{"gene":"FAM120A","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2008,"finding":"FAM120A (Ossa/C9orf10) is an RNA-binding protein that, upon oxidative stress (UV irradiation), associates with regulatory domains of Src family kinases (SFKs) to activate them; activated SFKs then phosphorylate FAM120A on tyrosine residues, and tyrosine-phosphorylated FAM120A recruits the p85 subunit of PI3-kinase to act as a scaffold for PI3K and SFKs, activating the Akt antiapoptotic pathway.","method":"Co-immunoprecipitation, tyrosine phosphorylation assays, identification of p85 recruitment, functional survival assays in gastric carcinoma cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional assays in a single lab with multiple orthogonal methods (phosphorylation assay, p85 recruitment, survival readout)","pmids":["19015244"],"is_preprint":false},{"year":2008,"finding":"FAM120A (C9orf10) directly binds RNAs including IGF-II mRNA via its C-terminal domain and promotes extracellular secretion of IGF-II protein.","method":"RNA-binding assays, IGF-II secretion measurement in cancer cells with FAM120A manipulations","journal":"Molecular and cellular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method described in abstract without detailed controls reported","pmids":["19015244"],"is_preprint":false},{"year":2008,"finding":"FAM120A (C9orf10) is a component of Puralpha-containing mRNA–protein particles (Puralpha-mRNPs) in neurons, co-immunoprecipitating with Puralpha; expression is restricted to neurons and shows distinct regional/developmental patterns in mouse brain compared to Puralpha.","method":"Co-immunoprecipitation, immunohistochemistry with neuron-specific markers, developmental Western blotting in mouse brain","journal":"The journal of histochemistry and cytochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identification in a characterization study; no functional validation of the interaction","pmids":["18413649"],"is_preprint":false},{"year":2015,"finding":"FAM120A acts as a scaffold protein in the IL13Rα2 signaling pathway: it co-immunoprecipitates with IL13Rα2 and recruits PI3K, enabling Src family kinase-mediated phosphorylation and activation of PI3K, thereby mediating IL13Rα2-triggered activation of FAK and the PI3K/AKT/mTOR pathways to drive colon cancer invasion and metastasis.","method":"Co-immunoprecipitation, FAM120A silencing (siRNA/shRNA), in vitro migration/invasion assays, in vivo liver colonization assay in nude mice, pathway activation (phospho-FAK, phospho-AKT readouts)","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro functional assays, and in vivo metastasis model with multiple orthogonal readouts in a single focused study","pmids":["25896327"],"is_preprint":false},{"year":2019,"finding":"FAM120A interacts with Ago2 in the cytoplasm and binds homopolymeric poly(G) sequences in 3'-UTRs of ~2000 mRNAs (identified by iCLIP); FAM120A-bound Ago2 target mRNAs are not subject to Ago2-mediated degradation, indicating FAM120A sequesters Ago2 complexes to attenuate miRNA-mediated target repression.","method":"Immunoprecipitation followed by mass spectrometry (Ago2-IP/MS), individual nucleotide resolution cross-linking and immunoprecipitation (iCLIP), reporter assays with 3'-UTR constructs in mouse embryonic stem cells","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — iCLIP (transcriptome-wide), Ago2 co-IP/MS, and reporter assays providing multiple orthogonal methods in a single rigorous study","pmids":["31289130"],"is_preprint":false},{"year":2023,"finding":"FAM120A functions as a transcription co-activator downstream of mTORC1-SRPK2 signaling: mTORC1-activated SRPK2 phosphorylates SRSF1, enhancing SRSF1 binding to FAM120A; FAM120A directly interacts with lipogenic transcription factor SREBP1 at active promoters and bridges newly transcribed lipogenic mRNAs from RNA Pol II to an SRSF1/U1-70K-containing splicing machinery, thereby coupling transcription and splicing of lipogenesis enzymes to promote fatty acid synthesis and cell proliferation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, FAM120A knockdown with transcriptomic and splicing analyses, in vitro kinase assays (SRPK2 phosphorylation of SRSF1), RNA stability assays, cell proliferation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, in vitro kinase assay, transcriptomics/splicing analysis, functional proliferation assays) in a single rigorous study","pmids":["37595559"],"is_preprint":false},{"year":2024,"finding":"FAM120A binds SLC7A11 mRNA and enhances its stability, thereby inhibiting ferroptosis; upstream, METTL3-induced m6A modification and YTHDC1-induced stability