits CDH1-mediated cell adhesion in a process independent from Rho activation (PubMed:11976333). In lymphoid follicles, transmits P2RY8- and S1PR2-dependent signals that lead to inhibition of germinal center (GC) B cell growth and migration outside the GC niche","subcellular_location":"Cell membrane; Melanosome; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14344/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GNA13","classification":"Not Classified","n_dependent_lines":41,"n_total_lines":1208,"dependency_fraction":0.03394039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GNB1","stoichiometry":0.2},{"gene":"SLC16A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GNA13","total_profiled":1310},"omim":[{"mim_id":"615650","title":"REGULATOR OF G PROTEIN SIGNALING 22; RGS22","url":"https://www.omim.org/entry/615650"},{"mim_id":"613394","title":"MICRO RNA 138-1; MIR138-1","url":"https://www.omim.org/entry/613394"},{"mim_id":"609736","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 88A; CCDC88A","url":"https://www.omim.org/entry/609736"},{"mim_id":"609146","title":"RIC8 GUANINE NUCLEOTIDE EXCHANGE FACTOR A; RIC8A","url":"https://www.omim.org/entry/609146"},{"mim_id":"607392","title":"WW DOMAIN-CONTAINING TRANSCRIPTION REGULATOR 1; WWTR1","url":"https://www.omim.org/entry/607392"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":136.4}],"url":"https://www.proteinatlas.org/search/GNA13"},"hgnc":{"alias_symbol":["G13","MGC46138"],"prev_symbol":[]},"alphafold":{"accession":"Q14344","domains":[{"cath_id":"3.40.50.300","chopping":"49-75_203-375","consensus_level":"high","plddt":93.5746,"start":49,"end":375},{"cath_id":"1.10.400.10","chopping":"77-190","consensus_level":"high","plddt":96.7603,"start":77,"end":190}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14344","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14344-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14344-F1-predicted_aligned_error_v6.png","plddt_mean":91.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GNA13","jax_strain_url":"https://www.jax.org/strain/search?query=GNA13"},"sequence":{"accession":"Q14344","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14344.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14344/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14344"}},"corpus_meta":[{"pmid":"25193986","id":"PMC_25193986","title":"MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of β-catenin signaling.","date":"2014","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25193986","citation_count":98,"is_preprint":false},{"pmid":"25889182","id":"PMC_25889182","title":"MicroRNA-31 controls G protein alpha-13 (GNA13) expression and cell invasion in breast cancer cells.","date":"2015","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25889182","citation_count":75,"is_preprint":false},{"pmid":"23329838","id":"PMC_23329838","title":"MicroRNA-182 and microRNA-200a control G-protein subunit α-13 (GNA13) expression and cell invasion synergistically in prostate cancer cells.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23329838","citation_count":72,"is_preprint":false},{"pmid":"26616858","id":"PMC_26616858","title":"Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the Gα13/RhoA axis in B cells.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/26616858","citation_count":68,"is_preprint":false},{"pmid":"26989201","id":"PMC_26989201","title":"GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo.","date":"2016","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/26989201","citation_count":51,"is_preprint":false},{"pmid":"30267476","id":"PMC_30267476","title":"GNA13 promotes tumor growth and angiogenesis by upregulating CXC chemokines via the NF-κB signaling pathway in colorectal cancer cells.","date":"2018","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30267476","citation_count":42,"is_preprint":false},{"pmid":"29255247","id":"PMC_29255247","title":"GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29255247","citation_count":40,"is_preprint":false},{"pmid":"28214564","id":"PMC_28214564","title":"Downregulation of GNA13-ERK network in prefrontal cortex of schizophrenia brain identified by combined focused and targeted quantitative proteomics.","date":"2017","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/28214564","citation_count":36,"is_preprint":false},{"pmid":"33423045","id":"PMC_33423045","title":"GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33423045","citation_count":28,"is_preprint":false},{"pmid":"30651791","id":"PMC_30651791","title":"miRNA-30d serves a critical function in colorectal cancer initiation, progression and invasion via directly targeting the GNA13 gene.","date":"2018","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30651791","citation_count":16,"is_preprint":false},{"pmid":"27424208","id":"PMC_27424208","title":"The GNA13-RhoA signaling axis suppresses expression of tumor protective Kallikreins.","date":"2016","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/27424208","citation_count":15,"is_preprint":false},{"pmid":"34786068","id":"PMC_34786068","title":"Overexpressed GNA13 induces temozolomide sensitization via down-regulating MGMT and p-RELA in glioma.