{"gene":"FAM135A","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2025,"finding":"FAM135A is activated downstream of the GRPR signaling axis (GRP→GRPR→FAM135A) in prostate cancer cells; pharmacological GRPR inhibition represses FAM135A expression via MED15 activation.","method":"RNA-seq, ChIP-seq, in vitro co-culture perineural invasion assay, in vivo sciatic-nerve invasion mouse model, FAM135A silencing (loss-of-function)","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, ChIP-seq, in vitro and in vivo functional assays) in a single lab establishing a defined signaling pathway","pmids":["41250119"],"is_preprint":false},{"year":2025,"finding":"FAM135A undergoes cytoplasmic-to-nuclear translocation mediated by the nuclear transporter protein RAN, resulting in nuclear-enriched FAM135A (nFAM135A).","method":"Subcellular fractionation/localization experiments and mechanistic follow-up identifying RAN as the transporter","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, single lab, multiple methods in one study","pmids":["41250119"],"is_preprint":false},{"year":2025,"finding":"Nuclear FAM135A (nFAM135A) acts as a transcriptional regulator that drives expression of Teneurin Transmembrane Protein 3 (TENM3), which is required for nFAM135A-induced cancer-nerve invasion.","method":"ChIP-seq (identifying TENM3 as a transcriptional target), RNA-seq, and functional rescue/silencing experiments in prostate cancer cells","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus RNA-seq with functional validation, single lab","pmids":["41250119"],"is_preprint":false},{"year":2025,"finding":"FAM135A silencing abrogates tumor malignancy and neural invasion in vitro (in AR-positive LNCaP and AR-negative DU145/PC3 cells) and controls tumor growth and improves motor function in an in vivo PCa-sciatic nerve invasion mouse model.","method":"Loss-of-function (FAM135A silencing) in co-culture perineural invasion assay and in vivo sciatic-nerve invasion mouse model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo loss-of-function with defined phenotypic readouts, single lab","pmids":["41250119"],"is_preprint":false}],"current_model":"FAM135A is a nuclear-enriched protein in prostate cancer whose expression is driven by GRPR signaling (GRP→GRPR, with MED15 mediating repression upon GRPR inhibition); its cytoplasmic-to-nuclear translocation depends on the transporter RAN, and once nuclear, nFAM135A acts as a transcriptional activator of TENM3 to promote perineural invasion."},"narrative":{"mechanistic_narrative":"FAM135A is a signaling-responsive transcriptional regulator that drives perineural invasion in prostate cancer [PMID:41250119]. Its expression is activated downstream of the GRP→GRPR signaling axis, and pharmacological GRPR inhibition represses FAM135A through MED15 activation [PMID:41250119]. The nuclear transporter RAN mediates cytoplasmic-to-nuclear translocation of FAM135A, generating a nuclear-enriched form (nFAM135A) that acts as a transcriptional activator of TENM3, a target required for cancer-nerve invasion [PMID:41250119]. Loss of FAM135A abrogates tumor malignancy and neural invasion in both AR-positive and AR-negative prostate cancer cells and limits tumor growth while improving motor function in a sciatic-nerve invasion mouse model [PMID:41250119]. Beyond this prostate cancer perineural-invasion axis, no further biochemical or structural detail for FAM135A has been characterized in the available corpus.","teleology":[{"year":2025,"claim":"Established that FAM135A is a downstream effector of GRPR signaling in prostate cancer, placing it within a defined upstream pathway rather than as an isolated factor.","evidence":"RNA-seq, ChIP-seq, and GRPR pharmacological inhibition with FAM135A silencing in prostate cancer cells","pmids":["41250119"],"confidence":"Medium","gaps":["Direct mechanism by which GRPR signaling and MED15 control FAM135A transcription not resolved","Whether FAM135A activation occurs in non-prostate contexts unknown"]},{"year":2025,"claim":"Identified RAN-mediated nuclear translocation as the step that converts cytoplasmic FAM135A into a transcriptionally active nuclear pool, defining how its activity is spatially controlled.","evidence":"Subcellular fractionation/localization experiments identifying RAN as the transporter in prostate cancer cells","pmids":["41250119"],"confidence":"Medium","gaps":["Nuclear localization signal or direct RAN-FAM135A interaction not biochemically defined","Signal triggering translocation not established"]},{"year":2025,"claim":"Showed that nuclear FAM135A functions as a transcriptional regulator of TENM3, providing the downstream gene required for its pro-invasive effect.","evidence":"ChIP-seq target identification, RNA-seq, and rescue/silencing experiments in prostate cancer cells","pmids":["41250119"],"confidence":"Medium","gaps":["Whether FAM135A binds DNA directly or acts via a co-regulator not determined","Full target gene set beyond TENM3 not delineated"]},{"year":2025,"claim":"Demonstrated functional requirement for FAM135A