{"gene":"PARVA","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2015,"finding":"PARVA (α-parvin) forms a complex with SGK1 and ILK, and its overexpression enhances ILK phosphorylation, leading to downstream phosphorylation of Akt and inhibition of GSK3β; pharmacological inactivation of ILK reverses PARVA-induced cell invasion, placing PARVA upstream of ILK in a pro-invasive signaling axis.","method":"Co-immunoprecipitation to demonstrate PARVA-SGK1-ILK complex; expression microarray pathway analysis; loss-of-function (siRNA knockdown) and gain-of-function (overexpression) with invasion, colony formation, and tube formation assays; in vivo mouse tumor/metastasis models; ILK inhibitor rescue experiment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying complex, supported by loss- and gain-of-function with defined phenotypic readout and ILK inhibitor epistasis; single lab, multiple orthogonal methods","pmids":["25738875"],"is_preprint":false},{"year":2018,"finding":"The A-to-I edited form of miR-378a-3p preferentially binds the 3'-UTR of PARVA mRNA and inhibits PARVA expression, thereby suppressing melanoma metastasis in vivo; the unedited (wild-type) miR-378a-3p does not target PARVA, establishing PARVA as a functionally relevant downstream target of RNA-editing-dependent miRNA regulation.","method":"3'-UTR luciferase reporter assay demonstrating edited miR-378a-3p binding to PARVA 3'-UTR; PARVA expression analysis by qRT-PCR/Western blot in metastatic vs. non-metastatic melanoma cells; in vivo melanoma metastasis mouse model with edited vs. wild-type miR-378a-3p","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional 3'-UTR reporter assay plus in vivo metastasis model; single lab but multiple orthogonal methods confirming PARVA as direct target","pmids":["29386624"],"is_preprint":false}],"current_model":"PARVA (α-parvin) acts as a pro-invasive scaffold that forms a complex with ILK and SGK1 to enhance ILK phosphorylation and downstream Akt/GSK3β signaling, promoting tumor cell invasion and metastasis; its expression is post-transcriptionally suppressed by the A-to-I edited form of miR-378a-3p via direct 3'-UTR binding, linking RNA editing to PARVA-dependent melanoma progression."},"narrative":{"mechanistic_narrative":"PARVA (α-parvin) functions as a pro-invasive scaffold that drives tumor cell invasion and metastasis through an ILK-dependent signaling axis [PMID:25738875]. PARVA forms a complex with SGK1 and ILK, and its overexpression enhances ILK phosphorylation, leading to downstream Akt phosphorylation and inhibition of GSK3β; pharmacological inactivation of ILK reverses PARVA-induced invasion, placing PARVA upstream of ILK in this axis [PMID:25738875]. PARVA expression is post-transcriptionally restrained by the A-to-I edited form of miR-378a-3p, which preferentially binds the PARVA 3'-UTR—unlike the unedited miRNA—thereby suppressing melanoma metastasis and linking RNA editing to PARVA-dependent progression [PMID:29386624]. Beyond these two findings, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Established that PARVA acts upstream of ILK in a pro-invasive signaling cascade rather than merely correlating with invasion, defining a concrete molecular axis for its phenotypic effects.","evidence":"Reciprocal Co-IP demonstrating a PARVA-SGK1-ILK complex, combined with siRNA knockdown, overexpression, invasion/colony/tube-formation assays, in vivo metastasis models, and ILK inhibitor rescue","pmids":["25738875"],"confidence":"Medium","gaps":["Stoichiometry and direct binding interfaces of the PARVA-SGK1-ILK complex not resolved","Whether the effect generalizes beyond the cancer models tested is unaddressed","Mechanism by which PARVA enhances ILK phosphorylation (direct vs. scaffolding) not defined"]},{"year":2018,"claim":"Identified how PARVA expression is controlled, showing that A-to-I RNA editing redirects miR-378a-3p to target PARVA and thereby suppress metastasis, connecting an upstream regulatory layer to PARVA-driven progression.","evidence":"3'-UTR luciferase reporter assay with edited vs. wild-type miR-378a-3p, qRT-PCR/Western blot of PARVA in metastatic vs. non-metastatic melanoma cells, and an in vivo melanoma metastasis mouse model","pmids":["29386624"],"confidence":"Medium","gaps":["Editing enzyme responsible for generating