{"gene":"FAM13A","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2016,"finding":"FAM13A interacts with protein phosphatase 2A (PP2A) and recruits PP2A together with glycogen synthase kinase 3β (GSK3β) and β-catenin, inducing β-catenin degradation. Fam13a-knockout mice were resistant to cigarette smoke-induced and elastase-induced emphysema, and this resistance was reversed by co-administration of a β-catenin inhibitor, placing FAM13A upstream of β-catenin stability.","method":"Co-immunoprecipitation followed by mass spectrometry (IP-MS); Fam13a knockout mouse model; pharmacological rescue with β-catenin inhibitor","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP/MS identified the complex, genetic KO with defined emphysema phenotype, and pharmacological epistasis (β-catenin inhibitor reversal) across two independent injury models in one rigorous study","pmids":["26862784"],"is_preprint":false},{"year":2015,"finding":"B56-containing PP2A and Akt act antagonistically to control reversible phosphorylation of Fam13a on Ser-322. When phosphorylated by Akt at Ser-322, Fam13a binds 14-3-3 with enhanced affinity, leading to cytoplasmic sequestration. B56-containing PP2As dephosphorylate phospho-Ser-322 and promote nuclear localization of Fam13a. Additionally, Fam13a has the ability to activate the Wnt pathway in human lung cancer cells.","method":"In vitro phosphorylation assay; site-directed mutagenesis (Ser-322); subcellular fractionation; co-immunoprecipitation with 14-3-3; Fam13a-knockout mouse generation; Wnt reporter assays in lung cancer cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation assay with mutagenesis of the regulatory residue, reciprocal Co-IP with 14-3-3, subcellular localization with functional link, and genetic KO validation; multiple orthogonal methods in one study","pmids":["25609086"],"is_preprint":false},{"year":2021,"finding":"FAM13A forms a cellular protein complex with TGFβ2 and AP3D1 (adaptor protein 3 subunit). This complex mediates TGFβ2 secretion through an AP-3-dependent intracellular transport pathway, with FAM13A acting as a negative regulator targeting a late stage of transport involving dissociation of coat-cargo interaction. TGFβ2 is identified as a transmembrane protein delivered to late endosomal compartments for subsequent exosomal secretion via this pathway.","method":"Co-immunoprecipitation; protein-protein interaction network analysis; functional transport/secretion assays in cells","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP established the trimeric complex and functional secretion assay placed FAM13A in the AP-3 transport pathway; single lab with two orthogonal methods","pmids":["34166600"],"is_preprint":false},{"year":2017,"finding":"FAM13A knockdown in lung epithelial cells (A549 and primary bronchial epithelial cells from CF patients) leads to increased RhoA activity, induction of F-actin stress fibers, and changes in epithelial-mesenchymal transition (EMT) markers including E-cadherin, α-smooth muscle actin, and vimentin. IL-1β and TGFβ reduce FAM13A expression.","method":"siRNA knockdown; RhoA activity assay; immunofluorescence of F-actin; western blotting for EMT markers; primary CF patient cells","journal":"Journal of cystic fibrosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RhoA activity assay directly measured the pathway output after KD; validated in primary patient cells alongside cell line; single lab with multiple readouts","pmids":["29239766"],"is_preprint":false},{"year":2023,"finding":"AKT kinase phosphorylates FAM13A at serine residue 312 following cigarette smoke extract treatment, and this phosphorylation is recognized by the CUL4A/DDB1/DCAF1 E3 ubiquitin ligase complex, leading to ubiquitination-mediated degradation of FAM13A. Reduced FAM13A protein levels resulting from this pathway accelerate epithelial cell proliferation during lung injury recovery.","method":"In vitro kinase assay; site-directed mutagenesis; co-immunoprecipitation with DCAF1/CUL4A; ubiquitination assay; in vivo mouse injury models (influenza, naphthalene); cell proliferation assays","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphorylation residue identified by mutagenesis, E3 ligase complex identified by Co-IP, ubiquitination confirmed in vitro, functional consequence validated in two independent mouse injury models","pmids":["36749583"],"is_preprint":false},{"year":2024,"finding":"The long isoform of FAM13A, predominantly expressed in multiciliated airway epithelial cells, contains a functional N-terminal RhoGAP domain with directly demonstrated RhoGAP activity using purified proteins. In Xenopus laevis, Fam13a deficiency impaired cilia-dependent embryo motility. In human primary epithelial cells, long-isoform deficiency reduced cilia coordination in mucociliary transport assays without affecting multiciliogenesis.","method":"In vitro RhoGAP activity assay with purified proteins; Xenopus Fam13a morpholino knockdown; mucociliary transport assays in human primary airway epithelial cells; isoform-specific expression analysis","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro biochemical demonstration of RhoGAP activity with purified protein, orthologous in vivo validation in Xenopus, and functional human cell assay; multiple orthogonal methods","pmids":["38691660"],"is_preprint":false},{"year":2020,"finding":"FAM13A knockdown in preadipocytes accelerates adipocyte differentiation. Fam13a knockout mice show a lower visceral-to-subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge and subcutaneous adipocytes shift toward a greater number of smaller adipocytes with improved adipogenic potential.","method":"siRNA knockdown in human preadipocyte models; Fam13a knockout mouse adipose phenotyping under high-fat diet; adipocyte size/number analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined adipose phenotype in vivo and in vitro knockdown in human cells; single lab, two orthogonal models","pmids":["32193374"],"is_preprint":false},{"year":2020,"finding":"Loss of Fam13a in mice leads to activation of AMP-activated protein kinase (AMPK) and increased mitochondrial respiration in primary hepatocytes, protecting from high-fat diet-induced fatty liver. FAM13A thus acts as a repressor of AMPK activity in hepatic glucose and lipid metabolism.","method":"Fam13a knockout mice on high-fat diet; AMPK activity assay; mitochondrial respiration measurement in primary hepatocytes; reporter assay for regulatory variant rs2276936","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined metabolic phenotype, AMPK activity directly measured in primary cells; single