{"gene":"FAM135B","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2014,"finding":"FAM135B was identified as a novel cancer-implicated gene with the ability to promote malignancy of esophageal squamous cell carcinoma (ESCC) cells, based on functional assays in ESCC cell lines.","method":"Functional malignancy assays in ESCC cells following identification by whole-genome and whole-exome sequencing","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional assays in cells with defined phenotypic readout, but limited mechanistic detail in abstract; single study","pmids":["24670651"],"is_preprint":false},{"year":2020,"finding":"FAM135B directly interacts with growth factor GRN (progranulin), forming a feedforward loop with AKT/mTOR signaling to promote ESCC cell proliferation in vitro and in vivo. FAM135B transgenic mice showed heavier tumor burden and higher serum GRN levels compared to wild-type mice after carcinogen treatment.","method":"Co-immunoprecipitation (direct interaction with GRN), ectopic expression and transgenic mouse model, western blot for AKT/mTOR pathway components, xenograft tumor assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown by Co-IP, supported by in vivo transgenic model and in vitro proliferation assays; single lab","pmids":["33323378"],"is_preprint":false},{"year":2020,"finding":"Silencing FAM135B in ESCC cells inhibits colony formation, promotes G2/M cell cycle arrest following irradiation, and increases radiosensitivity. Transcriptome sequencing and western blot demonstrated that FAM135B regulates the downstream PI3K/Akt/mTOR signaling pathway. Silencing FAM135B showed synergy with the mTOR inhibitor rapamycin in increasing radiosensitivity and inducing apoptosis.","method":"siRNA knockdown, colony formation assay, flow cytometry (cell cycle), transcriptome sequencing, western blot for PI3K/Akt/mTOR pathway, pharmacological inhibitor (rapamycin) combination","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts (cell cycle, colony formation, pathway western blot, synergy with inhibitor); single lab","pmids":["33340561"],"is_preprint":false},{"year":2022,"finding":"FAM135B physically binds to the chromodomain of TIP60 (KAT5) histone acetyltransferase, enhances its histone acetyltransferase activity, and promotes the assembly of the TIP60-ATM complex under resting conditions. Upon DNA damage, FAM135B is released from TIP60, and the pre-assembled TIP60-ATM complex participates in DNA damage response (DDR). FAM135B promotes both homologous recombination and non-homologous end-joining repair, and its overexpression accelerates clearance of γH2AX and 53BP1 foci, while its elimination attenuates these effects.","method":"Co-immunoprecipitation, proximity ligation assay, GST pull-down, immunofluorescence (γH2AX/53BP1 foci), flow cytometry, comet assay, xenograft tumor model, FAM135B transgenic mouse model, immunohistochemistry","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal binding methods (Co-IP, PLA, GST pull-down), direct enzymatic activity enhancement shown, in vitro and in vivo validation; single lab but rigorous multi-method approach","pmids":["35979619"],"is_preprint":false},{"year":2018,"finding":"FAM135B knockdown in wild-type spinal motor neurons (sMNs) reduced their survival and contributed to neurite defects, similar to phenotypes observed in SBMA patient-derived sMNs, indicating a functional role of FAM135B in motor neuron survival and neurite integrity. FAM135B was found to be drastically downregulated in SBMA sMNs by microarray analysis.","method":"siRNA knockdown in iPSC-derived spinal motor neurons, cell survival assay, neurite morphology analysis, microarray gene expression profiling","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined cellular phenotype (survival, neurite defects) in relevant cell type; single lab, single study","pmids":["30391288"],"is_preprint":false},{"year":2024,"finding":"FAM135B promotes ESCC migration, invasion, and EMT by interacting with the intermediate domain of TRAF2 and NCK-interacting kinase (TNIK), thereby activating the Wnt/β-catenin signaling pathway. FAM135B siRNA reversed the pro-migration/invasion effect of TNIK. Additionally, METTL3-mediated N6-methyladenosine (m6A) modification positively regulates FAM135B expression, with METTL3 acting as its m6A writer; METTL3 pro-EMT effects were reversed by FAM135B silencing.","method":"Co-immunoprecipitation (FAM135B-TNIK interaction), siRNA knockdown (FAM135B, METTL3), overexpression, in vitro migration/invasion assays, in vivo lung metastasis