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34786068","citation_count":10,"is_preprint":false},{"pmid":"37392861","id":"PMC_37392861","title":"GNA13 inhibits glioblastoma metastasis via the ERKs/FOXO3 signaling pathway.","date":"2023","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/37392861","citation_count":7,"is_preprint":false},{"pmid":"35413491","id":"PMC_35413491","title":"GNA13 promotes the proliferation and migration of lung squamous cell carcinoma cells through regulating the PI3K/AKT signaling pathway.","date":"2022","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/35413491","citation_count":6,"is_preprint":false},{"pmid":"31676466","id":"PMC_31676466","title":"The role of genes affected by human evolution marker GNA13 in schizophrenia.","date":"2019","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/31676466","citation_count":6,"is_preprint":false},{"pmid":"40205436","id":"PMC_40205436","title":"Zinc finger DHHC-type palmitoyltransferase 13-mediated S-palmitoylation of GNA13 from Sertoli cell-derived extracellular vesicles inhibits autophagy in spermatogonial stem cells.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/40205436","citation_count":4,"is_preprint":false},{"pmid":"38357893","id":"PMC_38357893","title":"The lncRNA TRG-AS1 promotes the growth of colorectal cancer cells through the regulation of P2RY10/GNA13.","date":"2024","source":"Scandinavian journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/38357893","citation_count":4,"is_preprint":false},{"pmid":"39966435","id":"PMC_39966435","title":"A postzygotic GNA13 variant upregulates the RHOA/ROCK pathway and alters melanocyte function in a mosaic skin hypopigmentation syndrome.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39966435","citation_count":3,"is_preprint":false},{"pmid":"39345963","id":"PMC_39345963","title":"Biological roles of THRAP3, STMN1 and GNA13 in human blood cancer cells.","date":"2024","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/39345963","citation_count":3,"is_preprint":false},{"pmid":"38965558","id":"PMC_38965558","title":"GNA13 suppresses proliferation of ER+ breast cancer cells via ERα dependent upregulation of the MYC oncogene.","date":"2024","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/38965558","citation_count":3,"is_preprint":false},{"pmid":"39121017","id":"PMC_39121017","title":"Modified Electroconvulsive Therapy Normalizes Plasma GNA13 Following Schizophrenic Relapse.","date":"2024","source":"The journal of ECT","url":"https://pubmed.ncbi.nlm.nih.gov/39121017","citation_count":1,"is_preprint":false},{"pmid":"41081046","id":"PMC_41081046","title":"GNA13 promotes brain metastasis of non-small cell lung cancer and EMT through the WNT/β catenin signaling pathway.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/41081046","citation_count":0,"is_preprint":false},{"pmid":"41282466","id":"PMC_41282466","title":"[Retracted] miRNA-30d serves a critical function in colorectal cancer initiation, progression and invasion via directly targeting the GNA13 gene.","date":"2025","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41282466","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.24.24310661","title":"A postzygotic<i>GNA13</i>variant upregulates the RHOA/ROCK pathway and alters melanocyte function in a mosaic skin hypopigmentation syndrome","date":"2024-07-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.24.24310661","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14842,"output_tokens":4022,"usd":0.052428,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11835,"output_tokens":3735,"usd":0.076275,"stage2_stop_reason":"end_turn"},"total_usd":0.128703,"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\": 2013,\n      \"finding\": \"GNA13 knockdown in highly invasive PC3 prostate cancer cells inhibits invasion, migration, and Rho activation, establishing GNA13 as a required mediator of RhoA activity downstream of GPCRs in these cells. miR-182 and miR-141/200a directly target the 3'-UTR of GNA13, post-transcriptionally suppressing its expression and reducing invasion; restoration of GNA13 blocks this effect.