of FAM120A mRNA regulate FAM120A expression levels. FAM120A deficiency promotes ferroptosis and sensitizes gastric cancer cells to cisplatin.","method":"RNA immunoprecipitation (RIP), mRNA stability assays, m6A methylation assays, FAM120A knockdown with ferroptosis and cisplatin sensitivity readouts, in vivo xenograft experiments","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and mRNA stability assays with functional in vitro and in vivo validation in a single lab","pmids":["38565940"],"is_preprint":false},{"year":2024,"finding":"Increased phosphorylation of FAM120A (C9orf10/Ossa) in a bone-metastatic lung adenocarcinoma subline (H322L-BO4) activates Src family tyrosine kinases and increases anchorage-independent growth; shRNA-mediated reduction of FAM120A reduced bone metastasis and prolonged survival in mice.","method":"Phosphorylation assays, shRNA knockdown, anchorage-independent growth assay, intracardiac injection in vivo metastasis model in nude mice","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo metastasis model combined with phosphorylation and functional assays in a single lab","pmids":["38339971"],"is_preprint":false},{"year":2026,"finding":"FAM120A localizes to stress granules (SGs) via its intrinsically disordered RNA-binding domain, which is required for SG incorporation and cytoprotective function; in cisplatin-resistant NSCLC cells, FAM120A binds and stabilizes the lncRNA MALAT1, and MALAT1 overexpression is sufficient to restore cisplatin resistance upon FAM120A depletion.","method":"Enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq), RNA immunoprecipitation-qPCR, FAM120A domain deletion/mutation analysis, stress granule imaging, FAM120A knockdown with survival and SG formation readouts, MALAT1 overexpression rescue experiments","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — eCLIP-seq, RIP-qPCR, domain mutagenesis, and functional rescue in a single study with multiple orthogonal methods","pmids":["41328536"],"is_preprint":false}],"current_model":"FAM120A is a multifunctional RNA-binding scaffold protein that: (1) couples mTORC1-SRPK2-SRSF1 signaling to co-transcriptional splicing of lipogenic genes by bridging SREBP1 at promoters to the splicing machinery; (2) sequesters Ago2 complexes on poly(G)-containing 3'-UTRs to attenuate miRNA-mediated mRNA silencing; (3) acts as a scaffold downstream of IL13Rα2 and oxidative stress signals to recruit PI3K and activate Src/FAK/AKT survival pathways; (4) stabilizes SLC7A11 mRNA to suppress ferroptosis; (5) localizes to stress granules via its disordered RNA-binding domain where it stabilizes MALAT1 lncRNA to promote chemoresistance."},"narrative":{"mechanistic_narrative":"FAM120A (Ossa/C9orf10) is a multifunctional RNA-binding scaffold protein that couples RNA metabolism to cell survival, growth, and metastatic signaling [PMID:19015244, PMID:31289130]. In its scaffolding role, FAM120A is activated upon oxidative stress (UV) by associating with Src family kinases, becoming tyrosine-phosphorylated, and then recruiting the p85 subunit of PI3-kinase to assemble a Src/PI3K platform that drives Akt antiapoptotic signaling [PMID:19015244]; it performs the analogous function downstream of the IL13Rα2 receptor, bridging PI3K recruitment and Src-mediated activation to engage FAK and the PI3K/AKT/mTOR axis and promote colon cancer invasion and metastasis [PMID:25896327]. Consistent with this pro-metastatic activity, elevated FAM120A phosphorylation activates Src family kinases and supports anchorage-independent growth and bone metastasis [PMID:38339971]. As an RNA-binding protein, FAM120A interacts with Ago2 and binds homopolymeric poly(G) tracts in thousands of 3'-UTRs, shielding those transcripts from Ago2/miRNA-mediated degradation [PMID:31289130], and it stabilizes specific transcripts including SLC7A11 mRNA to suppress ferroptosis and confer cisplatin resistance [PMID:38565940]. FAM120A also acts as a co-activator that bridges SREBP1 at active promoters to an SRSF1/U1-70K splicing machinery downstream of mTORC1-SRPK2 signaling, coupling transcription and splicing of lipogenic genes to fatty acid synthesis and proliferation [PMID:37595559]. Through its intrinsically disordered RNA-binding domain it partitions into stress granules and stabilizes the lncRNA MALAT1 to promote chemoresistance [PMID:41328536].","teleology":[{"year":2008,"claim":"Established FAM120A as a stress-activated signaling scaffold, answering how oxidative stress is coupled to survival signaling.","evidence":"Co-IP, tyrosine phosphorylation assays, and survival readouts in gastric carcinoma