model, western blot (EMT markers, β-catenin pathway), m6A modification analysis","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction shown by Co-IP, genetic epistasis (FAM135B siRNA reverses TNIK/METTL3 effects), in vivo validation; single lab","pmids":["38881420"],"is_preprint":false},{"year":2024,"finding":"FAM135B promotes nuclear translocation of SRSF1 by synergistically binding with SRPK1, and regulates SRSF1-mediated alternative splicing of DNA repair genes. Specifically, FAM135B-induced exon IV inclusion of FAAP20 mediates its binding with FANCA and enhances the functional integrity of the FA core complex, activating the Fanconi Anemia (FA) pathway and leading to inter-strand crosslink (ICL) lesion repair and oxaliplatin insensitivity in colorectal cancer cells.","method":"Functional binding/interaction assays (FAM135B-SRPK1-SRSF1 complex), alternative splicing analysis, FAAP20 exon inclusion assay, FA pathway activation assay, chemosensitivity assays (oxaliplatin/L-OHP)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined molecular mechanism (splicing regulation via SRPK1/SRSF1 axis, FA pathway activation), multiple mechanistic steps validated; single lab","pmids":["39397154"],"is_preprint":false},{"year":2018,"finding":"Strong expression of FAM135B in ESCC tissues showed a significant negative correlation with KAT5 (TIP60) expression in Uygur ESCC patients, suggesting FAM135B may play its oncogenic role by negatively regulating KAT5 expression.","method":"Immunohistochemistry on 40 paired ESCC and adjacent tissues; correlation analysis (Kendall's coefficient)","journal":"Nan fang yi ke da xue xue bao","confidence":"Low","confidence_rationale":"Tier 3 / Weak — observational correlation by IHC only, no functional validation of the negative regulatory relationship; single study","pmids":["29502064"],"is_preprint":false},{"year":2026,"finding":"FAM135B interacts with IFI16, inhibiting its ubiquitination and proteasomal degradation by competitively blocking IFI16 binding to the E3 ubiquitin ligase TRIM21. This stabilizes IFI16 at lysines 143 and 561 (deubiquitination sites), initiating IFI16-dependent STING signaling and increasing cytotoxic T-cell activity in triple-negative breast cancer.","method":"Co-immunoprecipitation (FAM135B-IFI16 interaction), competitive binding assay (FAM135B vs TRIM21 for IFI16), ubiquitination assay, site-directed mutagenesis (K143, K561), STING pathway activation assays, single-cell sequencing, functional T-cell cytotoxicity assays","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined molecular mechanism with multiple orthogonal methods (Co-IP, ubiquitination assay, mutagenesis); single lab, recently published","pmids":["41218197"],"is_preprint":false},{"year":2026,"finding":"FAM135B binds to the IKK complex (IKKα/IKKβ) to stabilize it, inhibit IKKβ activation and P65 phosphorylation, and block the canonical NF-κB signaling pathway, thereby downregulating IL-6 expression and inhibiting JAK/STAT-mediated angiogenesis in glioblastoma. HNF4A was identified as an upstream transcription factor that directly binds to the FAM135B promoter to drive its expression.","method":"Co-immunoprecipitation and mass spectrometry (FAM135B-IKK complex), western blot (IKKβ, P65 phosphorylation), ELISA (IL-6), dual-luciferase reporter assay (HNF4A-FAM135B promoter), rescue experiments with NF-κB inhibitor PDTC and recombinant IL-6, orthotopic and subcutaneous xenograft models, tube formation and Transwell migration assays, immunohistochemistry","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP/MS, reporter assay, rescue experiments, in vivo models); mechanistically detailed; single lab","pmids":["42260484"],"is_preprint":false}],"current_model":"FAM135B is a multifunctional cancer-related protein that promotes cell survival, proliferation, and DNA damage repair by (1) directly binding GRN to activate an AKT/mTOR feedforward loop, (2) sustaining pre-assembled TIP60-ATM complexes to facilitate DNA damage response via both HR and NHEJ, (3) promoting nuclear SRSF1 translocation via SRPK1 to modulate alternative splicing of FA pathway components and drive chemoresistance, (4) interacting with TNIK to activate Wnt/β-catenin signaling and drive EMT, (5) stabilizing IFI16 against TRIM21-mediated ubiquitination to activate the STING innate immune pathway, and (6) binding and stabilizing the IKK complex to suppress NF-κB/IL-6-driven angiogenesis; its expression is positively regulated upstream by METTL3-mediated m6A modification and HNF4A-driven transcription."