lab with two orthogonal methods","pmids":["32151973"],"is_preprint":false},{"year":2021,"finding":"FAM13A deficiency increases Wnt/β-catenin activation in lung epithelial cells (especially alveolar type II cells) in vivo after cigarette smoke exposure, and enhances the proliferation and differentiation capacity of alveolar epithelial progenitor cells in ex vivo organoid culture, demonstrating a tempo-spatial role of FAM13A in restraining Wnt-mediated alveolar epithelial repair/regeneration.","method":"Fam13a-knockout crossed with TCF/Lef:H2B-GFP Wnt reporter mice; flow cytometry; alveolar organoid culture; immunofluorescence; single-cell RNA-seq from COPD lungs","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Wnt reporter in KO mice combined with ex vivo organoid functional readout; single lab with multiple orthogonal methods","pmids":["34224973"],"is_preprint":false},{"year":2021,"finding":"FAM13A overexpression in airway epithelial cells accelerates build-up of epithelial resistance and increases E-cadherin expression, while reducing CSE-induced CXCL8 secretion. FAM13A-knockout airway epithelial cells show augmented TGF-β1-induced collagen (COL1A1) and MMP2 expression mediated by increased β-catenin expression, indicating FAM13A protects from TGF-β1-induced fibrotic responses by sequestering β-catenin.","method":"CRISPR-Cas9 FAM13A knockout in airway epithelial cells; lipid nanoparticle-mediated FAM13A overexpression; transepithelial electrical resistance measurement; western blotting; ELISA for CXCL8","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO and overexpression with defined barrier and fibrotic molecular phenotypes; single lab with multiple orthogonal readouts","pmids":["34105356"],"is_preprint":false},{"year":2021,"finding":"FAM13A silencing in NSCLC cells disrupts F-actin cytoskeleton architecture and suppresses migration and invasion, particularly under hypoxic conditions. FAM13A knockdown also induces S-phase cell cycle arrest and reduces proliferation, without affecting apoptosis.","method":"Lentiviral shRNA knockdown; MTS proliferation assay; wound healing assay; invasion assay; BrdU assay; APC Annexin V apoptosis staining; F-actin immunofluorescence","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable KD with multiple functional readouts including cytoskeletal imaging; single lab","pmids":["33919074"],"is_preprint":false},{"year":2018,"finding":"FAM13A knockdown in human adipose-derived mesenchymal stem cells increases lipolysis approximately 1.5-fold and upregulates LIPE (hormone-sensitive lipase) expression, identifying FAM13A as a regulator of adipocyte lipolysis.","method":"siRNA knockdown in human mesenchymal stem cells; glycerol release lipolysis assay; gene expression by qPCR","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with direct lipolysis functional assay in primary human cells; single lab, single method type but quantitative functional readout","pmids":["29487953"],"is_preprint":false},{"year":2023,"finding":"FAM13A overexpression in airway epithelial 16HBE cells reduces paraquat-induced P21 (CDKN1A) expression and mitochondrial ROS production, indicating FAM13A negatively regulates cellular senescence via suppression of P21 and mitochondrial oxidative stress.","method":"FAM13A overexpression in 16HBE cells; paraquat-induced senescence model; qPCR for P21; MitoSOX staining for mitochondrial ROS; immunohistochemistry in COPD lung tissue","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with functional ROS and senescence marker readouts; single lab with two orthogonal molecular endpoints","pmids":["37605846"],"is_preprint":false},{"year":2021,"finding":"miR-30a-5p targets the FAM13A 3'-UTR (confirmed by dual-luciferase reporter assay), reducing FAM13A expression and promoting adipogenic differentiation of bone marrow mesenchymal stem cells. FAM13A reduces adipogenic differentiation by activating the Wnt/β-catenin signaling pathway.","method":"Dual-luciferase reporter assay; miR-30a-5p overexpression; western blotting for Wnt/β-catenin pathway proteins; Oil Red O staining; RT-qPCR","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase assay confirmed miRNA targeting; Wnt activation by FAM13A shown by western blot, but single lab with limited mechanistic depth","pmids":["34821370"],"is_preprint":false},{"year":2020,"finding":"Two-hybrid screening in a human lung cancer cDNA library identified several high-confidence protein partners of FAM13A, providing candidate interaction partners for further mechanistic investigation. Specific partners were identified but not individually validated in this study.","method":"Yeast two-hybrid screening with human lung cancer cDNA library","journal":"BMC research notes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid without biochemical validation of individual interactions in mammalian cells","pmids":["31900205"],"is_preprint":false},{"year":2026,"finding":"The long isoform of FAM13A is required for the emergence of mature airway and alveolar epithelial lineages from human iPSCs during directed differentiation. Specific loss of the long isoform dysregulates Wnt/β-catenin signaling during early patterning of NKX2-1+ lung progenitor cells in vitro.","method":"CRISPR-Cas9 isoform-specific disruption in human iPSCs; directed differentiation to lung epithelium; immunostaining; gene expression analysis","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific CRISPR KO in human iPSC differentiation model with defined lineage and pathway phenotypes; single lab study","pmids":["42083809"],"is_preprint":false},{"year":2018,"finding":"FAM13A overexpression in 3T3-L1 preadipocytes downregulates β-catenin signaling and renders preadipocytes more susceptible to apoptosis, and largely blocks adipogenesis induced by standard hormone cocktail; adipogenesis can be partially rescued by the PPARγ agonist pioglitazone, placing FAM13A upstream of PPARγ in adipogenesis.","method":"FAM13A overexpression in 3T3-L1 cells; western blotting for β-catenin; adipogenesis assay; apoptosis assay; pharmacological rescue with pioglitazone","journal":"International journal of obesity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with functional phenotype and pathway rescue; single lab, no knockin/endogenous validation","pmids":["30301961"],"is_preprint":false}],"current_model":"FAM13A is a multi-domain protein (containing a RhoGAP domain in its long isoform with demonstrated GTPase-activating activity toward RhoA) that functions primarily as a negative regulator of β-catenin/Wnt signaling by recruiting PP2A–GSK3β to promote β-catenin degradation; its subcellular localization is controlled by antagonistic phosphorylation at Ser-312/Ser-322 by AKT (promoting 14-3-3 binding and cytoplasmic retention) and dephosphorylation by B56-containing PP2A (promoting nuclear entry), and AKT-mediated phosphorylation also triggers ubiquitin-mediated degradation via the CUL4A/DCAF1 E3 ligase; FAM13A additionally represses AMPK activity in hepatocytes, regulates TGFβ2 secretion through an AP-3 transport pathway, negatively modulates RhoA activity and actin cytoskeleton dynamics in airway epithelium, and coordinates cilia-driven mucociliary transport through its long isoform, collectively linking it to lung epithelial progenitor maintenance, adipocyte differentiation, and hepatic lipid/glucose homeostasis."