{"gene":"LRATD1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2006,"finding":"FAM84A (LRATD1) protein localizes to the subcellular membrane region, specifically in areas lacking attachment with neighboring cells, and exogenous FAM84A expression increases cell motility in NIH3T3 cells. Phosphorylation of serine 38 of FAM84A was found to be associated with cell morphology changes.","method":"Immunocytochemical staining for localization; exogenous overexpression in NIH3T3 cells with motility assay; site-specific phosphorylation analysis","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization by ICC and functional overexpression assay in two independent contexts (NIH3T3 motility, serine-38 phosphorylation-morphology link), single lab","pmids":["16820875"],"is_preprint":false},{"year":2011,"finding":"FAM84A expression is regulated by the nuclear xenobiotic receptor CAR (constitutive androstane receptor): CAR activates the FAM84A promoter (reporter assay), PB treatment induces FAM84A protein in mouse liver, and FAM84A protein in liver/liver tumors is NOT phosphorylated at serine 38. Immunohistochemistry showed cytoplasmic localization of FAM84A protein in hepatocytes. Exogenous overexpression of FAM84A in HepG2 cells resulted in increased cell migration.","method":"HepG2 cell-based reporter assay for CAR-driven promoter activation; Western blotting for protein expression and serine-38 phosphorylation status; immunohistochemistry for subcellular localization; overexpression migration assay in HepG2 cells","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal methods (reporter assay, Western blot, IHC, migration assay) in single lab establishing CAR as transcriptional regulator and cytoplasmic localization with functional consequence","pmids":["21424122"],"is_preprint":false},{"year":2021,"finding":"LRATD1 is a substrate of human N-myristoyltransferases NMT1 and NMT2, identified by mining available interactome data (protein–protein interaction with NMT1/2 as proxy for substrate relationship), consistent with the principle that binding affinity to the enzyme predicts substrate specificity.","method":"Interactome data mining to identify NMT1/2-interacting proteins as substrates; in vitro NMT enzymatic assays establishing binding-affinity-based substrate identification framework","journal":"ACS catalysis","confidence":"Low","confidence_rationale":"Tier 4 / Weak — substrate identification was by interactome data mining, not direct in vitro myristoylation assay performed on LRATD1 itself; single study, no direct biochemical confirmation of LRATD1 myristoylation reported in abstract","pmids":["34956690"],"is_preprint":false},{"year":2021,"finding":"FAM84A expression is negatively regulated by miR-874-3p (direct target validated), and FAM84A promotes epithelial-mesenchymal transition (EMT) and activates the Wnt/β-catenin signaling pathway in papillary thyroid carcinoma cells; knockdown of FAM84A inhibited tumor development in vitro and in vivo.","method":"miR-874-3p target validation (implied luciferase/functional assay); FAM84A knockdown with EMT marker analysis and Wnt/β-catenin pathway readouts in vitro and in vivo xenograft","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with defined pathway readouts (EMT, Wnt/β-catenin) in vitro and in vivo, miRNA-target relationship established, single lab","pmids":["33751775"],"is_preprint":false},{"year":2025,"finding":"FAM84A represses colorectal cancer stem cells (CSCs) by physically interacting with β-catenin and promoting β-catenin ubiquitination and degradation. ALKBH5 (m6A eraser) demethylates m6A-modified FAM84A mRNA, causing FAM84A mRNA decay and reduced FAM84A protein expression, thereby relieving FAM84A-mediated suppression of CSC self-renewal.","method":"Integrated RNA-seq, MeRIP-seq, and Ribo-seq to identify FAM84A as ALKBH5 target; co-immunoprecipitation/interaction assay for FAM84A–β-catenin binding; ubiquitination assay for β-catenin degradation; ALKBH5 knockin/knockout mouse models with FAM84A pathway validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (MeRIP-seq, Ribo-seq, Co-IP, ubiquitination assay, genetic mouse models) in a single rigorous study establishing FAM84A–β-catenin interaction and functional consequence on CSC stemness","pmids":["41390849"],"is_preprint":false},{"year":2020,"finding":"miR-215 directly negatively regulates FAM84A expression, validated by dual-luciferase reporter system in rooster testis cells.","method":"Dual-luciferase reporter assay with miR-215 and FAM84A 3'UTR","journal":"Reproductive