},"narrative":{"mechanistic_narrative":"FAM135B is a cancer-associated, multifunctional scaffold protein that promotes tumor cell survival, proliferation, and DNA damage repair, first identified through whole-genome/exome sequencing as a gene capable of driving malignancy in esophageal squamous cell carcinoma (ESCC) [PMID:24670651]. It acts largely through direct protein-protein interactions that reconfigure signaling and repair complexes: it binds the growth factor GRN (progranulin) to engage a feedforward AKT/mTOR loop that sustains proliferation, with loss of FAM135B increasing radiosensitivity and synergizing with mTOR inhibition [PMID:33323378, PMID:33340561]. In the DNA damage response, FAM135B binds the chromodomain of the TIP60 (KAT5) acetyltransferase, enhances its activity, and maintains pre-assembled TIP60-ATM complexes under resting conditions; upon damage it is released, and it promotes both homologous recombination and non-homologous end-joining, accelerating clearance of γH2AX and 53BP1 foci [PMID:35979619]. FAM135B further controls genome-maintenance gene expression by synergizing with SRPK1 to drive nuclear SRSF1 translocation, directing alternative splicing of FAAP20 to activate the Fanconi Anemia pathway and confer chemoresistance [PMID:39397154]. Additional interactions tie FAM135B to migration and immune/inflammatory signaling: it binds TNIK to activate Wnt/β-catenin signaling and EMT [PMID:38881420], stabilizes IFI16 by competitively blocking TRIM21-mediated ubiquitination to initiate STING signaling [PMID:41218197], and binds the IKK complex to suppress NF-κB/IL-6-driven angiogenesis [PMID:42260484]. Its expression is positively controlled upstream by METTL3-mediated m6A modification [PMID:38881420] and HNF4A-driven transcription [PMID:42260484]. A distinct role in neuronal biology is indicated by the requirement of FAM135B for survival and neurite integrity of spinal motor neurons [PMID:30391288].","teleology":[{"year":2014,"claim":"Established FAM135B as a previously uncharacterized gene with oncogenic capacity, motivating mechanistic dissection of how it promotes malignancy.","evidence":"Whole-genome/whole-exome sequencing followed by functional malignancy assays in ESCC cell lines","pmids":["24670651"],"confidence":"Medium","gaps":["No molecular mechanism or interaction partner identified","Driver versus passenger role not resolved"]},{"year":2018,"claim":"Revealed a non-cancer role by showing FAM135B is required for motor neuron survival and neurite integrity, broadening its functional scope beyond tumor biology.","evidence":"siRNA knockdown in iPSC-derived spinal motor neurons with survival and neurite morphology readouts; microarray profiling of SBMA neurons","pmids":["30391288"],"confidence":"Medium","gaps":["Molecular pathway underlying neuronal survival role unknown","No mechanistic link to the cancer functions established"]},{"year":2018,"claim":"Provided the first hint of a functional relationship between FAM135B and KAT5/TIP60, via an inverse expression correlation in patient tissue.","evidence":"Immunohistochemistry on paired ESCC and adjacent tissues with correlation analysis","pmids":["29502064"],"confidence":"Low","gaps":["Observational correlation only, no functional validation of regulation","Direction and mechanism of the FAM135B-KAT5 relationship unresolved"]},{"year":2020,"claim":"Defined the first direct molecular partner and signaling axis, showing FAM135B binds GRN to drive an AKT/mTOR feedforward loop promoting proliferation.","evidence":"Co-IP for GRN binding, transgenic mouse and xenograft models, western blot of AKT/mTOR components","pmids":["33323378","33340561"],"confidence":"Medium","gaps":["Structural basis of FAM135B-GRN binding unknown","How FAM135B couples GRN to AKT/mTOR mechanistically not resolved","Single lab"]},{"year":2022,"claim":"Mechanistically embedded FAM135B in the DNA damage response by showing it sustains pre-assembled TIP60-ATM complexes and promotes both HR and NHEJ repair.","evidence":"Co-IP, PLA, GST pull-down, acetyltransferase activity assay, γH2AX/53BP1 foci imaging, comet assay, transgenic and xenograft models","pmids":["35979619"],"confidence":"High","gaps":["Trigger and mechanism for damage-induced release of FAM135B from TIP60 not defined","How a single factor promotes both HR and NHEJ unresolved"]},{"year":2024,"claim":"Extended FAM135B function to invasion/EMT through TNIK-Wnt/β-catenin signaling and identified METTL3/m6A as an upstream activator of its expression.","evidence":"Co-IP for TNIK, siRNA epistasis, migration/invasion