\",\n      \"method\": \"siRNA knockdown, 3'-UTR luciferase reporter assay, Boyden chamber invasion assay, miRNA inhibitors, ectopic miRNA expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal miRNA/target validation with luciferase reporter and rescue experiment, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23329838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GNA13 is a direct target of miR-29c; miR-29c suppresses GNA13 expression and consequently inhibits EMT in colorectal cancer cells through the ERK/GSK3β/β-catenin pathway.\",\n      \"method\": \"qRT-PCR, in vitro invasion/migration assays, in vivo metastasis assay, miRNA target validation, pathway analysis\",\n      \"journal\": \"Annals of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter and functional rescue implied but pathway placement in ERK/GSK3β/β-catenin established by correlative and knockdown approaches; single lab\",\n      \"pmids\": [\"25193986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GNA13 expression in breast cancer cells is post-transcriptionally controlled by miR-31, which directly targets the GNA13 3'-UTR. Overexpression of GNA13 in MCF-10a cells induces invasion; knockdown in MDA-MB-231 cells inhibits invasion. Rescue of GNA13 in miR-31-expressing cells partially restores invasion.\",\n      \"method\": \"3'-UTR luciferase reporter assay, RT-PCR, Western blotting, Boyden chamber invasion assay, ectopic miR-31 expression, miR-31 inhibitors\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with luciferase reporter and rescue experiment, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25889182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cancer-specific GNA13 mutations identified in Burkitt's lymphoma and DLBCL are inhibitory (loss-of-function) in nature. Re-expression of wild-type Gα13 in B-cell lymphoma cells bearing mutant GNA13 causes remarkable growth inhibition in vivo, but has limited impact in vitro, supporting a tumor suppressor role for the Gα13/RhoA axis in B cells.\",\n      \"method\": \"Multiple complementary functional approaches (in vitro and in vivo), mutant characterization, re-expression of wild-type GNA13\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary in vitro and in vivo approaches in a single study; single lab\",\n      \"pmids\": [\"26616858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Conditional knockout of GNA13 in germinal center B cells (AID-Cre model) leads to disordered GC architecture, altered migration, decreased filamentous actin, attenuated RhoA activity, impaired caspase-mediated apoptosis, and increased somatic hypermutation. Combined with MYC transgene, GNA13 deficiency promotes lymphomagenesis, establishing a tumor suppressor role for GNA13 in GC B cells.\",\n      \"method\": \"Conditional knockout mouse model (AID-Cre × Gna13 flox), in vivo GC architecture analysis, in vitro migration assay, RhoA activity assay, caspase activity assay, immunoglobulin VH somatic hypermutation analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with multiple orthogonal phenotypic readouts (migration, actin, RhoA, apoptosis, SHM) in vivo and in vitro, genetic epistasis with MYC\",\n      \"pmids\": [\"26989201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Enhanced GNA13 signaling in MCF-10a breast cells suppresses transcription of tumor-protective Kallikrein genes (KLK5, KLK6, KLK7, KLK8, KLK10) via negative regulation of RhoA/ROCK signaling. Rhotekin pulldown confirmed that GNA13 overexpression reduces active RhoA; blocking RhoA with C3-toxin or ROCK inhibitor phenocopies GNA13-mediated KLK suppression.\",\n      \"method\": \"Microarray, real-time PCR, promoter luciferase assay, Rhotekin pulldown (RhoA activity assay), C3-toxin and ROCK inhibitor treatment, GNA13 knockdown in MDA-MB-157 cells\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Rhotekin pulldown for RhoA activity plus pharmacological epistasis and KD rescue, single lab, multiple methods\",\n      \"pmids\": [\"27424208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GNA13 overexpression in colorectal cancer cells activates the NF-κB/p65 signaling pathway, leading to upregulation of chemokines CXCL1, CXCL2, and CXCL4, which promote proliferation and angiogenesis. NF-κB/p65 inhibition abrogates GNA13-induced migration, invasion, and chemokine upregulation.\",\n      \"method\": \"GNA13 overexpression/knockdown, Western blotting, NF-κB inhibitor treatment, ELISA/chemokine measurement, cell growth and invasion assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological epistasis with NF-κB inhibitor and gain/loss-of-function, single lab, limited mechanistic depth\",\n      \"pmids\": [\"30267476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GNA13 undergoes palmitoylation that is essential for its plasma membrane localization and stability in GCB-DLBCL cells. Palmitoylation-dependent membrane localization is required for GNA13's tumor suppressor function. GNA13 negatively regulates BCL2 expression in a palmitoylation-dependent manner; loss of palmitoylation abrogates GNA13-mediated BCL2 suppression.