biology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single method (luciferase reporter), single lab, but direct experimental validation of miRNA–target relationship","pmids":["32561231"],"is_preprint":false}],"current_model":"LRATD1 (FAM84A) is a cytoplasmic/membrane-proximal protein whose expression is transcriptionally driven by the nuclear receptor CAR and post-transcriptionally suppressed via m6A demethylation by ALKBH5 (leading to mRNA decay) and by direct miRNA targeting (miR-874-3p, miR-215); at the protein level, serine-38 phosphorylation modulates cell morphology, and FAM84A promotes cell migration/motility while also acting as a tumor suppressor in colorectal cancer stem cells by binding β-catenin and promoting its ubiquitination and degradation, thereby restraining Wnt/β-catenin signaling and EMT."},"narrative":{"mechanistic_narrative":"LRATD1 (FAM84A) is a cytoplasmic, membrane-proximal protein that influences cell motility and Wnt/β-catenin-dependent tumor cell behavior [PMID:16820875, PMID:41390849]. It localizes to subcellular membrane regions lacking cell–cell attachment and to the cytoplasm of hepatocytes, and its overexpression increases cell migration in fibroblast and hepatocyte models; phosphorylation of serine 38 is associated with cell morphology changes [PMID:16820875, PMID:21424122]. In colorectal cancer stem cells, FAM84A physically binds β-catenin and promotes its ubiquitination and degradation, restraining β-catenin-driven self-renewal [PMID:41390849], whereas in papillary thyroid carcinoma FAM84A promotes epithelial–mesenchymal transition and activates Wnt/β-catenin signaling [PMID:33751775], indicating context-dependent effects on this pathway. FAM84A expression is controlled at multiple levels: transcriptionally by the nuclear receptor CAR [PMID:21424122], post-transcriptionally through ALKBH5-mediated m6A demethylation that triggers mRNA decay [PMID:41390849], and through direct targeting by miR-874-3p and miR-215 [PMID:33751775, PMID:32561231]. Beyond these findings, the precise biochemical activity of the LRATD1 protein has not been characterized in the available corpus.","teleology":[{"year":2006,"claim":"Established the first functional readout for FAM84A by linking its membrane-proximal localization and serine-38 phosphorylation to cell motility and morphology, framing it as a regulator of cell migration.","evidence":"Immunocytochemical localization and exogenous overexpression motility assay in NIH3T3 cells, with site-specific phosphorylation analysis","pmids":["16820875"],"confidence":"Medium","gaps":["Molecular mechanism by which FAM84A increases motility not defined","Kinase responsible for serine-38 phosphorylation unknown","No direct binding partners identified"]},{"year":2011,"claim":"Identified an upstream transcriptional driver of FAM84A by showing the nuclear xenobiotic receptor CAR activates its promoter, placing FAM84A downstream of CAR signaling in liver.","evidence":"CAR-driven promoter reporter assay, Western blot, IHC, and overexpression migration assay in HepG2 cells and mouse liver","pmids":["21424122"],"confidence":"Medium","gaps":["Functional consequence of CAR-induced FAM84A in liver tumorigenesis not resolved","Reason serine-38 is unphosphorylated in liver versus other contexts unexplained"]},{"year":2020,"claim":"Extended post-transcriptional control of FAM84A by validating miR-215 as a direct repressor, indicating miRNA regulation of FAM84A across tissues.","evidence":"Dual-luciferase reporter assay with miR-215 and FAM84A 3'UTR in rooster testis cells","pmids":["32561231"],"confidence":"Medium","gaps":["Single reporter method without downstream functional consequence","Physiological context of miR-215–FAM84A axis in mammals not established"]},{"year":2021,"claim":"Connected FAM84A to Wnt/β-catenin signaling and EMT in cancer and added miR-874-3p as a direct upstream repressor, defining a tumor-promoting role in thyroid carcinoma.","evidence":"miR-874-3p target validation plus FAM84A knockdown with EMT and Wnt/β-catenin readouts in vitro and in xenografts","pmids":["33751775"],"confidence":"Medium","gaps":["Mechanism by which FAM84A activates Wnt/β-catenin here not biochemically defined","Apparent opposite effect on β-catenin versus colorectal CSC context unreconciled"]},{"year":2021,"claim":"Nominated LRATD1 as an N-myristoylation substrate of NMT1/NMT2, hinting at a lipid-modification mechanism for its membrane association.","evidence":"Interactome data mining using NMT1/2 binding as a substrate proxy, framed by in vitro NMT