cells","pmids":["19015244"],"confidence":"Medium","gaps":["Phosphosite identity on FAM120A not mapped","direct vs indirect SFK association not resolved","mechanism of stress sensing unknown"]},{"year":2008,"claim":"Initial evidence that FAM120A is an RNA-binding protein, linking it to mRNA-protein particles and secretion.","evidence":"RNA-binding assays and IGF-II secretion measurement in cancer cells; Co-IP with Puralpha and immunohistochemistry in mouse brain","pmids":["19015244","18413649"],"confidence":"Low","gaps":["RNA-binding specificity not characterized at this stage","Puralpha interaction lacks functional validation","neuronal role undefined"]},{"year":2015,"claim":"Defined FAM120A as the scaffold that transmits IL13Rα2 receptor signaling to PI3K/FAK/AKT, explaining its pro-metastatic function.","evidence":"Reciprocal Co-IP, siRNA/shRNA silencing, in vitro invasion assays, and in vivo liver colonization in nude mice","pmids":["25896327"],"confidence":"High","gaps":["Structural basis of the IL13Rα2-FAM120A-PI3K assembly not resolved","whether RNA-binding contributes to this scaffolding role unknown"]},{"year":2019,"claim":"Revealed a post-transcriptional function: FAM120A sequesters Ago2 on poly(G) 3'-UTRs to protect transcripts from miRNA silencing.","evidence":"Ago2-IP/MS, transcriptome-wide iCLIP, and 3'-UTR reporter assays in mouse embryonic stem cells","pmids":["31289130"],"confidence":"High","gaps":["How FAM120A blocks Ago2 catalytic activity mechanistically unknown","physiological targets in disease contexts not defined"]},{"year":2023,"claim":"Connected FAM120A to growth signaling by showing it bridges transcription and splicing of lipogenic genes downstream of mTORC1-SRPK2.","evidence":"Co-IP, ChIP, in vitro SRPK2 kinase assays, knockdown transcriptomics/splicing analysis, and proliferation assays","pmids":["37595559"],"confidence":"High","gaps":["Generality beyond lipogenic genes not established","structural detail of the Pol II-FAM120A-spliceosome bridge unknown"]},{"year":2024,"claim":"Linked FAM120A RNA-stabilizing activity to ferroptosis resistance and chemosensitivity via SLC7A11 mRNA, and placed it under m6A control.","evidence":"RIP, mRNA stability and m6A assays, knockdown with ferroptosis/cisplatin readouts, and xenografts in gastric cancer","pmids":["38565940"],"confidence":"Medium","gaps":["Direct binding site on SLC7A11 mRNA not mapped","whether the poly(G)/Ago2 mechanism underlies this stabilization untested"]},{"year":2024,"claim":"Reinforced the phospho-FAM120A/Src axis as a driver of metastasis in lung adenocarcinoma.","evidence":"Phosphorylation assays, shRNA knockdown, anchorage-independent growth, and intracardiac metastasis model in nude mice","pmids":["38339971"],"confidence":"Medium","gaps":["Phosphorylation sites driving the effect not identified","upstream kinase/trigger in this context unclear"]},{"year":2026,"claim":"Identified the disordered RNA-binding domain as the determinant of stress-granule localization and showed MALAT1 stabilization mediates chemoresistance.","evidence":"eCLIP-seq, RIP-qPCR, domain mutagenesis, stress granule imaging, and MALAT1 overexpression rescue in cisplatin-resistant NSCLC","pmids":["41328536"],"confidence":"Medium","gaps":["Mechanism by which MALAT1 confers resistance not detailed","relationship between SG partitioning and RNA stabilization unresolved"]},{"year":null,"claim":"How FAM120A's distinct scaffolding (PI3K/Src) and RNA-binding (Ago2, mRNA stabilization, splicing) activities are coordinated within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating signaling and RNA-binding domains","domain dependencies across functions not systematically dissected","regulatory switch between activities unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,4,6,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6]}],"complexes":["stress granule","Puralpha-mRNP"],"partners":["AGO2","PIK3R1","IL13RA2","SRSF1","SREBF1","PURA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZB2","full_name":"Constitutive coactivator of PPAR-gamma-like protein 1","aliases":["Oxidative stress-associated SRC activator","Protein FAM120A"],"length_aa":1118,"mass_kda":121.9,"function":"Component of the oxidative stress-induced survival signaling. May regulate the activation of SRC family protein kinases (PubMed:19015244). May act as a scaffolding protein enabling SRC family protein kinases to phosphorylate and activate PI3-kinase (PubMed:19015244). Binds IGF2 RNA and promotes the production of IGF2 protein (PubMed:19015244)","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NZB2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM120A","classification":"Not