\",\n      \"method\": \"Palmitoylation assay, subcellular fractionation, GNA13 mutant overexpression (palmitoylation-deficient), Western blotting for BCL2, cell viability assay with BCL2 inhibitor\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation-deficient mutants used to establish causality, multiple cell-based readouts, single lab\",\n      \"pmids\": [\"33423045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GNA13 overexpression in glioma cells downregulates PRKACA (a PKA subunit), leading to reduced phosphorylation of RELA and decreased MGMT expression, sensitizing glioma cells to temozolomide through the GNA13/PRKACA/p-RELA and GNA13/PRKACA/MGMT signaling axes.\",\n      \"method\": \"GNA13 overexpression, Western blotting for PRKACA, p-RELA, MGMT, bioinformatic analysis (GSE80729, GSE43452), cell viability assay with TMZ\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily Western blotting and bioinformatics without direct rescue or in vitro kinase assays\",\n      \"pmids\": [\"34786068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GNA13 acts upstream of the ERK signaling pathway in glioblastoma cells; GNA13 knockdown increases ERK phosphorylation and promotes migration/invasion, while GNA13 overexpression inhibits ERK phosphorylation and suppresses metastasis. GNA13 regulates FOXO3 as a downstream effector of ERK, and the ERK inhibitor U0126 rescues the pro-metastatic phenotype induced by GNA13 knockdown.\",\n      \"method\": \"GNA13 knockdown/overexpression, Western blotting for p-ERK, pharmacological epistasis with U0126 (ERK inhibitor), qRT-PCR for FOXO3, migration/invasion assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with ERK inhibitor rescuing GNA13-KD phenotype, gain and loss of function, single lab\",\n      \"pmids\": [\"37392861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GNA13 suppresses proliferation in ER+ breast cancer cells via an ERα-dependent mechanism that regulates MYC expression at both transcript and protein levels. Loss of GNA13 upregulates MYC signaling pathways; simultaneous silencing of MYC reverses the proliferative effect caused by GNA13 loss, demonstrating epistasis between GNA13 and MYC downstream of ERα.\",\n      \"method\": \"GNA13 knockdown/overexpression, RNA-sequencing, MYC co-silencing (genetic epistasis), orthotopic xenograft model, soft-agar colony formation assay, Western blotting\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (GNA13 KD + MYC co-KD rescue) and in vivo xenograft, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38965558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A gain-of-function R200K missense mutation in GNA13 hyperactivates the RHOA/ROCK signaling pathway, increasing actin polymerization and myosin light chain phosphorylation, promoting melanocyte rounding and impairing cell migration/adhesion without affecting proliferation. R200K Gα13 also hyperactivates the YAP signaling pathway. The resulting defect in melanosome transfer to keratinocytes causes hypopigmentation.\",\n      \"method\": \"In-depth functional investigations in patient-derived cells, actin polymerization assay, myosin light chain phosphorylation Western blot, cell morphology and migration assay, YAP pathway analysis, comparison to wild-type GNA13\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in patient-derived cells with a defined GOF mutation; single study but multiple readouts\",\n      \"pmids\": [\"39966435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DHHC13 (zinc finger DHHC-type palmitoyltransferase 13) catalyzes S-palmitoylation of GNA13 at Cys14 and Cys18 residues in Sertoli cells, which is required for GNA13 plasma membrane localization and its selective enrichment in Sertoli cell-derived extracellular vesicles. Palmitoylated GNA13 delivered via EVs to spermatogonial stem cells suppresses autophagy through interaction with ARHGEF12, promoting RhoA activity; inhibition of GNA13 palmitoylation reduces ARHGEF12 interaction, diminishes RhoA activity, and elevates autophagy.\",\n      \"method\": \"Site-directed mutagenesis of palmitoylation sites (Cys14/Cys18), palmitoylation assay, subcellular fractionation, EV isolation, Co-immunoprecipitation (GNA13–ARHGEF12 interaction), RhoA activity assay, autophagy assay\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of palmitoylation sites, Co-IP for binding partner, and functional autophagy/RhoA readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40205436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GNA13 knockdown in lung squamous cell carcinoma cells reduces phosphorylation of PI3K and AKT, while GNA13 overexpression increases PI3K/AKT phosphorylation, placing GNA13 upstream of the PI3K/AKT pathway in regulating LUSC cell growth and migration.