assays","pmids":["34956690"],"confidence":"Low","gaps":["No direct in vitro myristoylation assay performed on LRATD1 itself","Functional impact of myristoylation on LRATD1 localization or activity untested"]},{"year":2025,"claim":"Defined a direct molecular mechanism: FAM84A binds β-catenin and drives its ubiquitination and degradation, with ALKBH5-mediated m6A demethylation controlling FAM84A abundance, establishing FAM84A as a tumor suppressor in colorectal cancer stem cells.","evidence":"Integrated RNA-seq/MeRIP-seq/Ribo-seq, Co-IP, β-catenin ubiquitination assay, and ALKBH5 knockin/knockout mouse models","pmids":["41390849"],"confidence":"High","gaps":["Whether FAM84A acts as or recruits an E3 ligase for β-catenin not resolved","Structural basis of the FAM84A–β-catenin interaction unknown","Reconciliation with FAM84A activating Wnt/β-catenin in other tumors unaddressed"]},{"year":null,"claim":"The intrinsic biochemical activity of the LRATD1 protein and how it switches between suppressing and activating Wnt/β-catenin signaling in different cancers remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined catalytic or molecular function for the LRATD1 protein","Determinants of context-dependent β-catenin regulation unknown","Direct test of NMT-mediated myristoylation and its consequences lacking"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96KN4","full_name":"Protein LRATD1","aliases":["LRAT domain-containing 1","Neurologic sensory protein 1","NSE1","Protein FAM84A"],"length_aa":292,"mass_kda":32.5,"function":"May play a role in cell morphology and motility","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96KN4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRATD1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRATD1","total_profiled":1310},"omim":[{"mim_id":"611234","title":"LRAT DOMAIN-CONTAINING PROTEIN 1; LRATD1","url":"https://www.omim.org/entry/611234"},{"mim_id":"160993","title":"N-MYRISTOYLTRANSFERASE 1; NMT1","url":"https://www.omim.org/entry/160993"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"epididymis","ntpm":30.4},{"tissue":"intestine","ntpm":38.4}],"url":"https://www.proteinatlas.org/search/LRATD1"},"hgnc":{"alias_symbol":["NSE1","FLJ35392"],"prev_symbol":["FAM84A"]},"alphafold":{"accession":"Q96KN4","domains":[{"cath_id":"3.90.1720.10","chopping":"83-228_241-289","consensus_level":"medium","plddt":88.6813,"start":83,"end":289}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96KN4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96KN4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96KN4-F1-predicted_aligned_error_v6.png","plddt_mean":76.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRATD1","jax_strain_url":"https://www.jax.org/strain/search?query=LRATD1"},"sequence":{"accession":"Q96KN4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96KN4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96KN4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96KN4"}},"corpus_meta":[{"pmid":"34937578","id":"PMC_34937578","title":"DNA methylation mediates the association between breastfeeding and early-life growth trajectories.","date":"2021","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/34937578","citation_count":37,"is_preprint":false},{"pmid":"21560193","id":"PMC_21560193","title":"Identification of a novel autoantigen in inflammatory bowel disease by protein microarray.","date":"2010","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21560193","citation_count":34,"is_preprint":false},{"pmid":"34956690","id":"PMC_34956690","title":"Binding Affinity Determines Substrate Specificity and Enables Discovery of Substrates for N-Myristoyltransferases.","date":"2021","source":"ACS catalysis","url":"https://pubmed.ncbi.nlm.nih.gov/34956690","citation_count":28,"is_preprint":false},{"pmid":"32881863","id":"PMC_32881863","title":"Detection of latent forms of Mycobacterium avium subsp. paratuberculosis infection using host biomarker-based ELISAs greatly improves paratuberculosis diagnostic sensitivity.