},"narrative":{"mechanistic_narrative":"FAM13A is a RhoGAP-domain protein that functions as a negative regulator of Wnt/β-catenin signaling and Rho-dependent cytoskeletal dynamics, coordinating epithelial repair, fibrosis, and metabolic homeostasis [PMID:26862784, PMID:38691660]. It recruits PP2A together with GSK3β and β-catenin to drive β-catenin degradation, and loss of this activity sensitizes lung epithelium to Wnt-mediated emphysematous injury and augments alveolar progenitor proliferation [PMID:26862784, PMID:34224973]. FAM13A subcellular partitioning is set by reversible phosphorylation at Ser-322: AKT-mediated phosphorylation enhances 14-3-3 binding and cytoplasmic sequestration, whereas B56-containing PP2A dephosphorylates this site to promote nuclear localization [PMID:25609086]. AKT phosphorylation at Ser-312 following cigarette smoke exposure creates a degron recognized by the CUL4A/DDB1/DCAF1 E3 ubiquitin ligase, triggering FAM13A ubiquitination and degradation that accelerates epithelial proliferation during injury recovery [PMID:36749583]. The long isoform carries a biochemically validated N-terminal RhoGAP domain, and FAM13A restrains RhoA activity and F-actin stress fiber formation in airway epithelium while supporting cilia-coordinated mucociliary transport [PMID:29239766, PMID:38691660]. FAM13A additionally negatively regulates TGFβ2 secretion via an AP-3/AP3D1 transport pathway [PMID:34166600], represses AMPK activity to govern hepatic lipid and glucose metabolism [PMID:32151973], and restrains adipocyte differentiation and lipolysis [PMID:32193374, PMID:29487953].","teleology":[{"year":2015,"claim":"Established how FAM13A nuclear-cytoplasmic distribution is controlled, defining a phospho-switch that gates its access to Wnt signaling machinery.","evidence":"In vitro phosphorylation with Ser-322 mutagenesis, 14-3-3 Co-IP, subcellular fractionation, and KO mice plus Wnt reporter in lung cancer cells","pmids":["25609086"],"confidence":"High","gaps":["Did not resolve which nuclear targets FAM13A engages once localized","Functional consequence of nuclear vs cytoplasmic pools on β-catenin not fully dissected"]},{"year":2016,"claim":"Defined the core biochemical mechanism by which FAM13A suppresses Wnt signaling — scaffolding a PP2A–GSK3β–β-catenin complex to drive β-catenin degradation — and tied it to emphysema resistance in vivo.","evidence":"IP-MS, Fam13a knockout mice, and pharmacological β-catenin inhibitor epistasis across two emphysema injury models","pmids":["26862784"],"confidence":"High","gaps":["Structural basis of the multiprotein scaffold not determined","Whether RhoGAP activity contributes to this complex unaddressed"]},{"year":2017,"claim":"Showed FAM13A restrains RhoA activity and actin cytoskeleton remodeling in lung epithelium, linking its loss to stress fiber formation and EMT marker changes.","evidence":"siRNA knockdown with RhoA activity assay and F-actin imaging in A549 and primary CF bronchial cells","pmids":["29239766"],"confidence":"Medium","gaps":["Direct GAP activity not biochemically demonstrated in this study","EMT marker changes correlative, not mechanistically linked to RhoA"]},{"year":2018,"claim":"Extended the β-catenin-suppressive role of FAM13A to adipogenesis and lipolysis, positioning it upstream of PPARγ.","evidence":"Overexpression in 3T3-L1 with pioglitazone rescue; knockdown lipolysis assays in human MSCs","pmids":["30301961","29487953"],"confidence":"Low","gaps":["3T3-L1 overexpression lacks endogenous/knockin validation","Direct β-catenin–PPARγ mechanistic link not established"]},{"year":2020,"claim":"Established FAM13A's roles in systemic metabolism, repressing AMPK and mitochondrial respiration in hepatocytes and restraining adipocyte differentiation and fat distribution.","evidence":"Fam13a KO mice on high-fat diet with AMPK and mitochondrial respiration assays in hepatocytes; adipose phenotyping and preadipocyte knockdown","pmids":["32151973","32193374"],"confidence":"Medium","gaps":["Molecular link between FAM13A and AMPK not defined","Mechanism connecting Wnt/β-catenin regulation to metabolic phenotypes unclear"]},{"year":2021,"claim":"Diversified FAM13A's mechanistic repertoire — identifying it as a negative regulator of AP-3-dependent TGFβ2 secretion, a restrainer of Wnt-mediated alveolar progenitor regeneration, and a protector against TGFβ1-driven fibrotic responses.","evidence":"Co-IP of FAM13A–TGFβ2–AP3D1 with secretion assays; KO Wnt-reporter mice with alveolar organoids; CRISPR KO/overexpression in airway epithelium with barrier and fibrotic readouts","pmids":["34166600","34224973","34105356","33919074"],"confidence":"Medium","gaps":["Whether TGFβ2 transport, Wnt suppression, and RhoGAP functions are mechanistically coupled is unknown","Domain requirements for AP-3 pathway regulation not mapped"]},{"year":2023,"claim":"Identified the degradation arm of FAM13A regulation, showing AKT phosphorylation at Ser-312 generates a CUL4A/DCAF1 degron that lowers FAM13A levels to accelerate epithelial proliferation during repair.","evidence":"In vitro kinase assay, Ser-312 mutagenesis, Co-IP with DCAF1/CUL4A, ubiquitination assay, and two mouse injury models","pmids":["36749583"],"confidence":"High","gaps":["Relationship between Ser-312 degron and Ser-322 localization switch not integrated","Whether degradation selectively affects specific FAM13A functions unknown"]},{"year":2024,"claim":"Provided direct biochemical proof of FAM13A RhoGAP activity in its long isoform and assigned an isoform-specific role in cilia-coordinated mucociliary transport.","evidence":"In vitro RhoGAP assay with purified protein, Xenopus morpholino knockdown, and mucociliary transport assays in human airway cells","pmids":["38691660"],"confidence":"High","gaps":["Rho substrate specificity beyond RhoA not fully delineated","How RhoGAP activity coordinates with