{"gene":"SACK1F","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2020,"finding":"FAM83F is farnesylated and interacts with CK1α, co-localizing with it at the plasma membrane. This interaction is essential for FAM83F to activate canonical Wnt signalling. FAM83F acts upstream of GSK-3β, as GSK-3 inhibition rescues the Wnt signalling attenuation caused by FAM83F loss. A farnesyl-deficient FAM83F mutant (introduced by CRISPR/Cas9) redirects the FAM83F-CK1α complex away from the plasma membrane and significantly attenuates Wnt signalling.","method":"Co-localization, co-immunoprecipitation, CRISPR/Cas9 genome editing of farnesyl-deficient mutant, Xenopus embryo axis duplication assay, genetic rescue by GSK-3 inhibition, FAM83F ablation in colorectal cancer cells","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (interaction, localization, mutagenesis, genetic epistasis, Xenopus in vivo assay) in one rigorous study, with mechanistic mutant validation","pmids":["33361109"],"is_preprint":false},{"year":2020,"finding":"IMiDs (immunomodulatory imide drugs) induce FAM83F degradation via the CRBN-Cul4A E3 ligase complex, and this degradation requires FAM83F's association with CK1α. FAM83F degradation by IMiDs attenuates canonical Wnt signalling in colorectal cancer cells and removes CK1α from the plasma membrane, phenocopying genetic ablation of FAM83F. No other FAM83 family member is degraded by IMiDs.","method":"IMiD treatment, CRBN-dependent ubiquitin-proteasome degradation assay, Western blot, Wnt signalling reporter assay, subcellular fractionation/localization","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (degradation assays, localization, signalling readouts) and mechanistic linkage to CK1α interaction confirmed; consistent with companion paper PMID:33361109","pmids":["33361334"],"is_preprint":false},{"year":2019,"finding":"FAM83F (Fam83F) interacts with p53, decreases its ubiquitination and proteasomal degradation, thereby stabilizing and increasing p53 protein levels. FAM83F is induced in response to DNA damage, and its overexpression increases p53 transcriptional activity in cell culture and in zebrafish embryos. Downregulation of FAM83F decreases transcription of p53 target genes after DNA damage and increases cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assay, FAM83F overexpression/knockdown, zebrafish embryo overexpression, p53 target gene transcription assay, cell proliferation assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction, ubiquitination mechanistic assay, in vivo zebrafish validation, and loss-of-function with defined transcriptional readout in one study","pmids":["30692643"],"is_preprint":false},{"year":2019,"finding":"FAM83F activates MAPK signalling through a physical interaction with BRAF and RAF proteins, and impairs TGFβ anti-proliferative signalling transduction in thyroid follicular cells. Stable overexpression of FAM83F in PCCL3 cells leads to loss of thyroid differentiation gene expression (e.g., NIS), reactivation of stem cell markers (LIN28B, SOX2), induction of cell migration, and resistance to doxorubicin-induced apoptosis.","method":"Stable cell line overexpression (PCCL3), co-immunoprecipitation with BRAF/RAF, gene expression analysis, cell migration assay, apoptosis assay, immunohistochemistry","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — interaction with BRAF/RAF by co-IP, multiple functional readouts in stable overexpression model, single lab","pmids":["30881348"],"is_preprint":false},{"year":2023,"finding":"c-Myc binds to the FAM83F promoter and activates FAM83F transcription. FAM83F in turn promotes cervical cancer cell proliferation and glycolysis through activation of the Wnt/β-catenin pathway; these effects are blocked by the Wnt/β-catenin inhibitor XAV939 and are impaired when FAM83F is knocked down.","method":"Chromatin immunoprecipitation (c-Myc binding to FAM83F promoter), FAM83F knockdown/overexpression, XAV939 treatment, cell proliferation/glycolysis assays, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for transcriptional regulation, pathway inhibitor rescue, in vivo xenograft, single lab","pmids":["38104106"],"is_preprint":false},{"year":2016,"finding":"miR-143 directly binds to the 3'-UTR of FAM83F mRNA, degrading it and reducing FAM83F protein levels in esophageal squamous cell carcinoma cells. Loss of FAM83F downstream of miR-143 inhibits cell proliferation, migration, and invasion, and induces G1/G0 phase arrest.","method":"Luciferase 3'-UTR reporter assay, miR-143 overexpression/silencing, Western blot, qRT-PCR, cell proliferation/migration/invasion/apoptosis/cell