in tumor malignancy and neural invasion across androgen-receptor states, linking the molecular pathway to in vivo disease phenotypes.","evidence":"FAM135A silencing in AR-positive and AR-negative cells, co-culture perineural invasion assay, and in vivo sciatic-nerve invasion mouse model","pmids":["41250119"],"confidence":"Medium","gaps":["All evidence from a single lab and single study","Therapeutic targetability not tested directly"]},{"year":null,"claim":"The intrinsic biochemical activity of FAM135A and its mechanism of DNA/chromatin engagement remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model or enzymatic activity characterized","No reciprocal validation of the RAN interaction","Function outside prostate cancer unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2]}],"complexes":[],"partners":["RAN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P2D6","full_name":"Protein FAM135A","aliases":[],"length_aa":1515,"mass_kda":169.8,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9P2D6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM135A","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":"CLNS1A","stoichiometry":0.2},{"gene":"GLUL","stoichiometry":0.2},{"gene":"TUBA1B","stoichiometry":0.2},{"gene":"UBA52","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FAM135A","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":28.1}],"url":"https://www.proteinatlas.org/search/FAM135A"},"hgnc":{"alias_symbol":["FLJ20176"],"prev_symbol":["KIAA1411"]},"alphafold":{"accession":"Q9P2D6","domains":[{"cath_id":"2.60.40.150","chopping":"2-185","consensus_level":"medium","plddt":89.6364,"start":2,"end":185},{"cath_id":"3.40.50","chopping":"342-419_1227-1239_1250-1514","consensus_level":"medium","plddt":90.1438,"start":342,"end":1514}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2D6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2D6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2D6-F1-predicted_aligned_error_v6.png","plddt_mean":59.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM135A","jax_strain_url":"https://www.jax.org/strain/search?query=FAM135A"},"sequence":{"accession":"Q9P2D6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2D6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2D6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2D6"}},"corpus_meta":[{"pmid":"36943627","id":"PMC_36943627","title":"LncRNA MIR17HG Suppresses Breast Cancer Proliferation and Migration as ceRNA to Target FAM135A by Sponging miR-454-3p.","date":"2023","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36943627","citation_count":25,"is_preprint":false},{"pmid":"35394261","id":"PMC_35394261","title":"Establishment and characterization of the third non-functional human pancreatic neuroendocrine tumor cell line.","date":"2022","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/35394261","citation_count":13,"is_preprint":false},{"pmid":"25991709","id":"PMC_25991709","title":"Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions.","date":"2015","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/25991709","citation_count":13,"is_preprint":false},{"pmid":"31784561","id":"PMC_31784561","title":"Construction of miRNA-target networks using microRNA profiles of CVB3-infected HeLa 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Association","url":"https://pubmed.ncbi.nlm.nih.gov/41700061","citation_count":0,"is_preprint":false},{"pmid":"41751003","id":"PMC_41751003","title":"Whole-Genome Resequencing Reveals Population Structure and Loci Associated with Growth and Meat-Quality Traits in Meigu Yanying Chickens.","date":"2026","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/41751003","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7650,"output_tokens":919,"usd":0.018367,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7436,"output_tokens":1684,"usd":0.03964,"stage2_stop_reason":"end_turn"},"total_usd":0.058007,"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\": 2025,\n      \"finding\": \"FAM135A is activated downstream of the GRPR signaling axis (GRP→GRPR→FAM135A) in prostate cancer cells; pharmacological GRPR inhibition represses FAM135A expression via MED15 activation.\",\n      \"method\": \"RNA-seq, ChIP-seq, in vitro co-culture perineural invasion assay, in vivo sciatic-nerve invasion mouse model, FAM135A silencing (loss-of-function)\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNA-seq, ChIP-seq, in vitro and in vivo functional assays) in a single lab establishing a defined signaling pathway\",\n      \"pmids\": [\"41250119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM135A undergoes cytoplasmic-to-nuclear translocation mediated by the nuclear transporter protein RAN, resulting in nuclear-enriched FAM135A (nFAM135A).\",\n      \"method\": \"Subcellular fractionation/localization experiments and mechanistic follow-up identifying RAN as the transporter\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, single lab, multiple methods in one study\",\n      \"pmids\": [\"41250119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear FAM135A (nFAM135A) acts as a transcriptional regulator that drives expression of Teneurin Transmembrane Protein 3 (TENM3), which is required for nFAM135A-induced cancer-nerve invasion.