the β-catenin scaffold function unresolved"]},{"year":2026,"claim":"Demonstrated the long isoform is required for lung epithelial lineage emergence from human iPSCs through Wnt/β-catenin regulation during early progenitor patterning.","evidence":"Isoform-specific CRISPR disruption in human iPSC-directed lung differentiation with lineage and pathway readouts","pmids":["42083809"],"confidence":"Medium","gaps":["Whether RhoGAP activity or β-catenin scaffolding drives the lineage phenotype not separated","Stage-specific Wnt regulation mechanism not detailed"]},{"year":null,"claim":"How FAM13A's distinct molecular activities — RhoGAP catalysis, PP2A/β-catenin scaffolding, AP-3 transport regulation, and AMPK repression — are partitioned across isoforms, subcellular pools, and tissues to produce its diverse phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating the RhoGAP domain with the β-catenin-degrading scaffold","Mechanism linking FAM13A to AMPK repression undefined","Validated direct binding partners from candidate screens still lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,15]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,6]}],"complexes":[],"partners":["PP2A","GSK3B","CTNNB1","YWHA+ (14-3-3)","AP3D1","TGFB2","CUL4A","DCAF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94988","full_name":"Protein FAM13A","aliases":[],"length_aa":1023,"mass_kda":116.9,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O94988/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM13A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MYO6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FAM13A","total_profiled":1310},"omim":[{"mim_id":"613300","title":"FAM13A ANTISENSE RNA 1; FAM13AAS1","url":"https://www.omim.org/entry/613300"},{"mim_id":"613299","title":"FAMILY WITH SEQUENCE SIMILARITY 13, MEMBER A; FAM13A","url":"https://www.omim.org/entry/613299"},{"mim_id":"606963","title":"PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; COPD","url":"https://www.omim.org/entry/606963"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM13A"},"hgnc":{"alias_symbol":["KIAA0914","ARHGAP48"],"prev_symbol":["FAM13A1"]},"alphafold":{"accession":"O94988","domains":[{"cath_id":"1.10.555.10","chopping":"33-235","consensus_level":"high","plddt":89.987,"start":33,"end":235},{"cath_id":"-","chopping":"666-728","consensus_level":"high","plddt":88.5549,"start":666,"end":728},{"cath_id":"1.10.287","chopping":"790-849","consensus_level":"high","plddt":90.2218,"start":790,"end":849},{"cath_id":"1.10.287","chopping":"949-1021","consensus_level":"high","plddt":89.4712,"start":949,"end":1021}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94988","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94988-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94988-F1-predicted_aligned_error_v6.png","plddt_mean":60.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM13A","jax_strain_url":"https://www.jax.org/strain/search?query=FAM13A"},"sequence":{"accession":"O94988","fasta_url":"https://rest.uniprot.org/uniprotkb/O94988.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94988/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94988"}},"corpus_meta":[{"pmid":"26862784","id":"PMC_26862784","title":"A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin.","date":"2016","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26862784","citation_count":105,"is_preprint":false},{"pmid":"31164635","id":"PMC_31164635","title":"microRNA-328 in exosomes derived from M2 macrophages exerts a promotive effect on the progression of pulmonary fibrosis via FAM13A in a rat model.","date":"2019","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31164635","citation_count":77,"is_preprint":false},{"pmid":"23776362","id":"PMC_23776362","title":"FAM13A locus in COPD is independently associated with lung cancer - evidence of a molecular genetic link between COPD and lung cancer.","date":"2010","source":"The application of clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23776362","citation_count":57,"is_preprint":false},{"pmid":"32193374","id":"PMC_32193374","title":"FAM13A affects body fat distribution and adipocyte function.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32193374","citation_count":51,"is_preprint":false},{"pmid":"25609086","id":"PMC_25609086","title":"Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25609086","citation_count":48,"is_preprint":false},{"pmid":"15234000","id":"PMC_15234000","title":"Cloning and characterization of FAM13A1--a gene near a milk protein QTL on BTA6: evidence for population-wide linkage disequilibrium in Israeli Holsteins.","date":"2004","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/15234000","citation_count":46,"is_preprint":false},{"pmid":"27612410","id":"PMC_27612410","title":"Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A.","date":"2016","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27612410","citation_count":45,"is_preprint":false},{"pmid":"30079747","id":"PMC_30079747","title":"Identification of Functional Variants in the FAM13A Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Locus by Massively Parallel Reporter Assays.","date":"2019","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30079747","citation_count":44,"is_preprint":false},{"pmid":"29239766","id":"PMC_29239766","title":"FAM13A is a modifier gene of cystic fibrosis lung phenotype regulating rhoa activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition.","date":"2017","source":"Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society","url":"https://pubmed.ncbi.nlm.nih.gov/29239766","citation_count":41,"is_preprint":false},{"pmid":"28197372","id":"PMC_28197372","title":"FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival.","date":"2016","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/28197372","citation_count":37,"is_preprint":false},{"pmid":"25163686","id":"PMC_25163686","title":"Moving beyond genetics: is FAM13A a major biological contributor in lung physiology and chronic lung diseases?","date":"2014","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25163686","citation_count":34,"is_preprint":false},{"pmid":"29487953","id":"PMC_29487953","title":"FAM13A and POM121C are candidate genes for fasting insulin: functional follow-up analysis of a genome-wide association study.","date":"2018","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/29487953","citation_count":28,"is_preprint":false},{"pmid":"23891779","id":"PMC_23891779","title":"Association of FAM13A polymorphisms with COPD and COPD-related phenotypes in Han Chinese.","date":"2013","source":"Clinical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23891779","citation_count":24,"is_preprint":false},{"pmid":"33919074","id":"PMC_33919074","title":"Hypoxia-Induced FAM13A Regulates the Proliferation and Metastasis of Non-Small Cell Lung Cancer Cells.