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32881863","citation_count":28,"is_preprint":false},{"pmid":"16820875","id":"PMC_16820875","title":"A gene encoding a family with sequence similarity 84, member A (FAM84A) enhanced migration of human colon cancer cells.","date":"2006","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16820875","citation_count":24,"is_preprint":false},{"pmid":"28116168","id":"PMC_28116168","title":"Early Transcriptional Changes Induced by Wnt/β-Catenin Signaling in Hippocampal Neurons.","date":"2016","source":"Neural plasticity","url":"https://pubmed.ncbi.nlm.nih.gov/28116168","citation_count":21,"is_preprint":false},{"pmid":"22842076","id":"PMC_22842076","title":"A de novo 4.4-Mb microdeletion in 2p24.3 → p24.2 in a girl with bilateral hearing impairment, microcephaly, digit abnormalities and Feingold syndrome.","date":"2012","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22842076","citation_count":16,"is_preprint":false},{"pmid":"21424122","id":"PMC_21424122","title":"Nuclear receptor CAR-regulated expression of the FAM84A gene during the development of mouse liver tumors.","date":"2011","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/21424122","citation_count":15,"is_preprint":false},{"pmid":"33751775","id":"PMC_33751775","title":"The direct miR-874-3p-target FAM84A promotes tumor development in papillary thyroid cancer.","date":"2021","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33751775","citation_count":13,"is_preprint":false},{"pmid":"37370144","id":"PMC_37370144","title":"Epigenome-wide association study identifies novel genes associated with ischemic stroke.","date":"2023","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/37370144","citation_count":12,"is_preprint":false},{"pmid":"32561231","id":"PMC_32561231","title":"An integrated analysis of testis miRNA and mRNA transcriptome reveals important functional miRNA-targets in reproduction traits of roosters.","date":"2020","source":"Reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/32561231","citation_count":9,"is_preprint":false},{"pmid":"22865701","id":"PMC_22865701","title":"Genome-wide linkage and positional association study of blood pressure response to dietary sodium intervention: the GenSalt Study.","date":"2012","source":"American journal of epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/22865701","citation_count":9,"is_preprint":false},{"pmid":"36685960","id":"PMC_36685960","title":"Genetic parameters estimation and genome molecular marker identification for gestation length in pigs.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36685960","citation_count":8,"is_preprint":false},{"pmid":"35771046","id":"PMC_35771046","title":"Genome-wide Scan of Dental Fear and Anxiety Nominates Novel Genes.","date":"2022","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/35771046","citation_count":5,"is_preprint":false},{"pmid":"41390849","id":"PMC_41390849","title":"Targeting of the m6A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41390849","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9929,"output_tokens":1807,"usd":0.028446,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8654,"output_tokens":2422,"usd":0.05191,"stage2_stop_reason":"end_turn"},"total_usd":0.080356,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"FAM84A (LRATD1) protein localizes to the subcellular membrane region, specifically in areas lacking attachment with neighboring cells, and exogenous FAM84A expression increases cell motility in NIH3T3 cells. Phosphorylation of serine 38 of FAM84A was found to be associated with cell morphology changes.\",\n      \"method\": \"Immunocytochemical staining for localization; exogenous overexpression in NIH3T3 cells with motility assay; site-specific phosphorylation analysis\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization by ICC and functional overexpression assay in two independent contexts (NIH3T3 motility, serine-38 phosphorylation-morphology link), single lab\",\n      \"pmids\": [\"16820875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FAM84A expression is regulated by the nuclear xenobiotic receptor CAR (constitutive androstane receptor): CAR activates the FAM84A promoter (reporter assay), PB treatment induces FAM84A protein in mouse liver, and FAM84A protein in liver/liver tumors is NOT phosphorylated at serine 38. Immunohistochemistry showed cytoplasmic localization of FAM84A protein in hepatocytes. Exogenous overexpression of FAM84A in HepG2 cells resulted in increased cell migration.\",\n      \"method\": \"HepG2 cell-based reporter assay for CAR-driven promoter activation; Western blotting for protein expression and serine-38 phosphorylation status; immunohistochemistry for subcellular localization; overexpression migration assay in HepG2 cells\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal methods (reporter assay, Western blot, IHC, migration assay) in single lab establishing CAR as transcriptional regulator and cytoplasmic localization with functional consequence\",\n      \"pmids\": [\"21424122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRATD1 is a substrate of human N-myristoyltransferases NMT1 and NMT2, identified by mining available interactome data (protein–protein interaction with NMT1/2 as proxy for substrate relationship), consistent with the principle that binding affinity to the enzyme predicts substrate specificity.