\",\n      \"method\": \"ChIP-seq (identifying TENM3 as a transcriptional target), RNA-seq, and functional rescue/silencing experiments in prostate cancer cells\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus RNA-seq with functional validation, single lab\",\n      \"pmids\": [\"41250119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM135A silencing abrogates tumor malignancy and neural invasion in vitro (in AR-positive LNCaP and AR-negative DU145/PC3 cells) and controls tumor growth and improves motor function in an in vivo PCa-sciatic nerve invasion mouse model.\",\n      \"method\": \"Loss-of-function (FAM135A silencing) in co-culture perineural invasion assay and in vivo sciatic-nerve invasion mouse model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo loss-of-function with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"41250119\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM135A is a nuclear-enriched protein in prostate cancer whose expression is driven by GRPR signaling (GRP→GRPR, with MED15 mediating repression upon GRPR inhibition); its cytoplasmic-to-nuclear translocation depends on the transporter RAN, and once nuclear, nFAM135A acts as a transcriptional activator of TENM3 to promote perineural invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM135A is a signaling-responsive transcriptional regulator that drives perineural invasion in prostate cancer [#0, #2]. Its expression is activated downstream of the GRP\\u2192GRPR signaling axis, and pharmacological GRPR inhibition represses FAM135A through MED15 activation [#0]. The nuclear transporter RAN mediates cytoplasmic-to-nuclear translocation of FAM135A, generating a nuclear-enriched form (nFAM135A) that acts as a transcriptional activator of TENM3, a target required for cancer-nerve invasion [#1, #2]. Loss of FAM135A abrogates tumor malignancy and neural invasion in both AR-positive and AR-negative prostate cancer cells and limits tumor growth while improving motor function in a sciatic-nerve invasion mouse model [#3]. Beyond this prostate cancer perineural-invasion axis, no further biochemical or structural detail for FAM135A has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Established that FAM135A is a downstream effector of GRPR signaling in prostate cancer, placing it within a defined upstream pathway rather than as an isolated factor.\",\n      \"evidence\": \"RNA-seq, ChIP-seq, and GRPR pharmacological inhibition with FAM135A silencing in prostate cancer cells\",\n      \"pmids\": [\"41250119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism by which GRPR signaling and MED15 control FAM135A transcription not resolved\",\n        \"Whether FAM135A activation occurs in non-prostate contexts unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified RAN-mediated nuclear translocation as the step that converts cytoplasmic FAM135A into a transcriptionally active nuclear pool, defining how its activity is spatially controlled.\",\n      \"evidence\": \"Subcellular fractionation/localization experiments identifying RAN as the transporter in prostate cancer cells\",\n      \"pmids\": [\"41250119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Nuclear localization signal or direct RAN-FAM135A interaction not biochemically defined\",\n        \"Signal triggering translocation not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that nuclear FAM135A functions as a transcriptional regulator of TENM3, providing the downstream gene required for its pro-invasive effect.\",\n      \"evidence\": \"ChIP-seq target identification, RNA-seq, and rescue/silencing experiments in prostate cancer cells\",\n      \"pmids\": [\"41250119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FAM135A binds DNA directly or acts via a co-regulator not determined\",\n        \"Full target gene set beyond TENM3 not delineated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated functional requirement for FAM135A in tumor malignancy and neural invasion across androgen-receptor states, linking the molecular pathway to in vivo disease phenotypes.\",\n      \"evidence\": \"FAM135A silencing in AR-positive and AR-negative cells, co-culture perineural invasion assay, and in vivo sciatic-nerve invasion mouse model\",\n      \"pmids\": [\"41250119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"All evidence from a single lab and single study\",\n        \"Therapeutic targetability not tested directly\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic biochemical activity of FAM135A and its mechanism of DNA/chromatin engagement remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model or enzymatic activity characterized\",\n        \"No reciprocal validation of the RAN interaction\",\n        \"Function outside prostate cancer unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}