the active miR-378a-3p not characterized in this entry","Whether PARVA is the sole functionally relevant target of the edited miRNA is not established","Quantitative contribution of PARVA repression to the overall metastatic phenotype unresolved"]},{"year":null,"claim":"The structural basis of PARVA's scaffolding within the ILK complex and the breadth of its functions outside the melanoma/invasion context remain unknown.","evidence":"No further discoveries in the provided timeline","pmids":[],"confidence":"Medium","gaps":["No structural model of the PARVA-SGK1-ILK complex","No subcellular localization data in the corpus","Functions of PARVA outside tumor invasion not examined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["ILK","SGK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NVD7","full_name":"Alpha-parvin","aliases":["Actopaxin","CH-ILKBP","Calponin-like integrin-linked kinase-binding protein","Matrix-remodeling-associated protein 2"],"length_aa":372,"mass_kda":42.2,"function":"Plays a role in sarcomere organization and in smooth muscle cell contraction. Required for normal development of the embryonic cardiovascular system, and for normal septation of the heart outflow tract. Plays a role in sprouting angiogenesis and is required for normal adhesion of vascular smooth muscle cells to endothelial cells during blood vessel development (By similarity). Plays a role in the reorganization of the actin cytoskeleton, formation of lamellipodia and ciliogenesis. Plays a role in the establishment of cell polarity, cell adhesion, cell spreading, and directed cell migration. Within the IPP (ILK-PINCH-PARVIN) complex, binds to F-actin, promoting F-actin bundling, a process required to generate force for actin cytoskeleton reorganization and subsequent dynamic cell adhesion events such as cell spreading and migration (PubMed:30367047)","subcellular_location":"Cell junction, focal adhesion; Cell membrane; Cytoplasm, cytoskeleton; Cytoplasm, myofibril, sarcomere, Z line","url":"https://www.uniprot.org/uniprotkb/Q9NVD7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PARVA","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":383,"dependency_fraction":0.044386422976501305},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ILK","stoichiometry":10.0},{"gene":"EMC8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PARVA","total_profiled":1310},"omim":[{"mim_id":"608122","title":"PARVIN, GAMMA; PARVG","url":"https://www.omim.org/entry/608122"},{"mim_id":"608121","title":"PARVIN, BETA; PARVB","url":"https://www.omim.org/entry/608121"},{"mim_id":"608120","title":"PARVIN, ALPHA; PARVA","url":"https://www.omim.org/entry/608120"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Actin filaments","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PARVA"},"hgnc":{"alias_symbol":["FLJ12254","FLJ10793"],"prev_symbol":["MXRA2"]},"alphafold":{"accession":"Q9NVD7","domains":[{"cath_id":"1.10.418.10","chopping":"85-239","consensus_level":"high","plddt":88.6372,"start":85,"end":239},{"cath_id":"1.10.418.10","chopping":"248-368","consensus_level":"high","plddt":92.7552,"start":248,"end":368}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVD7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVD7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVD7-F1-predicted_aligned_error_v6.png","plddt_mean":79.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PARVA","jax_strain_url":"https://www.jax.org/strain/search?query=PARVA"},"sequence":{"accession":"Q9NVD7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVD7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVD7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVD7"}},"corpus_meta":[{"pmid":"15994558","id":"PMC_15994558","title":"Genome 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/29705700","citation_count":20,"is_preprint":false},{"pmid":"25092591","id":"PMC_25092591","title":"Tick burden and prevalence of Theileria parva infection in Tarime zebu cattle in the lake zone of Tanzania.","date":"2014","source":"Tropical animal health and production","url":"https://pubmed.ncbi.nlm.nih.gov/25092591","citation_count":19,"is_preprint":false},{"pmid":"26432023","id":"PMC_26432023","title":"Isolation and characterization of a virus infecting the freshwater algae Chrysochromulina parva.","date":"2015","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/26432023","citation_count":19,"is_preprint":false},{"pmid":"9379055","id":"PMC_9379055","title":"Distinct CD4+ T cell helper requirements in Theileria parva-immune and -naive bovine CTL precursors.