Classified","n_dependent_lines":59,"n_total_lines":1208,"dependency_fraction":0.048841059602649006},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000048828","cell_line_id":"CID001512","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"UPF1","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"HNRNPA2B1","stoichiometry":0.2},{"gene":"HNRNPC","stoichiometry":0.2},{"gene":"HNRNPD","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001512","total_profiled":1310},"omim":[{"mim_id":"612265","title":"FAMILY WITH SEQUENCE SIMILARITY 120, MEMBER A; FAM120A","url":"https://www.omim.org/entry/612265"},{"mim_id":"300741","title":"FAMILY WITH SEQUENCE SIMILARITY 120, MEMBER C; FAM120C","url":"https://www.omim.org/entry/300741"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM120A"},"hgnc":{"alias_symbol":["KIAA0183","OSSA"],"prev_symbol":["C9orf10"]},"alphafold":{"accession":"Q9NZB2","domains":[{"cath_id":"3.40.50.1010","chopping":"5-226","consensus_level":"high","plddt":89.2157,"start":5,"end":226},{"cath_id":"-","chopping":"239-337","consensus_level":"medium","plddt":84.7088,"start":239,"end":337},{"cath_id":"-","chopping":"552-842","consensus_level":"medium","plddt":92.8001,"start":552,"end":842}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZB2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZB2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZB2-F1-predicted_aligned_error_v6.png","plddt_mean":67.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM120A","jax_strain_url":"https://www.jax.org/strain/search?query=FAM120A"},"sequence":{"accession":"Q9NZB2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZB2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZB2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZB2"}},"corpus_meta":[{"pmid":"25896327","id":"PMC_25896327","title":"IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25896327","citation_count":81,"is_preprint":false},{"pmid":"19015244","id":"PMC_19015244","title":"A novel RNA-binding protein, Ossa/C9orf10, regulates activity of Src kinases to protect cells from oxidative stress-induced apoptosis.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19015244","citation_count":43,"is_preprint":false},{"pmid":"34423389","id":"PMC_34423389","title":"Paeoniflorin Suppresses Rheumatoid Arthritis Development via Modulating the Circ-FAM120A/miR-671-5p/MDM4 Axis.","date":"2021","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/34423389","citation_count":38,"is_preprint":false},{"pmid":"37595559","id":"PMC_37595559","title":"FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37595559","citation_count":28,"is_preprint":false},{"pmid":"31289130","id":"PMC_31289130","title":"Sequestration of microRNA-mediated target repression by the Ago2-associated RNA-binding protein FAM120A.","date":"2019","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31289130","citation_count":26,"is_preprint":false},{"pmid":"38565940","id":"PMC_38565940","title":"FAM120A deficiency improves resistance to cisplatin in gastric cancer by promoting ferroptosis.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/38565940","citation_count":20,"is_preprint":false},{"pmid":"18413649","id":"PMC_18413649","title":"C9orf10 protein, a novel protein component of Puralpha-containing mRNA-protein particles (Puralpha-mRNPs): characterization of developmental and regional expressions in the mouse brain.","date":"2008","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/18413649","citation_count":12,"is_preprint":false},{"pmid":"22575460","id":"PMC_22575460","title":"Influence of BONITmatrix(®) and OSSA NOVA on the expression of bone specific genes.","date":"2012","source":"Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft","url":"https://pubmed.ncbi.nlm.nih.gov/22575460","citation_count":6,"is_preprint":false},{"pmid":"38339971","id":"PMC_38339971","title":"C9orf10/Ossa regulates the bone metastasis of established lung adenocarcinoma cell subline H322L-BO4 in a mouse model.","date":"2024","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/38339971","citation_count":2,"is_preprint":false},{"pmid":"41328536","id":"PMC_41328536","title":"A stress granule-associated RNA-binding protein FAM120A drives cisplatin resistance in non-small cell lung cancer.","date":"2026","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41328536","citation_count":0,"is_preprint":false},{"pmid":"41667820","id":"PMC_41667820","title":"FAM120A - a protein inserted in the ALS disease network.