\",\n      \"method\": \"GNA13 siRNA knockdown and overexpression, Western blotting for p-PI3K and p-AKT, MTT assay, wound healing, Transwell invasion assay, in vivo LUSC mouse model\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily Western blotting without direct enzymatic or epistasis rescue validation\",\n      \"pmids\": [\"35413491\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GNA13 encodes Gα13, the α-subunit of a heterotrimeric G12/13 family G-protein that transduces GPCR signals primarily through RhoA activation (via ARHGEF12/LARG-type GEFs) and downstream ROCK/actin remodeling; its plasma membrane localization and stability require S-palmitoylation at Cys14/Cys18 (catalyzed by DHHC13), and it regulates diverse downstream pathways—including RhoA/ROCK, ERK, NF-κB, PI3K/AKT, Wnt/β-catenin, and YAP—in a context-dependent manner that can be either oncogenic (promoting invasion and EMT in epithelial cancers) or tumor-suppressive (in germinal center B-cell lymphomas and ER+ breast cancer), with its expression post-transcriptionally controlled by multiple miRNAs (miR-182, miR-200a/141, miR-31, miR-29c, miR-30d).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GNA13 encodes Gα13, the α-subunit of a G12/13-family heterotrimeric G-protein that transduces signals into RhoA activation and downstream actin remodeling, governing cell migration, invasion, and survival in a strongly context-dependent manner [#0, #4]. Its membrane targeting and stability depend on S-palmitoylation at Cys14/Cys18, catalyzed by DHHC13; this lipid modification is required both for Gα13 plasma-membrane localization and for engagement of the RhoGEF ARHGEF12 to drive RhoA activity, and loss of palmitoylation abolishes Gα13 function [#7, #12]. In epithelial cancers (prostate, colorectal, breast, lung), GNA13 acts as a pro-invasive/oncogenic mediator, promoting migration, EMT, and invasion through RhoA and additional effector arms including ERK/GSK3β/β-catenin, NF-κB/p65-driven chemokine induction, and PI3K/AKT signaling [#0, #1, #6, #13]. In sharp contrast, GNA13 is tumor-suppressive in germinal-center B cells, where inhibitory lymphoma-associated mutations and conditional knockout disrupt the Gα13/RhoA axis, derange GC architecture, impair apoptosis, increase somatic hypermutation, and cooperate with MYC to drive lymphomagenesis; this suppressor role requires palmitoylation-dependent negative regulation of BCL2 [#3, #4, #7]. A similar growth-restraining function operates in ER+ breast cancer, where GNA13 limits MYC expression downstream of ERα [#10]. Across these settings GNA13 expression is post-transcriptionally repressed by multiple miRNAs that directly target its 3'-UTR, including miR-182, miR-141/200a, miR-29c, and miR-31 [#0, #1, #2]. A gain-of-function R200K missense mutation in GNA13 hyperactivates RHOA/ROCK and YAP signaling, increasing actin polymerization and myosin light-chain phosphorylation; the resulting defect in melanosome transfer from melanocytes to keratinocytes causes a hypopigmentation disorder [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established GNA13 as a required transducer of RhoA activation driving cancer cell invasion, and identified miRNA-mediated 3'-UTR repression as a control point over this activity.\",\n      \"evidence\": \"siRNA knockdown, Rho activity and invasion assays, and 3'-UTR luciferase reporters with miR-182 and miR-141/200a in prostate cancer cells\",\n      \"pmids\": [\"23329838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GEF and GPCR receptor identity upstream of GNA13 not defined here\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended GNA13 effector reach beyond RhoA by placing it upstream of the ERK/GSK3β/β-catenin axis controlling EMT, under repression by miR-29c.\",\n      \"evidence\": \"miRNA target validation, pathway analysis, and in vitro/in vivo metastasis assays in colorectal cancer cells\",\n      \"pmids\": [\"25193986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from GNA13 to ERK not mechanistically resolved\", \"Pathway placement partly correlative\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed pro-invasive, oncogenic GNA13 function in breast epithelium via miR-31 control, while parallel lymphoma work revealed the opposite — that GNA13 mutations are loss-of-function and GNA13/RhoA is tumor-suppressive in B cells.