and lung metastasis assays, m6A modification analysis","pmids":["38881420"],"confidence":"Medium","gaps":["How FAM135B-TNIK binding activates Wnt signaling mechanistically unclear","m6A site(s) on FAM135B transcript not mapped"]},{"year":2024,"claim":"Connected FAM135B to splicing control of DNA repair, showing it drives nuclear SRSF1 translocation via SRPK1 to alter FAAP20 splicing and activate the FA pathway, conferring chemoresistance.","evidence":"Interaction assays for FAM135B-SRPK1-SRSF1, exon-inclusion and FA pathway activation assays, oxaliplatin chemosensitivity assays in colorectal cancer cells","pmids":["39397154"],"confidence":"Medium","gaps":["Direct versus indirect nature of FAM135B-SRPK1 interaction not fully resolved","Whether this splicing role operates outside colorectal cancer untested"]},{"year":2026,"claim":"Identified FAM135B as a positive regulator of innate immune signaling by stabilizing IFI16 against TRIM21-mediated degradation to activate STING.","evidence":"Co-IP, competitive binding assay, ubiquitination assay, site-directed mutagenesis (K143/K561), STING activation and T-cell cytotoxicity assays in triple-negative breast cancer","pmids":["41218197"],"confidence":"Medium","gaps":["Structural basis of FAM135B-IFI16 versus TRIM21-IFI16 competition not defined","Single lab, recently published"]},{"year":2026,"claim":"Showed FAM135B suppresses NF-κB/IL-6-driven angiogenesis by stabilizing and inhibiting the IKK complex, and identified HNF4A as a direct transcriptional driver of FAM135B.","evidence":"Co-IP/MS for IKK complex, western blot of IKKβ/P65, IL-6 ELISA, dual-luciferase HNF4A promoter assay, rescue experiments, orthotopic/subcutaneous xenografts in glioblastoma","pmids":["42260484"],"confidence":"Medium","gaps":["Mechanism by which binding both stabilizes and inhibits IKK is unresolved","Reconciliation of this anti-NF-κB role with pro-tumor roles in other contexts unclear"]},{"year":null,"claim":"It remains unknown whether FAM135B's many context-specific interactions reflect a single unifying biochemical activity (e.g., a generic scaffold) or independent functions, and no structural or domain-level model explains its partner selectivity.","evidence":"No structural or unifying biochemical study present in the corpus","pmids":[],"confidence":"Low","gaps":["No structural model of FAM135B","No defined catalytic or enzymatic activity","Partner-selectivity determinants unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,8,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,9]}],"complexes":[],"partners":["GRN","KAT5","ATM","TNIK","SRPK1","SRSF1","IFI16","IKBKB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q49AJ0","full_name":"Protein FAM135B","aliases":[],"length_aa":1406,"mass_kda":155.8,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q49AJ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM135B","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FAM135B","total_profiled":1310},"omim":[{"mim_id":"621534","title":"FAMILY WITH SEQUENCE SIMILARITY 135, MEMBER B; FAM135B","url":"https://www.omim.org/entry/621534"},{"mim_id":"619928","title":"PHD FINGER PROTEIN 24; PHF24","url":"https://www.omim.org/entry/619928"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear membrane","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adrenal gland","ntpm":2.5},{"tissue":"brain","ntpm":6.6},{"tissue":"retina","ntpm":9.1},{"tissue":"testis","ntpm":3.6}],"url":"https://www.proteinatlas.org/search/FAM135B"},"hgnc":{"alias_symbol":["C8ORFK32"],"prev_symbol":[]},"alphafold":{"accession":"Q49AJ0","domains":[{"cath_id":"2.60.40.150","chopping":"2-182","consensus_level":"medium","plddt":87.1199,"start":2,"end":182},{"cath_id":"-","chopping":"229-328","consensus_level":"medium","plddt":90.2652,"start":229,"end":328},{"cath_id":"3.40.50","chopping":"342-420_1120-1128_1141-1400","consensus_level":"medium","plddt":91.7066,"start":342,"end":1400}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q49AJ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q49AJ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q49AJ0-F1-predicted_aligned_error_v6.png","plddt_mean":60.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM135B","jax_strain_url":"https://www.jax.org/strain/search?query=FAM135B"},"sequence":{"accession":"Q49AJ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q49AJ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q49AJ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q49AJ0"}},"corpus_meta":[{"pmid":"24670651","id":"PMC_24670651","title":"Identification of genomic alterations in oesophageal squamous cell cancer.