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41667820","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7213,"output_tokens":2573,"usd":0.030117,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9776,"output_tokens":2997,"usd":0.061902,"stage2_stop_reason":"end_turn"},"total_usd":0.092019,"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\": 2008,\n      \"finding\": \"FAM120A (Ossa/C9orf10) is an RNA-binding protein that, upon oxidative stress (UV irradiation), associates with regulatory domains of Src family kinases (SFKs) to activate them; activated SFKs then phosphorylate FAM120A on tyrosine residues, and tyrosine-phosphorylated FAM120A recruits the p85 subunit of PI3-kinase to act as a scaffold for PI3K and SFKs, activating the Akt antiapoptotic pathway.\",\n      \"method\": \"Co-immunoprecipitation, tyrosine phosphorylation assays, identification of p85 recruitment, functional survival assays in gastric carcinoma cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional assays in a single lab with multiple orthogonal methods (phosphorylation assay, p85 recruitment, survival readout)\",\n      \"pmids\": [\"19015244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FAM120A (C9orf10) directly binds RNAs including IGF-II mRNA via its C-terminal domain and promotes extracellular secretion of IGF-II protein.\",\n      \"method\": \"RNA-binding assays, IGF-II secretion measurement in cancer cells with FAM120A manipulations\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method described in abstract without detailed controls reported\",\n      \"pmids\": [\"19015244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FAM120A (C9orf10) is a component of Puralpha-containing mRNA–protein particles (Puralpha-mRNPs) in neurons, co-immunoprecipitating with Puralpha; expression is restricted to neurons and shows distinct regional/developmental patterns in mouse brain compared to Puralpha.\",\n      \"method\": \"Co-immunoprecipitation, immunohistochemistry with neuron-specific markers, developmental Western blotting in mouse brain\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identification in a characterization study; no functional validation of the interaction\",\n      \"pmids\": [\"18413649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FAM120A acts as a scaffold protein in the IL13Rα2 signaling pathway: it co-immunoprecipitates with IL13Rα2 and recruits PI3K, enabling Src family kinase-mediated phosphorylation and activation of PI3K, thereby mediating IL13Rα2-triggered activation of FAK and the PI3K/AKT/mTOR pathways to drive colon cancer invasion and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, FAM120A silencing (siRNA/shRNA), in vitro migration/invasion assays, in vivo liver colonization assay in nude mice, pathway activation (phospho-FAK, phospho-AKT readouts)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro functional assays, and in vivo metastasis model with multiple orthogonal readouts in a single focused study\",\n      \"pmids\": [\"25896327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM120A interacts with Ago2 in the cytoplasm and binds homopolymeric poly(G) sequences in 3'-UTRs of ~2000 mRNAs (identified by iCLIP); FAM120A-bound Ago2 target mRNAs are not subject to Ago2-mediated degradation, indicating FAM120A sequesters Ago2 complexes to attenuate miRNA-mediated target repression.\",\n      \"method\": \"Immunoprecipitation followed by mass spectrometry (Ago2-IP/MS), individual nucleotide resolution cross-linking and immunoprecipitation (iCLIP), reporter assays with 3'-UTR constructs in mouse embryonic stem cells\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — iCLIP (transcriptome-wide), Ago2 co-IP/MS, and reporter assays providing multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31289130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM120A functions as a transcription co-activator downstream of mTORC1-SRPK2 signaling: mTORC1-activated SRPK2 phosphorylates SRSF1, enhancing SRSF1 binding to FAM120A; FAM120A directly interacts with lipogenic transcription factor SREBP1 at active promoters and bridges newly transcribed lipogenic mRNAs from RNA Pol II to an SRSF1/U1-70K-containing splicing machinery, thereby coupling transcription and splicing of lipogenesis enzymes to promote fatty acid synthesis and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, FAM120A knockdown with transcriptomic and splicing analyses, in vitro kinase assays (SRPK2 phosphorylation of SRSF1), RNA stability assays, cell proliferation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, in vitro kinase assay, transcriptomics/splicing analysis, functional proliferation assays) in a single rigorous study\",\n      \"pmids\": [\"37595559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM120A binds SLC7A11 mRNA and enhances its stability, thereby inhibiting ferroptosis; upstream, METTL3-induced m6A modification and YTHDC1-induced stability of FAM120A mRNA regulate FAM120A expression levels. FAM120A deficiency promotes ferroptosis and sensitizes gastric cancer cells to cisplatin.