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33919074","citation_count":19,"is_preprint":false},{"pmid":"34224973","id":"PMC_34224973","title":"Tempo-spatial regulation of the Wnt pathway by FAM13A modulates the stemness of alveolar epithelial progenitors.","date":"2021","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/34224973","citation_count":19,"is_preprint":false},{"pmid":"29187867","id":"PMC_29187867","title":"FAM13A as a Novel Hypoxia-Induced Gene in Non-Small Cell Lung Cancer.","date":"2017","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29187867","citation_count":18,"is_preprint":false},{"pmid":"32151973","id":"PMC_32151973","title":"FAM13A Represses AMPK Activity and Regulates Hepatic Glucose and Lipid Metabolism.","date":"2020","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/32151973","citation_count":18,"is_preprint":false},{"pmid":"29621588","id":"PMC_29621588","title":"The rs2609255 polymorphism in the FAM13A gene is reproducibly associated with silicosis susceptibility in a Chinese 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Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37605846","citation_count":7,"is_preprint":false},{"pmid":"37391706","id":"PMC_37391706","title":"FAM13A polymorphisms are associated with a specific susceptibility to clinical progression of oral cancer in alcohol drinkers.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37391706","citation_count":6,"is_preprint":false},{"pmid":"38691660","id":"PMC_38691660","title":"The FAM13A Long Isoform Regulates Cilia Movement and Coordination in Airway Mucociliary Transport.","date":"2024","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38691660","citation_count":5,"is_preprint":false},{"pmid":"37330023","id":"PMC_37330023","title":"LncRNA FAM13A-AS1, transcriptionally regulated by PHOX2B, modulates hepatocellular carcinoma chemoresistance via stabilizing PPARγ.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/37330023","citation_count":5,"is_preprint":false},{"pmid":"31900205","id":"PMC_31900205","title":"Two-hybrid screening of FAM13A protein partners in lung epithelial cells.","date":"2020","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/31900205","citation_count":5,"is_preprint":false},{"pmid":"23021125","id":"PMC_23021125","title":"Polymorphism of the FAM13A, ABCG2, OPN, LAP3, HCAP-G, PPARGC1A genes and somatic cell count of Jersey cows--preliminary study.","date":"2012","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/23021125","citation_count":5,"is_preprint":false},{"pmid":"34672860","id":"PMC_34672860","title":"FAM13A promotes proliferation of bovine preadipocytes by targeting Hypoxia-Inducible factor-1 signaling 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Vietnam.","date":"2023","source":"Advances in respiratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37366807","citation_count":3,"is_preprint":false},{"pmid":"33573279","id":"PMC_33573279","title":"rs6837671A>G in FAM13A Is a Trans-Ethnic Genetic Variant Interacting with Vitamin D Levels to Affect Chronic Obstructive Pulmonary Disease.","date":"2021","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33573279","citation_count":1,"is_preprint":false},{"pmid":"37107672","id":"PMC_37107672","title":"The Influence of FAM13A and PPAR-γ2 Gene Polymorphisms on the Metabolic State of Postmenopausal Women.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37107672","citation_count":0,"is_preprint":false},{"pmid":"40087586","id":"PMC_40087586","title":"Exploring FAM13A-N-Myc interactions to uncover potential targets in MYCN-amplified neuroblastoma: a study of protein interactions and molecular dynamics 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silica.","date":"2025","source":"Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia","url":"https://pubmed.ncbi.nlm.nih.gov/40531729","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28819,"output_tokens":4730,"usd":0.078703,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12971,"output_tokens":3637,"usd":0.07789,"stage2_stop_reason":"end_turn"},"total_usd":0.156593,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"FAM13A interacts with protein phosphatase 2A (PP2A) and recruits PP2A together with glycogen synthase kinase 3β (GSK3β) and β-catenin, inducing β-catenin degradation. Fam13a-knockout mice were resistant to cigarette smoke-induced and elastase-induced emphysema, and this resistance was reversed by co-administration of a β-catenin inhibitor, placing FAM13A upstream of β-catenin stability.\",\n      \"method\": \"Co-immunoprecipitation followed by mass spectrometry (IP-MS); Fam13a knockout mouse model; pharmacological rescue with β-catenin inhibitor\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP/MS identified the complex, genetic KO with defined emphysema phenotype, and pharmacological epistasis (β-catenin inhibitor reversal) across two independent injury models in one rigorous study\",\n      \"pmids\": [\"26862784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"B56-containing PP2A and Akt act antagonistically to control reversible phosphorylation of Fam13a on Ser-322. When phosphorylated by Akt at Ser-322, Fam13a binds 14-3-3 with enhanced affinity, leading to cytoplasmic sequestration. B56-containing PP2As dephosphorylate phospho-Ser-322 and promote nuclear localization of Fam13a. Additionally, Fam13a has the ability to activate the Wnt pathway in human lung cancer cells.\",\n      \"method\": \"In vitro phosphorylation assay; site-directed mutagenesis (Ser-322); subcellular fractionation; co-immunoprecipitation with 14-3-3; Fam13a-knockout mouse generation; Wnt reporter assays in lung cancer cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation assay with mutagenesis of the regulatory residue, reciprocal Co-IP with 14-3-3, subcellular localization with functional link, and genetic KO validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"25609086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM13A forms a cellular protein complex with TGFβ2 and AP3D1 (adaptor protein 3 subunit). This complex mediates TGFβ2 secretion through an AP-3-dependent intracellular transport pathway, with FAM13A acting as a negative regulator targeting a late stage of transport involving dissociation of coat-cargo interaction. TGFβ2 is identified as a transmembrane protein delivered to late endosomal compartments for subsequent exosomal secretion via this pathway.