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/24670651","citation_count":908,"is_preprint":false},{"pmid":"29927694","id":"PMC_29927694","title":"DNA methylation biomarkers for head and neck squamous cell carcinoma.","date":"2018","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29927694","citation_count":68,"is_preprint":false},{"pmid":"31199602","id":"PMC_31199602","title":"Comprehensive genomic profiling of small cell lung cancer in Chinese patients and the implications for therapeutic potential.","date":"2019","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31199602","citation_count":51,"is_preprint":false},{"pmid":"34746153","id":"PMC_34746153","title":"Titin Mutation Is Associated With Tumor Mutation Burden and Promotes Antitumor Immunity in Lung Squamous Cell Carcinoma.","date":"2021","source":"Frontiers in cell and developmental 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research","url":"https://pubmed.ncbi.nlm.nih.gov/40490927","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18756,"output_tokens":3095,"usd":0.051347,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10522,"output_tokens":3365,"usd":0.068367,"stage2_stop_reason":"end_turn"},"total_usd":0.119714,"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\": 2014,\n      \"finding\": \"FAM135B was identified as a novel cancer-implicated gene with the ability to promote malignancy of esophageal squamous cell carcinoma (ESCC) cells, based on functional assays in ESCC cell lines.\",\n      \"method\": \"Functional malignancy assays in ESCC cells following identification by whole-genome and whole-exome sequencing\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional assays in cells with defined phenotypic readout, but limited mechanistic detail in abstract; single study\",\n      \"pmids\": [\"24670651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM135B directly interacts with growth factor GRN (progranulin), forming a feedforward loop with AKT/mTOR signaling to promote ESCC cell proliferation in vitro and in vivo. FAM135B transgenic mice showed heavier tumor burden and higher serum GRN levels compared to wild-type mice after carcinogen treatment.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction with GRN), ectopic expression and transgenic mouse model, western blot for AKT/mTOR pathway components, xenograft tumor assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown by Co-IP, supported by in vivo transgenic model and in vitro proliferation assays; single lab\",\n      \"pmids\": [\"33323378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Silencing FAM135B in ESCC cells inhibits colony formation, promotes G2/M cell cycle arrest following irradiation, and increases radiosensitivity. Transcriptome sequencing and western blot demonstrated that FAM135B regulates the downstream PI3K/Akt/mTOR signaling pathway. Silencing FAM135B showed synergy with the mTOR inhibitor rapamycin in increasing radiosensitivity and inducing apoptosis.\",\n      \"method\": \"siRNA knockdown, colony formation assay, flow cytometry (cell cycle), transcriptome sequencing, western blot for PI3K/Akt/mTOR pathway, pharmacological inhibitor (rapamycin) combination\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts (cell cycle, colony formation, pathway western blot, synergy with inhibitor); single lab\",\n      \"pmids\": [\"33340561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM135B physically binds to the chromodomain of TIP60 (KAT5) histone acetyltransferase, enhances its histone acetyltransferase activity, and promotes the assembly of the TIP60-ATM complex under resting conditions. Upon DNA damage, FAM135B is released from TIP60, and the pre-assembled TIP60-ATM complex participates in DNA damage response (DDR). FAM135B promotes both homologous recombination and non-homologous end-joining repair, and its overexpression accelerates clearance of γH2AX and 53BP1 foci, while its elimination attenuates these effects.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, GST pull-down, immunofluorescence (γH2AX/53BP1 foci), flow cytometry, comet assay, xenograft tumor model, FAM135B transgenic mouse model, immunohistochemistry\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal binding methods (Co-IP, PLA, GST pull-down), direct enzymatic activity enhancement shown, in vitro and in vivo validation; single lab but rigorous multi-method approach\",\n      \"pmids\": [\"35979619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAM135B knockdown in wild-type spinal motor neurons (sMNs) reduced their survival and contributed to neurite defects, similar to phenotypes observed in SBMA patient-derived sMNs, indicating a functional role of FAM135B in motor neuron survival and neurite integrity. FAM135B was found to be drastically downregulated in SBMA sMNs by microarray analysis.