\",\n      \"method\": \"Interactome data mining to identify NMT1/2-interacting proteins as substrates; in vitro NMT enzymatic assays establishing binding-affinity-based substrate identification framework\",\n      \"journal\": \"ACS catalysis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — substrate identification was by interactome data mining, not direct in vitro myristoylation assay performed on LRATD1 itself; single study, no direct biochemical confirmation of LRATD1 myristoylation reported in abstract\",\n      \"pmids\": [\"34956690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM84A expression is negatively regulated by miR-874-3p (direct target validated), and FAM84A promotes epithelial-mesenchymal transition (EMT) and activates the Wnt/β-catenin signaling pathway in papillary thyroid carcinoma cells; knockdown of FAM84A inhibited tumor development in vitro and in vivo.\",\n      \"method\": \"miR-874-3p target validation (implied luciferase/functional assay); FAM84A knockdown with EMT marker analysis and Wnt/β-catenin pathway readouts in vitro and in vivo xenograft\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with defined pathway readouts (EMT, Wnt/β-catenin) in vitro and in vivo, miRNA-target relationship established, single lab\",\n      \"pmids\": [\"33751775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM84A represses colorectal cancer stem cells (CSCs) by physically interacting with β-catenin and promoting β-catenin ubiquitination and degradation. ALKBH5 (m6A eraser) demethylates m6A-modified FAM84A mRNA, causing FAM84A mRNA decay and reduced FAM84A protein expression, thereby relieving FAM84A-mediated suppression of CSC self-renewal.\",\n      \"method\": \"Integrated RNA-seq, MeRIP-seq, and Ribo-seq to identify FAM84A as ALKBH5 target; co-immunoprecipitation/interaction assay for FAM84A–β-catenin binding; ubiquitination assay for β-catenin degradation; ALKBH5 knockin/knockout mouse models with FAM84A pathway validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (MeRIP-seq, Ribo-seq, Co-IP, ubiquitination assay, genetic mouse models) in a single rigorous study establishing FAM84A–β-catenin interaction and functional consequence on CSC stemness\",\n      \"pmids\": [\"41390849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-215 directly negatively regulates FAM84A expression, validated by dual-luciferase reporter system in rooster testis cells.\",\n      \"method\": \"Dual-luciferase reporter assay with miR-215 and FAM84A 3'UTR\",\n      \"journal\": \"Reproductive biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (luciferase reporter), single lab, but direct experimental validation of miRNA–target relationship\",\n      \"pmids\": [\"32561231\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRATD1 (FAM84A) is a cytoplasmic/membrane-proximal protein whose expression is transcriptionally driven by the nuclear receptor CAR and post-transcriptionally suppressed via m6A demethylation by ALKBH5 (leading to mRNA decay) and by direct miRNA targeting (miR-874-3p, miR-215); at the protein level, serine-38 phosphorylation modulates cell morphology, and FAM84A promotes cell migration/motility while also acting as a tumor suppressor in colorectal cancer stem cells by binding β-catenin and promoting its ubiquitination and degradation, thereby restraining Wnt/β-catenin signaling and EMT.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRATD1 (FAM84A) is a cytoplasmic, membrane-proximal protein that influences cell motility and Wnt/\\u03b2-catenin-dependent tumor cell behavior [#0, #4]. It localizes to subcellular membrane regions lacking cell\\u2013cell attachment and to the cytoplasm of hepatocytes, and its overexpression increases cell migration in fibroblast and hepatocyte models; phosphorylation of serine 38 is associated with cell morphology changes [#0, #1]. In colorectal cancer stem cells, FAM84A physically binds \\u03b2-catenin and promotes its ubiquitination and degradation, restraining \\u03b2-catenin-driven self-renewal [#4], whereas in papillary thyroid carcinoma FAM84A promotes epithelial\\u2013mesenchymal transition and activates Wnt/\\u03b2-catenin signaling [#3], indicating context-dependent effects on this pathway. FAM84A expression is controlled at multiple levels: transcriptionally by the nuclear receptor CAR [#1], post-transcriptionally through ALKBH5-mediated m6A demethylation that triggers mRNA decay [#4], and through direct targeting by miR-874-3p and miR-215 [#3, #5]. Beyond these findings, the precise biochemical activity of the LRATD1 protein has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first functional readout for FAM84A by linking its membrane-proximal localization and serine-38 phosphorylation to cell motility and morphology, framing it as a regulator of cell migration.