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9379055","citation_count":19,"is_preprint":false},{"pmid":"29258832","id":"PMC_29258832","title":"Characterization of the Theileria parva sporozoite proteome.","date":"2017","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/29258832","citation_count":18,"is_preprint":false},{"pmid":"34328094","id":"PMC_34328094","title":"Chemical compositions and experimental and computational modeling activity of sea cucumber Holothuria parva ethanolic extract against herpes simplex virus type 1.","date":"2021","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/34328094","citation_count":18,"is_preprint":false},{"pmid":"32245418","id":"PMC_32245418","title":"Re-annotation of the Theileria parva genome refines 53% of the proteome and uncovers essential components of N-glycosylation, a conserved pathway in many organisms.","date":"2020","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32245418","citation_count":18,"is_preprint":false},{"pmid":"22981919","id":"PMC_22981919","title":"MDM2 regulates a novel form of incomplete neoplastic transformation of Theileria parva infected lymphocytes.","date":"2012","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22981919","citation_count":18,"is_preprint":false},{"pmid":"7739669","id":"PMC_7739669","title":"Sequence and expression of a 90-kilodalton heat-shock protein family member of Theileria parva.","date":"1994","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/7739669","citation_count":18,"is_preprint":false},{"pmid":"9006954","id":"PMC_9006954","title":"Characterization of a secretory type Theileria parva glutaredoxin homologue identified by novel screening procedure.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9006954","citation_count":18,"is_preprint":false},{"pmid":"10731569","id":"PMC_10731569","title":"Theileria parva genomics reveals an atypical apicomplexan genome.","date":"2000","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/10731569","citation_count":17,"is_preprint":false},{"pmid":"11018447","id":"PMC_11018447","title":"Characterisation of NF-kappa B complexes in Theileria parva-transformedT cells.","date":"2000","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/11018447","citation_count":17,"is_preprint":false},{"pmid":"8948324","id":"PMC_8948324","title":"Theileria parva sporozoite entry into bovine lymphocytes involves both parasite and host cell signal transduction processes.","date":"1996","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/8948324","citation_count":17,"is_preprint":false},{"pmid":"2410290","id":"PMC_2410290","title":"Theileria parva: expression of a sporozoite surface coat antigen.","date":"1985","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/2410290","citation_count":17,"is_preprint":false},{"pmid":"6789420","id":"PMC_6789420","title":"Evaluation of an enzyme immunoassay for serodiagnosis of infections with Theileria parva and T annulata.","date":"1980","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/6789420","citation_count":16,"is_preprint":false},{"pmid":"25660425","id":"PMC_25660425","title":"Transfection of live, tick derived sporozoites of the protozoan Apicomplexan parasite Theileria parva.","date":"2015","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/25660425","citation_count":16,"is_preprint":false},{"pmid":"26930209","id":"PMC_26930209","title":"Absolute Quantification of the Host-To-Parasite DNA Ratio in Theileria parva-Infected Lymphocyte Cell Lines.