\",\n      \"method\": \"siRNA knockdown in iPSC-derived spinal motor neurons, cell survival assay, neurite morphology analysis, microarray gene expression profiling\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined cellular phenotype (survival, neurite defects) in relevant cell type; single lab, single study\",\n      \"pmids\": [\"30391288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM135B promotes ESCC migration, invasion, and EMT by interacting with the intermediate domain of TRAF2 and NCK-interacting kinase (TNIK), thereby activating the Wnt/β-catenin signaling pathway. FAM135B siRNA reversed the pro-migration/invasion effect of TNIK. Additionally, METTL3-mediated N6-methyladenosine (m6A) modification positively regulates FAM135B expression, with METTL3 acting as its m6A writer; METTL3 pro-EMT effects were reversed by FAM135B silencing.\",\n      \"method\": \"Co-immunoprecipitation (FAM135B-TNIK interaction), siRNA knockdown (FAM135B, METTL3), overexpression, in vitro migration/invasion assays, in vivo lung metastasis model, western blot (EMT markers, β-catenin pathway), m6A modification analysis\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction shown by Co-IP, genetic epistasis (FAM135B siRNA reverses TNIK/METTL3 effects), in vivo validation; single lab\",\n      \"pmids\": [\"38881420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM135B promotes nuclear translocation of SRSF1 by synergistically binding with SRPK1, and regulates SRSF1-mediated alternative splicing of DNA repair genes. Specifically, FAM135B-induced exon IV inclusion of FAAP20 mediates its binding with FANCA and enhances the functional integrity of the FA core complex, activating the Fanconi Anemia (FA) pathway and leading to inter-strand crosslink (ICL) lesion repair and oxaliplatin insensitivity in colorectal cancer cells.\",\n      \"method\": \"Functional binding/interaction assays (FAM135B-SRPK1-SRSF1 complex), alternative splicing analysis, FAAP20 exon inclusion assay, FA pathway activation assay, chemosensitivity assays (oxaliplatin/L-OHP)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined molecular mechanism (splicing regulation via SRPK1/SRSF1 axis, FA pathway activation), multiple mechanistic steps validated; single lab\",\n      \"pmids\": [\"39397154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Strong expression of FAM135B in ESCC tissues showed a significant negative correlation with KAT5 (TIP60) expression in Uygur ESCC patients, suggesting FAM135B may play its oncogenic role by negatively regulating KAT5 expression.\",\n      \"method\": \"Immunohistochemistry on 40 paired ESCC and adjacent tissues; correlation analysis (Kendall's coefficient)\",\n      \"journal\": \"Nan fang yi ke da xue xue bao\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — observational correlation by IHC only, no functional validation of the negative regulatory relationship; single study\",\n      \"pmids\": [\"29502064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FAM135B interacts with IFI16, inhibiting its ubiquitination and proteasomal degradation by competitively blocking IFI16 binding to the E3 ubiquitin ligase TRIM21. This stabilizes IFI16 at lysines 143 and 561 (deubiquitination sites), initiating IFI16-dependent STING signaling and increasing cytotoxic T-cell activity in triple-negative breast cancer.\",\n      \"method\": \"Co-immunoprecipitation (FAM135B-IFI16 interaction), competitive binding assay (FAM135B vs TRIM21 for IFI16), ubiquitination assay, site-directed mutagenesis (K143, K561), STING pathway activation assays, single-cell sequencing, functional T-cell cytotoxicity assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined molecular mechanism with multiple orthogonal methods (Co-IP, ubiquitination assay, mutagenesis); single lab, recently published\",\n      \"pmids\": [\"41218197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FAM135B binds to the IKK complex (IKKα/IKKβ) to stabilize it, inhibit IKKβ activation and P65 phosphorylation, and block the canonical NF-κB signaling pathway, thereby downregulating IL-6 expression and inhibiting JAK/STAT-mediated angiogenesis in glioblastoma. HNF4A was identified as an upstream transcription factor that directly binds to the FAM135B promoter to drive its expression.