\",\n      \"method\": \"Co-immunoprecipitation; protein-protein interaction network analysis; functional transport/secretion assays in cells\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP established the trimeric complex and functional secretion assay placed FAM13A in the AP-3 transport pathway; single lab with two orthogonal methods\",\n      \"pmids\": [\"34166600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FAM13A knockdown in lung epithelial cells (A549 and primary bronchial epithelial cells from CF patients) leads to increased RhoA activity, induction of F-actin stress fibers, and changes in epithelial-mesenchymal transition (EMT) markers including E-cadherin, α-smooth muscle actin, and vimentin. IL-1β and TGFβ reduce FAM13A expression.\",\n      \"method\": \"siRNA knockdown; RhoA activity assay; immunofluorescence of F-actin; western blotting for EMT markers; primary CF patient cells\",\n      \"journal\": \"Journal of cystic fibrosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RhoA activity assay directly measured the pathway output after KD; validated in primary patient cells alongside cell line; single lab with multiple readouts\",\n      \"pmids\": [\"29239766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AKT kinase phosphorylates FAM13A at serine residue 312 following cigarette smoke extract treatment, and this phosphorylation is recognized by the CUL4A/DDB1/DCAF1 E3 ubiquitin ligase complex, leading to ubiquitination-mediated degradation of FAM13A. Reduced FAM13A protein levels resulting from this pathway accelerate epithelial cell proliferation during lung injury recovery.\",\n      \"method\": \"In vitro kinase assay; site-directed mutagenesis; co-immunoprecipitation with DCAF1/CUL4A; ubiquitination assay; in vivo mouse injury models (influenza, naphthalene); cell proliferation assays\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphorylation residue identified by mutagenesis, E3 ligase complex identified by Co-IP, ubiquitination confirmed in vitro, functional consequence validated in two independent mouse injury models\",\n      \"pmids\": [\"36749583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The long isoform of FAM13A, predominantly expressed in multiciliated airway epithelial cells, contains a functional N-terminal RhoGAP domain with directly demonstrated RhoGAP activity using purified proteins. In Xenopus laevis, Fam13a deficiency impaired cilia-dependent embryo motility. In human primary epithelial cells, long-isoform deficiency reduced cilia coordination in mucociliary transport assays without affecting multiciliogenesis.\",\n      \"method\": \"In vitro RhoGAP activity assay with purified proteins; Xenopus Fam13a morpholino knockdown; mucociliary transport assays in human primary airway epithelial cells; isoform-specific expression analysis\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro biochemical demonstration of RhoGAP activity with purified protein, orthologous in vivo validation in Xenopus, and functional human cell assay; multiple orthogonal methods\",\n      \"pmids\": [\"38691660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM13A knockdown in preadipocytes accelerates adipocyte differentiation. Fam13a knockout mice show a lower visceral-to-subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge and subcutaneous adipocytes shift toward a greater number of smaller adipocytes with improved adipogenic potential.\",\n      \"method\": \"siRNA knockdown in human preadipocyte models; Fam13a knockout mouse adipose phenotyping under high-fat diet; adipocyte size/number analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined adipose phenotype in vivo and in vitro knockdown in human cells; single lab, two orthogonal models\",\n      \"pmids\": [\"32193374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of Fam13a in mice leads to activation of AMP-activated protein kinase (AMPK) and increased mitochondrial respiration in primary hepatocytes, protecting from high-fat diet-induced fatty liver. FAM13A thus acts as a repressor of AMPK activity in hepatic glucose and lipid metabolism.\",\n      \"method\": \"Fam13a knockout mice on high-fat diet; AMPK activity assay; mitochondrial respiration measurement in primary hepatocytes; reporter assay for regulatory variant rs2276936\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined metabolic phenotype, AMPK activity directly measured in primary cells; single lab with two orthogonal methods\",\n      \"pmids\": [\"32151973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM13A deficiency increases Wnt/β-catenin activation in lung epithelial cells (especially alveolar type II cells) in vivo after cigarette smoke exposure, and enhances the proliferation and differentiation capacity of alveolar epithelial progenitor cells in ex vivo organoid culture, demonstrating a tempo-spatial role of FAM13A in restraining Wnt-mediated alveolar epithelial repair/regeneration.\",\n      \"method\": \"Fam13a-knockout crossed with TCF/Lef:H2B-GFP Wnt reporter mice; flow cytometry; alveolar organoid culture; immunofluorescence; single-cell RNA-seq from COPD lungs\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Wnt reporter in KO mice combined with ex vivo organoid functional readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34224973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM13A overexpression in airway epithelial cells accelerates build-up of epithelial resistance and increases E-cadherin expression, while reducing CSE-induced CXCL8 secretion. FAM13A-knockout airway epithelial cells show augmented TGF-β1-induced collagen (COL1A1) and MMP2 expression mediated by increased β-catenin expression, indicating FAM13A protects from TGF-β1-induced fibrotic responses by sequestering β-catenin.\",\n      \"method\": \"CRISPR-Cas9 FAM13A knockout in airway epithelial cells; lipid nanoparticle-mediated FAM13A overexpression; transepithelial electrical resistance measurement; western blotting; ELISA for CXCL8\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO and overexpression with defined barrier and fibrotic molecular phenotypes; single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"34105356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM13A silencing in NSCLC cells disrupts F-actin cytoskeleton architecture and suppresses migration and invasion, particularly under hypoxic conditions. FAM13A knockdown also induces S-phase cell cycle arrest and reduces proliferation, without affecting apoptosis.