{"gene":"FAM117B","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2023,"finding":"FAM117B competes with NRF2 for binding to KEAP1, thereby reducing ubiquitination-mediated degradation of NRF2 and activating the KEAP1/NRF2 signaling pathway, promoting gastric cancer cell growth and chemoresistance in an NRF2-dependent manner.","method":"Co-immunoprecipitation, ubiquitination assays, competitive binding experiments, NRF2-dependent rescue experiments, in vitro and in vivo tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, competitive binding, NRF2-dependent rescue with loss-of-function) in a single focused study establishing the molecular mechanism","pmids":["36719368"],"is_preprint":false},{"year":2026,"finding":"FAM117B physically interacts with DYRK1A (confirmed by Co-IP) and acts as an upstream regulator of DYRK1A; DYRK1A in turn phosphorylates PLK2, upregulating PLK2 protein expression and promoting colorectal cancer cell proliferation, migration, invasion, and metastasis. DYRK1A overexpression reversed the inhibitory effects of FAM117B knockdown, and PLK2 knockdown counteracted DYRK1A-mediated effects.","method":"Co-immunoprecipitation, Western blotting, epistasis rescue experiments (DYRK1A overexpression vs FAM117B KD; PLK2 KD vs DYRK1A OE), in vivo subcutaneous and splenic-to-liver metastasis models","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and genetic epistasis in a single lab, multiple orthogonal functional assays but no in vitro kinase reconstitution confirming direct phosphorylation by the FAM117B-DYRK1A complex","pmids":["41504297"],"is_preprint":false},{"year":2025,"finding":"GLCCI1 regulates the DYRK1A/FAM117B axis to activate NRF2 signaling by inhibiting NRF2 ubiquitination degradation; GLCCI1 overexpression reversed OVA-induced mitochondrial dysfunction in bronchial epithelial cells via enhancement of DYRK1A/FAM117B activity upstream of KEAP1/NRF2.","method":"In vitro OVA stimulation of bronchial epithelial cells, GLCCI1 overexpression, measurement of NRF2 ubiquitination, mitochondrial function assays, in vivo allergic asthma mouse model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiments with NRF2 ubiquitination assay and pathway placement in a single lab; FAM117B's specific mechanistic role within the DYRK1A axis is implied but not fully dissected at the molecular level in the abstract","pmids":["40490147"],"is_preprint":false}],"current_model":"FAM117B promotes oncogenic signaling by (1) competing with NRF2 for KEAP1 binding, thereby blocking NRF2 ubiquitination and degradation to activate antioxidant/chemoresistance responses, and (2) acting as an upstream activator of DYRK1A, which phosphorylates PLK2 to drive cancer cell proliferation and metastasis; additionally, FAM117B functions downstream of GLCCI1 within a DYRK1A/FAM117B/NRF2 axis that regulates mitochondrial homeostasis."},"narrative":{"mechanistic_narrative":"FAM117B is an adaptor-type regulator of KEAP1/NRF2 signaling that promotes oncogenic and stress-response programs. It competes with NRF2 for binding to KEAP1, reducing ubiquitination-mediated degradation of NRF2 and thereby activating the KEAP1/NRF2 pathway to drive gastric cancer cell growth and chemoresistance in an NRF2-dependent manner [PMID:36719368]. FAM117B also physically interacts with DYRK1A and acts upstream of it; activated DYRK1A phosphorylates PLK2 and raises PLK2 levels to promote colorectal cancer proliferation, migration, invasion, and metastasis [PMID:41504297]. Within a GLCCI1-controlled DYRK1A/FAM117B axis, this activity converges on KEAP1/NRF2 to restrain mitochondrial dysfunction in bronchial epithelial cells [PMID:40490147]. The biochemical basis of the FAM117B–DYRK1A regulatory step has not been reconstituted in the available corpus.","teleology":[{"year":2023,"claim":"Established the first molecular mechanism for FAM117B, showing it stabilizes NRF2 by competing for KEAP1 rather than acting through an unrelated route.","evidence":"Co-IP, ubiquitination and competitive binding assays with NRF2-dependent rescue in gastric cancer cell and tumor models","pmids":["36719368"],"confidence":"High","gaps":["No structural definition of the FAM117B–KEAP1 interface","Whether NRF2 stabilization is the sole oncogenic output of FAM117B not established"]},{"year":2025,"claim":"Placed FAM117B in a GLCCI1-regulated DYRK1A axis upstream of KEAP1/NRF2 controlling mitochondrial homeostasis, extending its role beyond cancer to epithelial stress responses.","evidence":"GLCCI1 overexpression with NRF2 ubiquitination and mitochondrial function assays in OVA-stimulated bronchial epithelial cells and an allergic asthma mouse model","pmids":["40490147"],"confidence":"Medium","gaps":["FAM117B's specific molecular step within the DYRK1A axis not dissected","Direct GLCCI1–FAM117B relationship not demonstrated"]},{"year":2026,"claim":"Defined a direct FAM117B–DYRK1A interaction and a downstream DYRK1A–PLK2 effector arm, identifying a second signaling branch through which FAM117B drives metastasis.","evidence":"Reciprocal Co-IP, Western blotting, and genetic epistasis rescue (DYRK1A OE vs FAM117B KD; PLK2 KD vs DYRK1A OE) in colorectal cancer cells with subcutaneous and splenic-to-liver metastasis models","pmids":["41504297"],"confidence":"Medium","gaps":["No in vitro kinase reconstitution confirming direct phosphorylation driven by the FAM117B–DYRK1A complex","Mechanism by which FAM117B activates DYRK1A unknown","Single-lab finding without independent