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry (FAM135B-IKK complex), western blot (IKKβ, P65 phosphorylation), ELISA (IL-6), dual-luciferase reporter assay (HNF4A-FAM135B promoter), rescue experiments with NF-κB inhibitor PDTC and recombinant IL-6, orthotopic and subcutaneous xenograft models, tube formation and Transwell migration assays, immunohistochemistry\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP/MS, reporter assay, rescue experiments, in vivo models); mechanistically detailed; single lab\",\n      \"pmids\": [\"42260484\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM135B is a multifunctional cancer-related protein that promotes cell survival, proliferation, and DNA damage repair by (1) directly binding GRN to activate an AKT/mTOR feedforward loop, (2) sustaining pre-assembled TIP60-ATM complexes to facilitate DNA damage response via both HR and NHEJ, (3) promoting nuclear SRSF1 translocation via SRPK1 to modulate alternative splicing of FA pathway components and drive chemoresistance, (4) interacting with TNIK to activate Wnt/β-catenin signaling and drive EMT, (5) stabilizing IFI16 against TRIM21-mediated ubiquitination to activate the STING innate immune pathway, and (6) binding and stabilizing the IKK complex to suppress NF-κB/IL-6-driven angiogenesis; its expression is positively regulated upstream by METTL3-mediated m6A modification and HNF4A-driven transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM135B is a cancer-associated, multifunctional scaffold protein that promotes tumor cell survival, proliferation, and DNA damage repair, first identified through whole-genome/exome sequencing as a gene capable of driving malignancy in esophageal squamous cell carcinoma (ESCC) [#0]. It acts largely through direct protein-protein interactions that reconfigure signaling and repair complexes: it binds the growth factor GRN (progranulin) to engage a feedforward AKT/mTOR loop that sustains proliferation, with loss of FAM135B increasing radiosensitivity and synergizing with mTOR inhibition [#1, #2]. In the DNA damage response, FAM135B binds the chromodomain of the TIP60 (KAT5) acetyltransferase, enhances its activity, and maintains pre-assembled TIP60-ATM complexes under resting conditions; upon damage it is released, and it promotes both homologous recombination and non-homologous end-joining, accelerating clearance of γH2AX and 53BP1 foci [#3]. FAM135B further controls genome-maintenance gene expression by synergizing with SRPK1 to drive nuclear SRSF1 translocation, directing alternative splicing of FAAP20 to activate the Fanconi Anemia pathway and confer chemoresistance [#6]. Additional interactions tie FAM135B to migration and immune/inflammatory signaling: it binds TNIK to activate Wnt/β-catenin signaling and EMT [#5], stabilizes IFI16 by competitively blocking TRIM21-mediated ubiquitination to initiate STING signaling [#8], and binds the IKK complex to suppress NF-κB/IL-6-driven angiogenesis [#9]. Its expression is positively controlled upstream by METTL3-mediated m6A modification [#5] and HNF4A-driven transcription [#9]. A distinct role in neuronal biology is indicated by the requirement of FAM135B for survival and neurite integrity of spinal motor neurons [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established FAM135B as a previously uncharacterized gene with oncogenic capacity, motivating mechanistic dissection of how it promotes malignancy.\",\n      \"evidence\": \"Whole-genome/whole-exome sequencing followed by functional malignancy assays in ESCC cell lines\",\n      \"pmids\": [\"24670651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism or interaction partner identified\", \"Driver versus passenger role not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a non-cancer role by showing FAM135B is required for motor neuron survival and neurite integrity, broadening its functional scope beyond tumor biology.\",\n      \"evidence\": \"siRNA knockdown in iPSC-derived spinal motor neurons with survival and neurite morphology readouts; microarray profiling of SBMA neurons\",\n      \"pmids\": [\"30391288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway underlying neuronal survival role unknown\", \"No mechanistic link to the cancer functions established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the first hint of a functional relationship between FAM135B and KAT5/TIP60, via an inverse expression correlation in patient tissue.