\",\n      \"method\": \"Lentiviral shRNA knockdown; MTS proliferation assay; wound healing assay; invasion assay; BrdU assay; APC Annexin V apoptosis staining; F-actin immunofluorescence\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable KD with multiple functional readouts including cytoskeletal imaging; single lab\",\n      \"pmids\": [\"33919074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAM13A knockdown in human adipose-derived mesenchymal stem cells increases lipolysis approximately 1.5-fold and upregulates LIPE (hormone-sensitive lipase) expression, identifying FAM13A as a regulator of adipocyte lipolysis.\",\n      \"method\": \"siRNA knockdown in human mesenchymal stem cells; glycerol release lipolysis assay; gene expression by qPCR\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with direct lipolysis functional assay in primary human cells; single lab, single method type but quantitative functional readout\",\n      \"pmids\": [\"29487953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM13A overexpression in airway epithelial 16HBE cells reduces paraquat-induced P21 (CDKN1A) expression and mitochondrial ROS production, indicating FAM13A negatively regulates cellular senescence via suppression of P21 and mitochondrial oxidative stress.\",\n      \"method\": \"FAM13A overexpression in 16HBE cells; paraquat-induced senescence model; qPCR for P21; MitoSOX staining for mitochondrial ROS; immunohistochemistry in COPD lung tissue\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with functional ROS and senescence marker readouts; single lab with two orthogonal molecular endpoints\",\n      \"pmids\": [\"37605846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-30a-5p targets the FAM13A 3'-UTR (confirmed by dual-luciferase reporter assay), reducing FAM13A expression and promoting adipogenic differentiation of bone marrow mesenchymal stem cells. FAM13A reduces adipogenic differentiation by activating the Wnt/β-catenin signaling pathway.\",\n      \"method\": \"Dual-luciferase reporter assay; miR-30a-5p overexpression; western blotting for Wnt/β-catenin pathway proteins; Oil Red O staining; RT-qPCR\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase assay confirmed miRNA targeting; Wnt activation by FAM13A shown by western blot, but single lab with limited mechanistic depth\",\n      \"pmids\": [\"34821370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Two-hybrid screening in a human lung cancer cDNA library identified several high-confidence protein partners of FAM13A, providing candidate interaction partners for further mechanistic investigation. Specific partners were identified but not individually validated in this study.\",\n      \"method\": \"Yeast two-hybrid screening with human lung cancer cDNA library\",\n      \"journal\": \"BMC research notes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid without biochemical validation of individual interactions in mammalian cells\",\n      \"pmids\": [\"31900205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The long isoform of FAM13A is required for the emergence of mature airway and alveolar epithelial lineages from human iPSCs during directed differentiation. Specific loss of the long isoform dysregulates Wnt/β-catenin signaling during early patterning of NKX2-1+ lung progenitor cells in vitro.\",\n      \"method\": \"CRISPR-Cas9 isoform-specific disruption in human iPSCs; directed differentiation to lung epithelium; immunostaining; gene expression analysis\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific CRISPR KO in human iPSC differentiation model with defined lineage and pathway phenotypes; single lab study\",\n      \"pmids\": [\"42083809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAM13A overexpression in 3T3-L1 preadipocytes downregulates β-catenin signaling and renders preadipocytes more susceptible to apoptosis, and largely blocks adipogenesis induced by standard hormone cocktail; adipogenesis can be partially rescued by the PPARγ agonist pioglitazone, placing FAM13A upstream of PPARγ in adipogenesis.\",\n      \"method\": \"FAM13A overexpression in 3T3-L1 cells; western blotting for β-catenin; adipogenesis assay; apoptosis assay; pharmacological rescue with pioglitazone\",\n      \"journal\": \"International journal of obesity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with functional phenotype and pathway rescue; single lab, no knockin/endogenous validation\",\n      \"pmids\": [\"30301961\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM13A is a multi-domain protein (containing a RhoGAP domain in its long isoform with demonstrated GTPase-activating activity toward RhoA) that functions primarily as a negative regulator of β-catenin/Wnt signaling by recruiting PP2A–GSK3β to promote β-catenin degradation; its subcellular localization is controlled by antagonistic phosphorylation at Ser-312/Ser-322 by AKT (promoting 14-3-3 binding and cytoplasmic retention) and dephosphorylation by B56-containing PP2A (promoting nuclear entry), and AKT-mediated phosphorylation also triggers ubiquitin-mediated degradation via the CUL4A/DCAF1 E3 ligase; FAM13A additionally represses AMPK activity in hepatocytes, regulates TGFβ2 secretion through an AP-3 transport pathway, negatively modulates RhoA activity and actin cytoskeleton dynamics in airway epithelium, and coordinates cilia-driven mucociliary transport through its long isoform, collectively linking it to lung epithelial progenitor maintenance, adipocyte differentiation, and hepatic lipid/glucose homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM13A is a RhoGAP-domain protein that functions as a negative regulator of Wnt/\\u03b2-catenin signaling and Rho-dependent cytoskeletal dynamics, coordinating epithelial repair, fibrosis, and metabolic homeostasis [#0, #5]. It recruits PP2A together with GSK3\\u03b2 and \\u03b2-catenin to drive \\u03b2-catenin degradation, and loss of this activity sensitizes lung epithelium to Wnt-mediated emphysematous injury and augments alveolar progenitor proliferation [#0, #8]. FAM13A subcellular partitioning is set by reversible phosphorylation at Ser-322: AKT-mediated phosphorylation enhances 14-3-3 binding and cytoplasmic sequestration, whereas B56-containing PP2A dephosphorylates this site to promote nuclear localization [#1]. AKT phosphorylation at Ser-312 following cigarette smoke exposure creates a degron recognized by the CUL4A/DDB1/DCAF1 E3 ubiquitin ligase, triggering FAM13A ubiquitination and degradation that accelerates epithelial proliferation during injury recovery [#4]. The long isoform carries a biochemically validated N-terminal RhoGAP domain, and FAM13A restrains RhoA activity and F-actin stress fiber formation in airway epithelium while supporting cilia-coordinated mucociliary transport [#3, #5]. FAM13A additionally negatively regulates TGF\\u03b22 secretion via an AP-3/AP3D1 transport pathway [#2], represses AMPK activity to govern hepatic lipid and glucose metabolism [#7], and restrains adipocyte differentiation and lipolysis [#6, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established how FAM13A nuclear-cytoplasmic distribution is controlled, defining a phospho-switch that gates its access to Wnt signaling machinery.