replication"]},{"year":null,"claim":"How FAM117B integrates its KEAP1/NRF2-stabilizing function with its DYRK1A-activating function remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FAM117B","Biochemical mechanism of DYRK1A activation undefined","Whether the two branches operate in the same cells or pathways unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["KEAP1","DYRK1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P1L5","full_name":"Protein FAM117B","aliases":["Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 13 protein"],"length_aa":589,"mass_kda":62.0,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6P1L5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM117B","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000138439","cell_line_id":"CID002023","localizations":[{"compartment":"centrosome","grade":3},{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"CTNNB1","stoichiometry":10.0},{"gene":"DYNLL1","stoichiometry":10.0},{"gene":"DYNLL2","stoichiometry":10.0},{"gene":"DCAF7","stoichiometry":10.0},{"gene":"DYRK1A","stoichiometry":4.0},{"gene":"RNF20","stoichiometry":0.2},{"gene":"YWHAG","stoichiometry":0.2},{"gene":"YWHAH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID002023","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM117B"},"hgnc":{"alias_symbol":["FLJ38771"],"prev_symbol":["ALS2CR13"]},"alphafold":{"accession":"Q6P1L5","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P1L5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P1L5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P1L5-F1-predicted_aligned_error_v6.png","plddt_mean":52.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM117B","jax_strain_url":"https://www.jax.org/strain/search?query=FAM117B"},"sequence":{"accession":"Q6P1L5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P1L5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P1L5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P1L5"}},"corpus_meta":[{"pmid":"33773637","id":"PMC_33773637","title":"Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.","date":"2021","source":"The Lancet. Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33773637","citation_count":165,"is_preprint":false},{"pmid":"26051272","id":"PMC_26051272","title":"Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk.","date":"2015","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26051272","citation_count":101,"is_preprint":false},{"pmid":"31430377","id":"PMC_31430377","title":"Genome-wide association study of cerebral small vessel disease reveals established and novel loci.","date":"2019","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31430377","citation_count":89,"is_preprint":false},{"pmid":"36719368","id":"PMC_36719368","title":"FAM117B promotes gastric cancer growth and drug resistance by targeting the KEAP1/NRF2 signaling pathway.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/36719368","citation_count":70,"is_preprint":false},{"pmid":"37900285","id":"PMC_37900285","title":"Insights from the protein interaction Universe of the multifunctional \"Goldilocks\" kinase DYRK1A.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37900285","citation_count":17,"is_preprint":false},{"pmid":"40490147","id":"PMC_40490147","title":"GLCCI1 ameliorates mitochondrial dysfunction in allergic asthma mice via DYRK1A/FAM117B-dependent NRF2 activation.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40490147","citation_count":5,"is_preprint":false},{"pmid":"41504297","id":"PMC_41504297","title":"FAM117B Promotes Colorectal Cancer Progression by Enhancing DYRK1A-mediated Phosphorylation of PLK2.","date":"2026","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/41504297","citation_count":1,"is_preprint":false},{"pmid":"41405732","id":"PMC_41405732","title":"Systematic Characterization of LUHMES Cell-Based Parkinson's Disease Models Reveals Potential Novel Drug Targets.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/41405732","citation_count":0,"is_preprint":false},{"pmid":"40688680","id":"PMC_40688680","title":"Inhibition of gastric adenocarcinoma proliferation by WSGC@MS: Role of KEAP1/NRF2 signaling pathway and autophagy regulation.","date":"2025","source":"Materials today. Bio","url":"https://pubmed.ncbi.nlm.nih.gov/40688680","citation_count":0,"is_preprint":false},{"pmid":"41466414","id":"PMC_41466414","title":"Genome-wide association for sarcoidosis identifies novel risk loci and genetic heritability in African and European ancestries: a meta-analysis from the Finngen, Million Veteran Program, UK Biobank, and Biobank Japan datasets.","date":"2025","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41466414","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8439,"output_tokens":1028,"usd":0.020369,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7536,"output_tokens":1614,"usd":0.039015,"stage2_stop_reason":"end_turn"},"total_usd":0.059384,"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\": 2023,\n      \"finding\": \"FAM117B competes with NRF2 for binding to KEAP1, thereby reducing ubiquitination-mediated degradation of NRF2 and activating the KEAP1/NRF2 signaling pathway, promoting gastric cancer cell growth and chemoresistance in an NRF2-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, competitive binding experiments, NRF2-dependent rescue experiments, in vitro and in vivo tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, competitive binding, NRF2-dependent rescue with loss-of-function) in a single focused study establishing the molecular mechanism\",\n      \"pmids\": [\"36719368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FAM117B physically interacts with DYRK1A (confirmed by Co-IP) and acts as an upstream regulator of DYRK1A; DYRK1A in turn phosphorylates PLK2, upregulating PLK2 protein expression and promoting colorectal cancer cell proliferation, migration, invasion, and metastasis. DYRK1A overexpression reversed the inhibitory effects of FAM117B knockdown, and PLK2 knockdown counteracted DYRK1A-mediated effects.