\",\n      \"evidence\": \"Immunocytochemical localization and exogenous overexpression motility assay in NIH3T3 cells, with site-specific phosphorylation analysis\",\n      \"pmids\": [\"16820875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which FAM84A increases motility not defined\", \"Kinase responsible for serine-38 phosphorylation unknown\", \"No direct binding partners identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified an upstream transcriptional driver of FAM84A by showing the nuclear xenobiotic receptor CAR activates its promoter, placing FAM84A downstream of CAR signaling in liver.\",\n      \"evidence\": \"CAR-driven promoter reporter assay, Western blot, IHC, and overexpression migration assay in HepG2 cells and mouse liver\",\n      \"pmids\": [\"21424122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CAR-induced FAM84A in liver tumorigenesis not resolved\", \"Reason serine-38 is unphosphorylated in liver versus other contexts unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended post-transcriptional control of FAM84A by validating miR-215 as a direct repressor, indicating miRNA regulation of FAM84A across tissues.\",\n      \"evidence\": \"Dual-luciferase reporter assay with miR-215 and FAM84A 3'UTR in rooster testis cells\",\n      \"pmids\": [\"32561231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single reporter method without downstream functional consequence\", \"Physiological context of miR-215\\u2013FAM84A axis in mammals not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected FAM84A to Wnt/\\u03b2-catenin signaling and EMT in cancer and added miR-874-3p as a direct upstream repressor, defining a tumor-promoting role in thyroid carcinoma.\",\n      \"evidence\": \"miR-874-3p target validation plus FAM84A knockdown with EMT and Wnt/\\u03b2-catenin readouts in vitro and in xenografts\",\n      \"pmids\": [\"33751775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FAM84A activates Wnt/\\u03b2-catenin here not biochemically defined\", \"Apparent opposite effect on \\u03b2-catenin versus colorectal CSC context unreconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Nominated LRATD1 as an N-myristoylation substrate of NMT1/NMT2, hinting at a lipid-modification mechanism for its membrane association.\",\n      \"evidence\": \"Interactome data mining using NMT1/2 binding as a substrate proxy, framed by in vitro NMT assays\",\n      \"pmids\": [\"34956690\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct in vitro myristoylation assay performed on LRATD1 itself\", \"Functional impact of myristoylation on LRATD1 localization or activity untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a direct molecular mechanism: FAM84A binds \\u03b2-catenin and drives its ubiquitination and degradation, with ALKBH5-mediated m6A demethylation controlling FAM84A abundance, establishing FAM84A as a tumor suppressor in colorectal cancer stem cells.\",\n      \"evidence\": \"Integrated RNA-seq/MeRIP-seq/Ribo-seq, Co-IP, \\u03b2-catenin ubiquitination assay, and ALKBH5 knockin/knockout mouse models\",\n      \"pmids\": [\"41390849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FAM84A acts as or recruits an E3 ligase for \\u03b2-catenin not resolved\", \"Structural basis of the FAM84A\\u2013\\u03b2-catenin interaction unknown\", \"Reconciliation with FAM84A activating Wnt/\\u03b2-catenin in other tumors unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic biochemical activity of the LRATD1 protein and how it switches between suppressing and activating Wnt/\\u03b2-catenin signaling in different cancers remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined catalytic or molecular function for the LRATD1 protein\", \"Determinants of context-dependent \\u03b2-catenin regulation unknown\", \"Direct test of NMT-mediated myristoylation and its consequences lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTNNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}