cycle assays","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validation of direct miRNA-mRNA interaction, multiple functional assays, single lab","pmids":["26758433"],"is_preprint":false},{"year":2024,"finding":"Fam83f protein is targeted to the lysosome when overexpressed in HEK293T cells, and this lysosomal localization is dependent on a C-terminal signal sequence. Loss of fam83f in zebrafish leads to downregulation of PI(3)P-binding proteins and impairment of autophagy, resulting in increased sensitivity to ionizing radiation and earlier hatching.","method":"Fam83f knockout zebrafish, live imaging/subcellular localization of overexpressed protein in HEK293T, C-terminal deletion mutagenesis, transcriptomic analysis, ionizing radiation sensitivity assay","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo with transcriptomic readout and localization mutagenesis, single lab","pmids":["39437839"],"is_preprint":false},{"year":2025,"finding":"FAM83F interacts with KIF23 in NSCLC cells. CAF-derived exosomes transfer FAM83F protein to NSCLC cells, and overexpression of KIF23 attenuates the suppressive effects of FAM83F-deficient exosomes on NSCLC cell malignancy and radiosensitivity.","method":"Co-immunoprecipitation (FAM83F–KIF23), exosome transfer assay, FAM83F knockdown in CAF-derived exosomes, KIF23 overexpression rescue, xenograft tumor formation assay","journal":"Cytotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for FAM83F–KIF23 interaction, single lab, limited mechanistic follow-up on the interaction itself","pmids":["39867833"],"is_preprint":false}],"current_model":"FAM83F is a farnesylated, plasma membrane-targeted protein that activates canonical Wnt signalling by binding and co-localizing CK1α at the plasma membrane upstream of GSK-3β; it also stabilizes p53 by reducing its ubiquitination and degradation in response to DNA damage, activates MAPK signalling via interaction with BRAF/RAF, is transcriptionally induced by c-Myc, is degraded by IMiDs through CRBN-Cul4A in a CK1α-dependent manner, and localizes to lysosomes via a C-terminal signal sequence where it supports autophagic responses."},"narrative":{"mechanistic_narrative":"FAM83F is a membrane- and lysosome-targeted signalling scaffold that couples casein kinase 1α (CK1α) to multiple growth-control pathways and influences cell proliferation, survival, and stress responses [PMID:33361109, PMID:30692643]. It is farnesylated, which targets a FAM83F–CK1α complex to the plasma membrane; this localization is essential for FAM83F to activate canonical Wnt signalling upstream of GSK-3β, since a farnesyl-deficient mutant redirects the complex away from the membrane and attenuates Wnt output [PMID:33361109]. The CK1α association also confers a specific vulnerability: among FAM83 family members, only FAM83F is degraded by immunomodulatory imide drugs via the CRBN-Cul4A E3 ligase, with degradation requiring the CK1α interaction and phenocopying genetic FAM83F loss by removing CK1α from the membrane and attenuating Wnt signalling [PMID:33361334]. Independently of Wnt, FAM83F stabilizes p53 by reducing its ubiquitination and proteasomal degradation following DNA damage, thereby promoting p53 target-gene transcription and restraining proliferation [PMID:30692643], and it activates MAPK signalling through physical interaction with BRAF/RAF [PMID:30881348]. FAM83F is transcriptionally induced by c-Myc and drives Wnt/β-catenin-dependent proliferation and glycolysis [PMID:38104106], and is also post-transcriptionally repressed by miR-143 [PMID:26758433]. A C-terminal signal sequence directs FAM83F to the lysosome, where it supports autophagy and modulates sensitivity to ionizing radiation [PMID:39437839].","teleology":[{"year":2016,"claim":"Established a layer of post-transcriptional control over FAM83F and linked its abundance to a proliferative phenotype, framing it as a cancer-relevant effector.","evidence":"Luciferase 3'-UTR reporter and miR-143 gain/loss-of-function with proliferation, migration, invasion, and cell-cycle assays in esophageal squamous cell carcinoma cells","pmids":["26758433"],"confidence":"Medium","gaps":["Does not define the molecular function of the FAM83F protein itself","No mechanism connecting FAM83F level to the proliferative output"]},{"year":2019,"claim":"Identified the first direct molecular activity of FAM83F — stabilizing p53 by limiting its ubiquitination — assigning it a role in the DNA-damage response.","evidence":"Co-IP and ubiquitination assays with FAM83F overexpression/knockdown, zebrafish embryo overexpression, and p53 