\",\n      \"method\": \"RNA immunoprecipitation (RIP), mRNA stability assays, m6A methylation assays, FAM120A knockdown with ferroptosis and cisplatin sensitivity readouts, in vivo xenograft experiments\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and mRNA stability assays with functional in vitro and in vivo validation in a single lab\",\n      \"pmids\": [\"38565940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Increased phosphorylation of FAM120A (C9orf10/Ossa) in a bone-metastatic lung adenocarcinoma subline (H322L-BO4) activates Src family tyrosine kinases and increases anchorage-independent growth; shRNA-mediated reduction of FAM120A reduced bone metastasis and prolonged survival in mice.\",\n      \"method\": \"Phosphorylation assays, shRNA knockdown, anchorage-independent growth assay, intracardiac injection in vivo metastasis model in nude mice\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo metastasis model combined with phosphorylation and functional assays in a single lab\",\n      \"pmids\": [\"38339971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FAM120A localizes to stress granules (SGs) via its intrinsically disordered RNA-binding domain, which is required for SG incorporation and cytoprotective function; in cisplatin-resistant NSCLC cells, FAM120A binds and stabilizes the lncRNA MALAT1, and MALAT1 overexpression is sufficient to restore cisplatin resistance upon FAM120A depletion.\",\n      \"method\": \"Enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq), RNA immunoprecipitation-qPCR, FAM120A domain deletion/mutation analysis, stress granule imaging, FAM120A knockdown with survival and SG formation readouts, MALAT1 overexpression rescue experiments\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — eCLIP-seq, RIP-qPCR, domain mutagenesis, and functional rescue in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"41328536\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM120A is a multifunctional RNA-binding scaffold protein that: (1) couples mTORC1-SRPK2-SRSF1 signaling to co-transcriptional splicing of lipogenic genes by bridging SREBP1 at promoters to the splicing machinery; (2) sequesters Ago2 complexes on poly(G)-containing 3'-UTRs to attenuate miRNA-mediated mRNA silencing; (3) acts as a scaffold downstream of IL13Rα2 and oxidative stress signals to recruit PI3K and activate Src/FAK/AKT survival pathways; (4) stabilizes SLC7A11 mRNA to suppress ferroptosis; (5) localizes to stress granules via its disordered RNA-binding domain where it stabilizes MALAT1 lncRNA to promote chemoresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM120A (Ossa/C9orf10) is a multifunctional RNA-binding scaffold protein that couples RNA metabolism to cell survival, growth, and metastatic signaling [#0, #4]. In its scaffolding role, FAM120A is activated upon oxidative stress (UV) by associating with Src family kinases, becoming tyrosine-phosphorylated, and then recruiting the p85 subunit of PI3-kinase to assemble a Src/PI3K platform that drives Akt antiapoptotic signaling [#0]; it performs the analogous function downstream of the IL13Rα2 receptor, bridging PI3K recruitment and Src-mediated activation to engage FAK and the PI3K/AKT/mTOR axis and promote colon cancer invasion and metastasis [#3]. Consistent with this pro-metastatic activity, elevated FAM120A phosphorylation activates Src family kinases and supports anchorage-independent growth and bone metastasis [#7]. As an RNA-binding protein, FAM120A interacts with Ago2 and binds homopolymeric poly(G) tracts in thousands of 3'-UTRs, shielding those transcripts from Ago2/miRNA-mediated degradation [#4], and it stabilizes specific transcripts including SLC7A11 mRNA to suppress ferroptosis and confer cisplatin resistance [#6]. FAM120A also acts as a co-activator that bridges SREBP1 at active promoters to an SRSF1/U1-70K splicing machinery downstream of mTORC1-SRPK2 signaling, coupling transcription and splicing of lipogenic genes to fatty acid synthesis and proliferation [#5]. Through its intrinsically disordered RNA-binding domain it partitions into stress granules and stabilizes the lncRNA MALAT1 to promote chemoresistance [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established FAM120A as a stress-activated signaling scaffold, answering how oxidative stress is coupled to survival signaling.