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26930209","citation_count":15,"is_preprint":false},{"pmid":"2469012","id":"PMC_2469012","title":"Isolation and characterization of RNA from the intracellular parasite Theileria parva.","date":"1989","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/2469012","citation_count":15,"is_preprint":false},{"pmid":"25748600","id":"PMC_25748600","title":"L-type calcium channels contribute to 5-HT3-receptor-evoked CaMKIIα and ERK activation and induction of emesis in the least shrew (Cryptotis parva).","date":"2015","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25748600","citation_count":15,"is_preprint":false},{"pmid":"25673078","id":"PMC_25673078","title":"Molecular evolution of a central region containing B cell epitopes in the gene encoding the p67 sporozoite antigen within a field population of Theileria parva.","date":"2015","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/25673078","citation_count":15,"is_preprint":false},{"pmid":"34305904","id":"PMC_34305904","title":"Development of a Potential Yeast-Based Vaccine Platform for Theileria parva Infection in Cattle.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34305904","citation_count":15,"is_preprint":false},{"pmid":"9668454","id":"PMC_9668454","title":"Detection and differentiation of Theileria annulata and Theileria parva using macroschizont-derived DNA probes.","date":"1998","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/9668454","citation_count":14,"is_preprint":false},{"pmid":"19194076","id":"PMC_19194076","title":"Quantitative analysis of cytokine mRNA expression and protozoan DNA load in Theileria parva-infected cattle.","date":"2009","source":"The Journal of veterinary medical science","url":"https://pubmed.ncbi.nlm.nih.gov/19194076","citation_count":14,"is_preprint":false},{"pmid":"31842995","id":"PMC_31842995","title":"Genetic and antigenic variation of the bovine tick-borne pathogen Theileria parva in the Great Lakes region of Central Africa.","date":"2019","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/31842995","citation_count":14,"is_preprint":false},{"pmid":"6412424","id":"PMC_6412424","title":"Ultrastructural characteristics of in vitro parasite-lymphocyte behaviour in invasions with Theileria annulata and Theileria parva.","date":"1983","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/6412424","citation_count":14,"is_preprint":false},{"pmid":"2574438","id":"PMC_2574438","title":"Infection of bovine T cell clones with genotypically distinct Theileria parva parasites and analysis of their cell surface phenotype.","date":"1989","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/2574438","citation_count":14,"is_preprint":false},{"pmid":"24513510","id":"PMC_24513510","title":"Cyclophosphamide causes activation of protein kinase A (PKA) in the brainstem of vomiting least shrews (Cryptotis parva).","date":"2014","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24513510","citation_count":13,"is_preprint":false},{"pmid":"19055776","id":"PMC_19055776","title":"Properties of non-coding DNA and identification of putative cis-regulatory elements in Theileria parva.","date":"2008","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19055776","citation_count":13,"is_preprint":false},{"pmid":"20381541","id":"PMC_20381541","title":"Characterisation of gp34, a GPI-anchored protein expressed by schizonts of Theileria parva and T. annulata.","date":"2010","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/20381541","citation_count":13,"is_preprint":false},{"pmid":"21288576","id":"PMC_21288576","title":"Treatment of cattle with DNA-encoded Flt3L and GM-CSF prior to immunization with Theileria parva candidate vaccine antigens induces CD4 and CD8 T cell IFN-γ responses but not CTL responses.","date":"2011","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/21288576","citation_count":13,"is_preprint":false},{"pmid":"28969779","id":"PMC_28969779","title":"Seasonal occurrence of Theileria parva infection and management practices amongst Maasai pastoralist communities in Monduli District, Northern Tanzania.","date":"2017","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/28969779","citation_count":13,"is_preprint":false},{"pmid":"7597783","id":"PMC_7597783","title":"Identification of candidate vaccine antigens of bovine hemoparasites Theileria parva and Babesia bovis by use of helper T cell clones.","date":"1995","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/7597783","citation_count":12,"is_preprint":false},{"pmid":"30782490","id":"PMC_30782490","title":"Gene gun DNA immunization of cattle induces humoral and CD4 T-cell-mediated immune responses against the Theileria parva polymorphic immunodominant molecule.","date":"2019","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/30782490","citation_count":12,"is_preprint":false},{"pmid":"34516364","id":"PMC_34516364","title":"Muricauda