\",\n      \"evidence\": \"In vitro phosphorylation with Ser-322 mutagenesis, 14-3-3 Co-IP, subcellular fractionation, and KO mice plus Wnt reporter in lung cancer cells\",\n      \"pmids\": [\"25609086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which nuclear targets FAM13A engages once localized\", \"Functional consequence of nuclear vs cytoplasmic pools on \\u03b2-catenin not fully dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the core biochemical mechanism by which FAM13A suppresses Wnt signaling \\u2014 scaffolding a PP2A\\u2013GSK3\\u03b2\\u2013\\u03b2-catenin complex to drive \\u03b2-catenin degradation \\u2014 and tied it to emphysema resistance in vivo.\",\n      \"evidence\": \"IP-MS, Fam13a knockout mice, and pharmacological \\u03b2-catenin inhibitor epistasis across two emphysema injury models\",\n      \"pmids\": [\"26862784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the multiprotein scaffold not determined\", \"Whether RhoGAP activity contributes to this complex unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed FAM13A restrains RhoA activity and actin cytoskeleton remodeling in lung epithelium, linking its loss to stress fiber formation and EMT marker changes.\",\n      \"evidence\": \"siRNA knockdown with RhoA activity assay and F-actin imaging in A549 and primary CF bronchial cells\",\n      \"pmids\": [\"29239766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GAP activity not biochemically demonstrated in this study\", \"EMT marker changes correlative, not mechanistically linked to RhoA\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the \\u03b2-catenin-suppressive role of FAM13A to adipogenesis and lipolysis, positioning it upstream of PPAR\\u03b3.\",\n      \"evidence\": \"Overexpression in 3T3-L1 with pioglitazone rescue; knockdown lipolysis assays in human MSCs\",\n      \"pmids\": [\"30301961\", \"29487953\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"3T3-L1 overexpression lacks endogenous/knockin validation\", \"Direct \\u03b2-catenin\\u2013PPAR\\u03b3 mechanistic link not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established FAM13A's roles in systemic metabolism, repressing AMPK and mitochondrial respiration in hepatocytes and restraining adipocyte differentiation and fat distribution.\",\n      \"evidence\": \"Fam13a KO mice on high-fat diet with AMPK and mitochondrial respiration assays in hepatocytes; adipose phenotyping and preadipocyte knockdown\",\n      \"pmids\": [\"32151973\", \"32193374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between FAM13A and AMPK not defined\", \"Mechanism connecting Wnt/\\u03b2-catenin regulation to metabolic phenotypes unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Diversified FAM13A's mechanistic repertoire \\u2014 identifying it as a negative regulator of AP-3-dependent TGF\\u03b22 secretion, a restrainer of Wnt-mediated alveolar progenitor regeneration, and a protector against TGF\\u03b21-driven fibrotic responses.\",\n      \"evidence\": \"Co-IP of FAM13A\\u2013TGF\\u03b22\\u2013AP3D1 with secretion assays; KO Wnt-reporter mice with alveolar organoids; CRISPR KO/overexpression in airway epithelium with barrier and fibrotic readouts\",\n      \"pmids\": [\"34166600\", \"34224973\", \"34105356\", \"33919074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TGF\\u03b22 transport, Wnt suppression, and RhoGAP functions are mechanistically coupled is unknown\", \"Domain requirements for AP-3 pathway regulation not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the degradation arm of FAM13A regulation, showing AKT phosphorylation at Ser-312 generates a CUL4A/DCAF1 degron that lowers FAM13A levels to accelerate epithelial proliferation during repair.\",\n      \"evidence\": \"In vitro kinase assay, Ser-312 mutagenesis, Co-IP with DCAF1/CUL4A, ubiquitination assay, and two mouse injury models\",\n      \"pmids\": [\"36749583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between Ser-312 degron and Ser-322 localization switch not integrated\", \"Whether degradation selectively affects specific FAM13A functions unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided direct biochemical proof of FAM13A RhoGAP activity in its long isoform and assigned an isoform-specific role in cilia-coordinated mucociliary transport.\",\n      \"evidence\": \"In vitro RhoGAP assay with purified protein, Xenopus morpholino knockdown, and mucociliary transport assays in human airway cells\",\n      \"pmids\": [\"38691660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rho substrate specificity beyond RhoA not fully delineated\", \"How RhoGAP activity coordinates with the \\u03b2-catenin scaffold function unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated the long isoform is required for lung epithelial lineage emergence from human iPSCs through Wnt/\\u03b2-catenin regulation during early progenitor patterning.\",\n      \"evidence\": \"Isoform-specific CRISPR disruption in human iPSC-directed lung differentiation with lineage and pathway readouts\",\n      \"pmids\": [\"42083809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RhoGAP activity or \\u03b2-catenin scaffolding drives the lineage phenotype not separated\", \"Stage-specific Wnt regulation mechanism not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FAM13A's distinct molecular activities \\u2014 RhoGAP catalysis, PP2A/\\u03b2-catenin scaffolding, AP-3 transport regulation, and AMPK repression \\u2014 are partitioned across isoforms, subcellular pools, and tissues to produce its diverse phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating the RhoGAP domain with the \\u03b2-catenin-degrading scaffold\", \"Mechanism linking FAM13A to AMPK repression undefined\", \"Validated direct binding partners from candidate screens still lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PP2A\", \"GSK3B\", \"CTNNB1\", \"YWHA+ (14-3-3)\", \"AP3D1\", \"TGFB2\", \"CUL4A\", \"DCAF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}