target-gene transcription readouts","pmids":["30692643"],"confidence":"High","gaps":["Mechanism by which FAM83F reduces p53 ubiquitination (direct vs. via an E3/DUB) not resolved","Relationship to FAM83F's other signalling roles unclear"]},{"year":2019,"claim":"Linked FAM83F to RAS/MAPK signalling via BRAF/RAF binding and showed it can drive dedifferentiation and chemoresistance, broadening its pathway connectivity beyond p53.","evidence":"Stable PCCL3 overexpression, co-IP with BRAF/RAF, gene-expression, migration, and apoptosis assays in thyroid follicular cells","pmids":["30881348"],"confidence":"Medium","gaps":["Direct vs. indirect nature of BRAF/RAF interaction not dissected","Single overexpression model in one cell type","No structural or mutational mapping of the interaction"]},{"year":2020,"claim":"Defined the core mechanism: farnesylation targets a FAM83F–CK1α complex to the plasma membrane to activate canonical Wnt signalling upstream of GSK-3β.","evidence":"Co-localization, co-IP, CRISPR farnesyl-deficient mutant, Xenopus axis-duplication assay, and GSK-3-inhibition rescue in colorectal cancer cells","pmids":["33361109"],"confidence":"High","gaps":["How membrane-localized CK1α activates Wnt mechanistically not fully defined","Relationship between this Wnt role and the p53/MAPK roles unresolved"]},{"year":2020,"claim":"Showed FAM83F is a CK1α-dependent, IMiD-responsive degron target unique among FAM83 proteins, providing a pharmacological route to suppress its Wnt activity.","evidence":"IMiD treatment with CRBN-Cul4A degradation assays, Western blot, Wnt reporter, and subcellular fractionation in colorectal cancer cells","pmids":["33361334"],"confidence":"High","gaps":["Structural basis of CRBN recognition of FAM83F–CK1α not defined","Whether IMiD degradation affects p53/MAPK roles not tested"]},{"year":2023,"claim":"Placed FAM83F downstream of c-Myc transcriptionally and confirmed Wnt/β-catenin-dependent control of proliferation and glycolysis in vivo.","evidence":"ChIP of c-Myc at the FAM83F promoter, knockdown/overexpression, XAV939 rescue, glycolysis assays, and xenograft model in cervical cancer","pmids":["38104106"],"confidence":"Medium","gaps":["Whether c-Myc induction operates in non-cancer contexts unknown","Direct metabolic targets of FAM83F not identified"]},{"year":2024,"claim":"Revealed a second subcellular pool of FAM83F at the lysosome, dependent on a C-terminal signal, and tied it to autophagy and radiation sensitivity.","evidence":"fam83f knockout zebrafish with transcriptomics, overexpression localization and C-terminal deletion in HEK293T, and ionizing-radiation assays","pmids":["39437839"],"confidence":"Medium","gaps":["Mechanism by which lysosomal FAM83F supports PI(3)P-binding proteins/autophagy unknown","Relationship between lysosomal and plasma-membrane pools unresolved"]},{"year":2025,"claim":"Identified KIF23 as a FAM83F interactor in an exosome-mediated stromal-to-tumor transfer context, hinting at intercellular signalling roles.","evidence":"Co-IP of FAM83F–KIF23, CAF-derived exosome transfer, KIF23 overexpression rescue, and xenograft assays in NSCLC","pmids":["39867833"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation of the FAM83F–KIF23 interaction","Functional consequence of the interaction at the molecular level undefined","Single lab"]},{"year":null,"claim":"How FAM83F's distinct activities — plasma-membrane CK1α/Wnt scaffolding, p53 stabilization, MAPK activation, and lysosomal autophagy support — are integrated and partitioned in a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking the membrane and lysosomal pools","Whether p53 stabilization and Wnt activation are mechanistically connected is unknown","No structural characterization of FAM83F or its complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]}],"complexes":[],"partners":["CSNK1A1","TP53","BRAF","RAF1","KIF23"],"other_free_text":[]}},"prefetch_data":{"uniprot":{},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"FAM83F","url":"https://depmap.org/portal/gene/FAM83F","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":[],"url":"https://opencell.sf.czbiohub.org/search/SACK1F","total_profiled":1310},"omim":[{"mim_id":"621522","title":"SCAFFOLDING CK1-ANCHORING PROTEIN F; SACK1F","url":"https://www.omim.org/entry/621522"}],"hpa":{"profiled":true,"resolved_as":"FAM83F","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":18.9},{"tissue":"testis","ntpm":38.9}],"url":"https://www.proteinatlas.org/search/FAM83F"},"hgnc":{"alias_symbol":[],"prev_symbol":["FAM83F"]},"alphafold":{},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SACK1F","jax_strain_url":"https://www.jax.org/strain/search?query=SACK1F"},"sequence":{}},"corpus_meta":[{"pmid":"32783691","id":"PMC_32783691","title":"Serum-Derived