onchidii sp. nov., isolated from a marine invertebrate from South China Sea, and transfers of Flagellimonas algicola, Flagellimonas pacifica and Flagellimonas maritima to Muricauda algicola comb. nov., Muricauda parva nom. nov. and Muricauda aurantiaca nom. nov., respectively, and emended description of the genus Muricauda.","date":"2021","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34516364","citation_count":12,"is_preprint":false},{"pmid":"32174041","id":"PMC_32174041","title":"Serum-free in vitro cultivation of Theileria annulata and Theileria parva schizont-infected lymphocytes.","date":"2020","source":"Transboundary and emerging diseases","url":"https://pubmed.ncbi.nlm.nih.gov/32174041","citation_count":12,"is_preprint":false},{"pmid":"29534988","id":"PMC_29534988","title":"Genetic diversity and population structure of Theileria parva in South Sudan.","date":"2018","source":"Ticks and tick-borne diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29534988","citation_count":12,"is_preprint":false},{"pmid":"25417727","id":"PMC_25417727","title":"Genetic and antigenic diversity of Theileria parva in cattle in Eastern and Southern zones of Tanzania. A study to support control of East Coast fever.","date":"2014","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/25417727","citation_count":12,"is_preprint":false},{"pmid":"30323022","id":"PMC_30323022","title":"Granzyme B Is an Essential Mediator in CD8+ T Cell Killing of Theileria parva-Infected Cells.","date":"2018","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/30323022","citation_count":12,"is_preprint":false},{"pmid":"27270385","id":"PMC_27270385","title":"Population genetic analysis of Theileria parva isolated in cattle and buffaloes in Tanzania using minisatellite and microsatellite markers.","date":"2016","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/27270385","citation_count":12,"is_preprint":false},{"pmid":"21621920","id":"PMC_21621920","title":"Analyses of genes encoding Theileria parva p104 and polymorphic immunodominant molecule (PIM) reveal evidence of the presence of cattle-type alleles in the South African T. parva population.","date":"2011","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/21621920","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50863,"output_tokens":1013,"usd":0.083892,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7168,"output_tokens":1374,"usd":0.035095,"stage2_stop_reason":"end_turn"},"total_usd":0.118987,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the 100 papers, I need to identify which ones are about the human/mammalian gene PARVA (alpha-parvin, also known as MXRA2/FLJ12254/FLJ10793) versus other organisms sharing the name \"parva\" (Theileria parva, Cryptotis parva, Emmonsia parva, etc.).\n\nAfter careful review:\n- Papers [1]-[100] are overwhelmingly about *Theileria parva* (a bovine parasite), *Cryptotis parva* (least shrew), *Emmonsia parva* (fungus), or other organisms. These are symbol/name collisions, not the mammalian PARVA gene.\n- Paper [10] (PMID:29386624) is about PARVA oncogene in melanoma — this is about the human PARVA gene.\n- Paper [42] (PMID:25738875) is about PARVA (α-parvin) in lung adenocarcinoma — this is about the human PARVA gene.\n\nThese are the only two papers about the canonical human PARVA protein.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"PARVA (α-parvin) forms a complex with SGK1 and ILK, and its overexpression enhances ILK phosphorylation, leading to downstream phosphorylation of Akt and inhibition of GSK3β; pharmacological inactivation of ILK reverses PARVA-induced cell invasion, placing PARVA upstream of ILK in a pro-invasive signaling axis.\",\n      \"method\": \"Co-immunoprecipitation to demonstrate PARVA-SGK1-ILK complex; expression microarray pathway analysis; loss-of-function (siRNA knockdown) and gain-of-function (overexpression) with invasion, colony formation, and tube formation assays; in vivo mouse tumor/metastasis models; ILK inhibitor rescue experiment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying complex, supported by loss- and gain-of-function with defined phenotypic readout and ILK inhibitor epistasis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25738875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The A-to-I edited form of miR-378a-3p preferentially binds the 3'-UTR of PARVA mRNA and inhibits PARVA expression, thereby suppressing melanoma metastasis in vivo; the unedited (wild-type) miR-378a-3p does not target PARVA, establishing PARVA as a functionally relevant downstream target of RNA-editing-dependent miRNA regulation.