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function with 3'-UTR reporters in breast cells; mutant characterization and wild-type re-expression with in vivo growth assays in B-cell lymphoma\",\n      \"pmids\": [\"25889182\", \"26616858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis for opposite directionality between epithelial and B cells unresolved\", \"In vitro vs in vivo discordance in lymphoma cells unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided genetic in vivo proof of GNA13 tumor suppression in germinal-center B cells and linked it to RhoA-dependent actin, migration, apoptosis, and somatic hypermutation control.\",\n      \"evidence\": \"AID-Cre conditional knockout mouse with RhoA, actin, caspase and SHM readouts and MYC genetic cooperation; plus RhoA/ROCK-dependent kallikrein suppression in breast cells\",\n      \"pmids\": [\"26989201\", \"27424208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream GPCR/GEF driving GC B-cell RhoA signaling not identified\", \"How attenuated RhoA increases SHM mechanistically unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified an NF-κB/p65 effector arm by which GNA13 induces chemokines to promote proliferation and angiogenesis in colorectal cancer.\",\n      \"evidence\": \"Gain/loss-of-function with NF-κB inhibitor epistasis and chemokine measurement in colorectal cancer cells\",\n      \"pmids\": [\"30267476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from GNA13 to NF-κB activation not defined\", \"Limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that palmitoylation is mechanistically required for GNA13 membrane localization, stability, and its tumor-suppressor function through BCL2 repression in lymphoma; separately placed GNA13 upstream of a PRKACA/RELA/MGMT axis in glioma.\",\n      \"evidence\": \"Palmitoylation-deficient mutants with fractionation and BCL2/cell-viability readouts in GCB-DLBCL; Western blot and bioinformatics for the glioma axis\",\n      \"pmids\": [\"33423045\", \"34786068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Palmitoyltransferase enzyme not yet identified at this stage\", \"Glioma PRKACA axis lacks direct rescue and is Low confidence\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed GNA13 upstream of PI3K/AKT signaling in lung squamous carcinoma growth and migration.\",\n      \"evidence\": \"siRNA knockdown and overexpression with p-PI3K/p-AKT Western blots and in vivo LUSC model\",\n      \"pmids\": [\"35413491\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No enzymatic or epistasis rescue validation\", \"Direct connection to PI3K/AKT undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a tumor-suppressive ERK/FOXO3 effector arm in glioblastoma in which GNA13 restrains ERK phosphorylation and metastasis.\",\n      \"evidence\": \"Gain/loss-of-function with U0126 ERK-inhibitor epistasis rescuing the GNA13-knockdown phenotype in glioblastoma cells\",\n      \"pmids\": [\"37392861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which GNA13 lowers ERK phosphorylation unresolved\", \"Reconciliation with pro-ERK roles in other cancers not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established GNA13 as a suppressor of ER+ breast cancer proliferation acting through an ERα-dependent restraint of MYC.\",\n      \"evidence\": \"Knockdown/overexpression with RNA-seq, MYC co-silencing genetic epistasis, and orthotopic xenograft\",\n      \"pmids\": [\"38965558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking GNA13 to ERα-dependent MYC control undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified DHHC13 as the palmitoyltransferase modifying GNA13 at Cys14/Cys18 and linked palmitoylation-dependent ARHGEF12 binding to RhoA-mediated autophagy suppression; and defined a disease-causing GOF R200K mutation that hyperactivates RHOA/ROCK and YAP to impair melanosome transfer and cause hypopigmentation.\",\n      \"evidence\": \"Cys14/Cys18 mutagenesis with Co-IP, RhoA and autophagy assays in Sertoli cell/EV system; patient-derived cell functional assays of actin, MLC phosphorylation and YAP for R200K\",\n      \"pmids\": [\"40205436\", \"39966435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of DHHC13 as the GNA13 palmitoyltransferase across other cell types untested\", \"Structural basis of R200K gain-of-function not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular determinant that switches GNA13/RhoA signaling between oncogenic (epithelial) and tumor-suppressive (B-cell, ER+ breast) outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism explains context-dependent directionality\", \"Upstream GPCRs and tissue-specific effector wiring not mapped\", \"Direct biochemical links to NF-κB, ERK, PI3K/AKT remain indirect\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ARHGEF12\",\n      \"ZDHHC13\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}