Exosomes-Mediated Circular RNA ARHGAP10 Modulates the Progression of Non-Small Cell Lung Cancer Through the miR-638/FAM83F Axis.","date":"2020","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/32783691","citation_count":29,"is_preprint":false},{"pmid":"30280778","id":"PMC_30280778","title":"MiR-940 inhibits the progression of NSCLC by targeting FAM83F.","date":"2018","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30280778","citation_count":29,"is_preprint":false},{"pmid":"38104106","id":"PMC_38104106","title":"Upregulation of FAM83F by c-Myc promotes cervical cancer growth and aerobic glycolysis via Wnt/β-catenin signaling activation.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38104106","citation_count":25,"is_preprint":false},{"pmid":"26758433","id":"PMC_26758433","title":"miR-143 inhibits tumor progression by targeting FAM83F in esophageal squamous cell carcinoma.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26758433","citation_count":25,"is_preprint":false},{"pmid":"30881348","id":"PMC_30881348","title":"The Highly Expressed FAM83F Protein in Papillary Thyroid Cancer Exerts a Pro-Oncogenic Role in Thyroid Follicular Cells.","date":"2019","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30881348","citation_count":23,"is_preprint":false},{"pmid":"31595558","id":"PMC_31595558","title":"MiR-1827 functions as a tumor suppressor in lung adenocarcinoma by targeting MYC and FAM83F.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31595558","citation_count":19,"is_preprint":false},{"pmid":"33361109","id":"PMC_33361109","title":"FAM83F regulates canonical Wnt signalling through an interaction with CK1α.","date":"2020","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/33361109","citation_count":18,"is_preprint":false},{"pmid":"33560141","id":"PMC_33560141","title":"Circ_0000735 enhances the proliferation, metastasis and glycolysis of non-small cell lung cancer by regulating the miR-635/FAM83F axis.","date":"2021","source":"Experimental lung research","url":"https://pubmed.ncbi.nlm.nih.gov/33560141","citation_count":17,"is_preprint":false},{"pmid":"30692643","id":"PMC_30692643","title":"Fam83F induces p53 stabilisation and promotes its activity.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30692643","citation_count":16,"is_preprint":false},{"pmid":"30556880","id":"PMC_30556880","title":"MiR-650 inhibits the progression of glioma by targeting FAM83F.","date":"2018","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30556880","citation_count":13,"is_preprint":false},{"pmid":"36206095","id":"PMC_36206095","title":"Blocking circ_0010235 suppresses acquired paclitaxel resistance of non-small cell lung cancer by sponging miR-512-5p to modulate FAM83F expression.","date":"2022","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/36206095","citation_count":12,"is_preprint":false},{"pmid":"33361334","id":"PMC_33361334","title":"IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling.","date":"2020","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/33361334","citation_count":11,"is_preprint":false},{"pmid":"39437839","id":"PMC_39437839","title":"Zebrafish reveal new roles for Fam83f in hatching and the DNA damage-mediated autophagic response.","date":"2024","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/39437839","citation_count":3,"is_preprint":false},{"pmid":"39867833","id":"PMC_39867833","title":"Cancer-associated fibroblast-derived exosomal FAM83F regulates KIF23 expression to promote the malignant progression and reduce radiosensitivity in non-small cell lung cancer.","date":"2025","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39867833","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9836,"output_tokens":2372,"usd":0.032544,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9500,"output_tokens":3058,"usd":0.061975,"stage2_stop_reason":"end_turn"},"total_usd":0.094519,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM83F is farnesylated and interacts with CK1α, co-localizing with it at the plasma membrane. This interaction is essential for FAM83F to activate canonical Wnt signalling. FAM83F acts upstream of GSK-3β, as GSK-3 inhibition rescues the Wnt signalling attenuation caused by FAM83F loss. A farnesyl-deficient FAM83F mutant (introduced by CRISPR/Cas9) redirects the FAM83F-CK1α complex away from the plasma membrane and significantly attenuates Wnt signalling.