\",\n      \"evidence\": \"Co-IP, tyrosine phosphorylation assays, and survival readouts in gastric carcinoma cells\",\n      \"pmids\": [\"19015244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite identity on FAM120A not mapped\", \"direct vs indirect SFK association not resolved\", \"mechanism of stress sensing unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Initial evidence that FAM120A is an RNA-binding protein, linking it to mRNA-protein particles and secretion.\",\n      \"evidence\": \"RNA-binding assays and IGF-II secretion measurement in cancer cells; Co-IP with Puralpha and immunohistochemistry in mouse brain\",\n      \"pmids\": [\"19015244\", \"18413649\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"RNA-binding specificity not characterized at this stage\", \"Puralpha interaction lacks functional validation\", \"neuronal role undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined FAM120A as the scaffold that transmits IL13Rα2 receptor signaling to PI3K/FAK/AKT, explaining its pro-metastatic function.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA/shRNA silencing, in vitro invasion assays, and in vivo liver colonization in nude mice\",\n      \"pmids\": [\"25896327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the IL13Rα2-FAM120A-PI3K assembly not resolved\", \"whether RNA-binding contributes to this scaffolding role unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a post-transcriptional function: FAM120A sequesters Ago2 on poly(G) 3'-UTRs to protect transcripts from miRNA silencing.\",\n      \"evidence\": \"Ago2-IP/MS, transcriptome-wide iCLIP, and 3'-UTR reporter assays in mouse embryonic stem cells\",\n      \"pmids\": [\"31289130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FAM120A blocks Ago2 catalytic activity mechanistically unknown\", \"physiological targets in disease contexts not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected FAM120A to growth signaling by showing it bridges transcription and splicing of lipogenic genes downstream of mTORC1-SRPK2.\",\n      \"evidence\": \"Co-IP, ChIP, in vitro SRPK2 kinase assays, knockdown transcriptomics/splicing analysis, and proliferation assays\",\n      \"pmids\": [\"37595559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality beyond lipogenic genes not established\", \"structural detail of the Pol II-FAM120A-spliceosome bridge unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked FAM120A RNA-stabilizing activity to ferroptosis resistance and chemosensitivity via SLC7A11 mRNA, and placed it under m6A control.\",\n      \"evidence\": \"RIP, mRNA stability and m6A assays, knockdown with ferroptosis/cisplatin readouts, and xenografts in gastric cancer\",\n      \"pmids\": [\"38565940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding site on SLC7A11 mRNA not mapped\", \"whether the poly(G)/Ago2 mechanism underlies this stabilization untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reinforced the phospho-FAM120A/Src axis as a driver of metastasis in lung adenocarcinoma.\",\n      \"evidence\": \"Phosphorylation assays, shRNA knockdown, anchorage-independent growth, and intracardiac metastasis model in nude mice\",\n      \"pmids\": [\"38339971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation sites driving the effect not identified\", \"upstream kinase/trigger in this context unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified the disordered RNA-binding domain as the determinant of stress-granule localization and showed MALAT1 stabilization mediates chemoresistance.\",\n      \"evidence\": \"eCLIP-seq, RIP-qPCR, domain mutagenesis, stress granule imaging, and MALAT1 overexpression rescue in cisplatin-resistant NSCLC\",\n      \"pmids\": [\"41328536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MALAT1 confers resistance not detailed\", \"relationship between SG partitioning and RNA stabilization unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FAM120A's distinct scaffolding (PI3K/Src) and RNA-binding (Ago2, mRNA stabilization, splicing) activities are coordinated within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating signaling and RNA-binding domains\", \"domain dependencies across functions not systematically dissected\", \"regulatory switch between activities unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 4, 6, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"stress granule\", \"Puralpha-mRNP\"],\n    \"partners\": [\"AGO2\", \"PIK3R1\", \"IL13RA2\", \"SRSF1\", \"SREBF1\", \"PURA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}