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, epistasis rescue experiments (DYRK1A overexpression vs FAM117B KD; PLK2 KD vs DYRK1A OE), in vivo subcutaneous and splenic-to-liver metastasis models\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and genetic epistasis in a single lab, multiple orthogonal functional assays but no in vitro kinase reconstitution confirming direct phosphorylation by the FAM117B-DYRK1A complex\",\n      \"pmids\": [\"41504297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLCCI1 regulates the DYRK1A/FAM117B axis to activate NRF2 signaling by inhibiting NRF2 ubiquitination degradation; GLCCI1 overexpression reversed OVA-induced mitochondrial dysfunction in bronchial epithelial cells via enhancement of DYRK1A/FAM117B activity upstream of KEAP1/NRF2.\",\n      \"method\": \"In vitro OVA stimulation of bronchial epithelial cells, GLCCI1 overexpression, measurement of NRF2 ubiquitination, mitochondrial function assays, in vivo allergic asthma mouse model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiments with NRF2 ubiquitination assay and pathway placement in a single lab; FAM117B's specific mechanistic role within the DYRK1A axis is implied but not fully dissected at the molecular level in the abstract\",\n      \"pmids\": [\"40490147\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM117B promotes oncogenic signaling by (1) competing with NRF2 for KEAP1 binding, thereby blocking NRF2 ubiquitination and degradation to activate antioxidant/chemoresistance responses, and (2) acting as an upstream activator of DYRK1A, which phosphorylates PLK2 to drive cancer cell proliferation and metastasis; additionally, FAM117B functions downstream of GLCCI1 within a DYRK1A/FAM117B/NRF2 axis that regulates mitochondrial homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM117B is an adaptor-type regulator of KEAP1/NRF2 signaling that promotes oncogenic and stress-response programs. It competes with NRF2 for binding to KEAP1, reducing ubiquitination-mediated degradation of NRF2 and thereby activating the KEAP1/NRF2 pathway to drive gastric cancer cell growth and chemoresistance in an NRF2-dependent manner [#0]. FAM117B also physically interacts with DYRK1A and acts upstream of it; activated DYRK1A phosphorylates PLK2 and raises PLK2 levels to promote colorectal cancer proliferation, migration, invasion, and metastasis [#1]. Within a GLCCI1-controlled DYRK1A/FAM117B axis, this activity converges on KEAP1/NRF2 to restrain mitochondrial dysfunction in bronchial epithelial cells [#2]. The biochemical basis of the FAM117B–DYRK1A regulatory step has not been reconstituted in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the first molecular mechanism for FAM117B, showing it stabilizes NRF2 by competing for KEAP1 rather than acting through an unrelated route.\",\n      \"evidence\": \"Co-IP, ubiquitination and competitive binding assays with NRF2-dependent rescue in gastric cancer cell and tumor models\",\n      \"pmids\": [\"36719368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural definition of the FAM117B–KEAP1 interface\", \"Whether NRF2 stabilization is the sole oncogenic output of FAM117B not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed FAM117B in a GLCCI1-regulated DYRK1A axis upstream of KEAP1/NRF2 controlling mitochondrial homeostasis, extending its role beyond cancer to epithelial stress responses.\",\n      \"evidence\": \"GLCCI1 overexpression with NRF2 ubiquitination and mitochondrial function assays in OVA-stimulated bronchial epithelial cells and an allergic asthma mouse model\",\n      \"pmids\": [\"40490147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FAM117B's specific molecular step within the DYRK1A axis not dissected\", \"Direct GLCCI1–FAM117B relationship not demonstrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a direct FAM117B–DYRK1A interaction and a downstream DYRK1A–PLK2 effector arm, identifying a second signaling branch through which FAM117B drives metastasis.\",\n      \"evidence\": \"Reciprocal Co-IP, Western blotting, and genetic epistasis rescue (DYRK1A OE vs FAM117B KD; PLK2 KD vs DYRK1A OE) in colorectal cancer cells with subcutaneous and splenic-to-liver metastasis models\",\n      \"pmids\": [\"41504297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro kinase reconstitution confirming direct phosphorylation driven by the FAM117B–DYRK1A complex\", \"Mechanism by which FAM117B activates DYRK1A unknown\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FAM117B integrates its KEAP1/NRF2-stabilizing function with its DYRK1A-activating function remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FAM117B\", \"Biochemical mechanism of DYRK1A activation undefined\", \"Whether the two branches operate in the same cells or pathways unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KEAP1\", \"DYRK1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}