\",\n      \"method\": \"3'-UTR luciferase reporter assay demonstrating edited miR-378a-3p binding to PARVA 3'-UTR; PARVA expression analysis by qRT-PCR/Western blot in metastatic vs. non-metastatic melanoma cells; in vivo melanoma metastasis mouse model with edited vs. wild-type miR-378a-3p\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional 3'-UTR reporter assay plus in vivo metastasis model; single lab but multiple orthogonal methods confirming PARVA as direct target\",\n      \"pmids\": [\"29386624\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PARVA (α-parvin) acts as a pro-invasive scaffold that forms a complex with ILK and SGK1 to enhance ILK phosphorylation and downstream Akt/GSK3β signaling, promoting tumor cell invasion and metastasis; its expression is post-transcriptionally suppressed by the A-to-I edited form of miR-378a-3p via direct 3'-UTR binding, linking RNA editing to PARVA-dependent melanoma progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PARVA (α-parvin) functions as a pro-invasive scaffold that drives tumor cell invasion and metastasis through an ILK-dependent signaling axis [#0]. PARVA forms a complex with SGK1 and ILK, and its overexpression enhances ILK phosphorylation, leading to downstream Akt phosphorylation and inhibition of GSK3β; pharmacological inactivation of ILK reverses PARVA-induced invasion, placing PARVA upstream of ILK in this axis [#0]. PARVA expression is post-transcriptionally restrained by the A-to-I edited form of miR-378a-3p, which preferentially binds the PARVA 3'-UTR—unlike the unedited miRNA—thereby suppressing melanoma metastasis and linking RNA editing to PARVA-dependent progression [#1]. Beyond these two findings, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that PARVA acts upstream of ILK in a pro-invasive signaling cascade rather than merely correlating with invasion, defining a concrete molecular axis for its phenotypic effects.\",\n      \"evidence\": \"Reciprocal Co-IP demonstrating a PARVA-SGK1-ILK complex, combined with siRNA knockdown, overexpression, invasion/colony/tube-formation assays, in vivo metastasis models, and ILK inhibitor rescue\",\n      \"pmids\": [\"25738875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Stoichiometry and direct binding interfaces of the PARVA-SGK1-ILK complex not resolved\",\n        \"Whether the effect generalizes beyond the cancer models tested is unaddressed\",\n        \"Mechanism by which PARVA enhances ILK phosphorylation (direct vs. scaffolding) not defined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified how PARVA expression is controlled, showing that A-to-I RNA editing redirects miR-378a-3p to target PARVA and thereby suppress metastasis, connecting an upstream regulatory layer to PARVA-driven progression.\",\n      \"evidence\": \"3'-UTR luciferase reporter assay with edited vs. wild-type miR-378a-3p, qRT-PCR/Western blot of PARVA in metastatic vs. non-metastatic melanoma cells, and an in vivo melanoma metastasis mouse model\",\n      \"pmids\": [\"29386624\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Editing enzyme responsible for generating the active miR-378a-3p not characterized in this entry\",\n        \"Whether PARVA is the sole functionally relevant target of the edited miRNA is not established\",\n        \"Quantitative contribution of PARVA repression to the overall metastatic phenotype unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of PARVA's scaffolding within the ILK complex and the breadth of its functions outside the melanoma/invasion context remain unknown.\",\n      \"evidence\": \"No further discoveries in the provided timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of the PARVA-SGK1-ILK complex\",\n        \"No subcellular localization data in the corpus\",\n        \"Functions of PARVA outside tumor invasion not examined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ILK\", \"SGK1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}