\",\n      \"evidence\": \"Immunohistochemistry on paired ESCC and adjacent tissues with correlation analysis\",\n      \"pmids\": [\"29502064\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Observational correlation only, no functional validation of regulation\", \"Direction and mechanism of the FAM135B-KAT5 relationship unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the first direct molecular partner and signaling axis, showing FAM135B binds GRN to drive an AKT/mTOR feedforward loop promoting proliferation.\",\n      \"evidence\": \"Co-IP for GRN binding, transgenic mouse and xenograft models, western blot of AKT/mTOR components\",\n      \"pmids\": [\"33323378\", \"33340561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of FAM135B-GRN binding unknown\", \"How FAM135B couples GRN to AKT/mTOR mechanistically not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mechanistically embedded FAM135B in the DNA damage response by showing it sustains pre-assembled TIP60-ATM complexes and promotes both HR and NHEJ repair.\",\n      \"evidence\": \"Co-IP, PLA, GST pull-down, acetyltransferase activity assay, γH2AX/53BP1 foci imaging, comet assay, transgenic and xenograft models\",\n      \"pmids\": [\"35979619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger and mechanism for damage-induced release of FAM135B from TIP60 not defined\", \"How a single factor promotes both HR and NHEJ unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended FAM135B function to invasion/EMT through TNIK-Wnt/β-catenin signaling and identified METTL3/m6A as an upstream activator of its expression.\",\n      \"evidence\": \"Co-IP for TNIK, siRNA epistasis, migration/invasion and lung metastasis assays, m6A modification analysis\",\n      \"pmids\": [\"38881420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FAM135B-TNIK binding activates Wnt signaling mechanistically unclear\", \"m6A site(s) on FAM135B transcript not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected FAM135B to splicing control of DNA repair, showing it drives nuclear SRSF1 translocation via SRPK1 to alter FAAP20 splicing and activate the FA pathway, conferring chemoresistance.\",\n      \"evidence\": \"Interaction assays for FAM135B-SRPK1-SRSF1, exon-inclusion and FA pathway activation assays, oxaliplatin chemosensitivity assays in colorectal cancer cells\",\n      \"pmids\": [\"39397154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect nature of FAM135B-SRPK1 interaction not fully resolved\", \"Whether this splicing role operates outside colorectal cancer untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified FAM135B as a positive regulator of innate immune signaling by stabilizing IFI16 against TRIM21-mediated degradation to activate STING.\",\n      \"evidence\": \"Co-IP, competitive binding assay, ubiquitination assay, site-directed mutagenesis (K143/K561), STING activation and T-cell cytotoxicity assays in triple-negative breast cancer\",\n      \"pmids\": [\"41218197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of FAM135B-IFI16 versus TRIM21-IFI16 competition not defined\", \"Single lab, recently published\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed FAM135B suppresses NF-κB/IL-6-driven angiogenesis by stabilizing and inhibiting the IKK complex, and identified HNF4A as a direct transcriptional driver of FAM135B.\",\n      \"evidence\": \"Co-IP/MS for IKK complex, western blot of IKKβ/P65, IL-6 ELISA, dual-luciferase HNF4A promoter assay, rescue experiments, orthotopic/subcutaneous xenografts in glioblastoma\",\n      \"pmids\": [\"42260484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which binding both stabilizes and inhibits IKK is unresolved\", \"Reconciliation of this anti-NF-κB role with pro-tumor roles in other contexts unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether FAM135B's many context-specific interactions reflect a single unifying biochemical activity (e.g., a generic scaffold) or independent functions, and no structural or domain-level model explains its partner selectivity.\",\n      \"evidence\": \"No structural or unifying biochemical study present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of FAM135B\", \"No defined catalytic or enzymatic activity\", \"Partner-selectivity determinants unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 8, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GRN\", \"KAT5\", \"ATM\", \"TNIK\", \"SRPK1\", \"SRSF1\", \"IFI16\", \"IKBKB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}