\",\n      \"method\": \"Co-localization, co-immunoprecipitation, CRISPR/Cas9 genome editing of farnesyl-deficient mutant, Xenopus embryo axis duplication assay, genetic rescue by GSK-3 inhibition, FAM83F ablation in colorectal cancer cells\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (interaction, localization, mutagenesis, genetic epistasis, Xenopus in vivo assay) in one rigorous study, with mechanistic mutant validation\",\n      \"pmids\": [\"33361109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IMiDs (immunomodulatory imide drugs) induce FAM83F degradation via the CRBN-Cul4A E3 ligase complex, and this degradation requires FAM83F's association with CK1α. FAM83F degradation by IMiDs attenuates canonical Wnt signalling in colorectal cancer cells and removes CK1α from the plasma membrane, phenocopying genetic ablation of FAM83F. No other FAM83 family member is degraded by IMiDs.\",\n      \"method\": \"IMiD treatment, CRBN-dependent ubiquitin-proteasome degradation assay, Western blot, Wnt signalling reporter assay, subcellular fractionation/localization\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (degradation assays, localization, signalling readouts) and mechanistic linkage to CK1α interaction confirmed; consistent with companion paper PMID:33361109\",\n      \"pmids\": [\"33361334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM83F (Fam83F) interacts with p53, decreases its ubiquitination and proteasomal degradation, thereby stabilizing and increasing p53 protein levels. FAM83F is induced in response to DNA damage, and its overexpression increases p53 transcriptional activity in cell culture and in zebrafish embryos. Downregulation of FAM83F decreases transcription of p53 target genes after DNA damage and increases cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, FAM83F overexpression/knockdown, zebrafish embryo overexpression, p53 target gene transcription assay, cell proliferation assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction, ubiquitination mechanistic assay, in vivo zebrafish validation, and loss-of-function with defined transcriptional readout in one study\",\n      \"pmids\": [\"30692643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM83F activates MAPK signalling through a physical interaction with BRAF and RAF proteins, and impairs TGFβ anti-proliferative signalling transduction in thyroid follicular cells. Stable overexpression of FAM83F in PCCL3 cells leads to loss of thyroid differentiation gene expression (e.g., NIS), reactivation of stem cell markers (LIN28B, SOX2), induction of cell migration, and resistance to doxorubicin-induced apoptosis.\",\n      \"method\": \"Stable cell line overexpression (PCCL3), co-immunoprecipitation with BRAF/RAF, gene expression analysis, cell migration assay, apoptosis assay, immunohistochemistry\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — interaction with BRAF/RAF by co-IP, multiple functional readouts in stable overexpression model, single lab\",\n      \"pmids\": [\"30881348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"c-Myc binds to the FAM83F promoter and activates FAM83F transcription. FAM83F in turn promotes cervical cancer cell proliferation and glycolysis through activation of the Wnt/β-catenin pathway; these effects are blocked by the Wnt/β-catenin inhibitor XAV939 and are impaired when FAM83F is knocked down.\",\n      \"method\": \"Chromatin immunoprecipitation (c-Myc binding to FAM83F promoter), FAM83F knockdown/overexpression, XAV939 treatment, cell proliferation/glycolysis assays, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for transcriptional regulation, pathway inhibitor rescue, in vivo xenograft, single lab\",\n      \"pmids\": [\"38104106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-143 directly binds to the 3'-UTR of FAM83F mRNA, degrading it and reducing FAM83F protein levels in esophageal squamous cell carcinoma cells. Loss of FAM83F downstream of miR-143 inhibits cell proliferation, migration, and invasion, and induces G1/G0 phase arrest.\",\n      \"method\": \"Luciferase 3'-UTR reporter assay, miR-143 overexpression/silencing, Western blot, qRT-PCR, cell proliferation/migration/invasion/apoptosis/cell cycle assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validation of direct miRNA-mRNA interaction, multiple functional assays, single lab\",\n      \"pmids\": [\"26758433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Fam83f protein is targeted to the lysosome when overexpressed in HEK293T cells, and this lysosomal localization is dependent on a C-terminal signal sequence. Loss of fam83f in zebrafish leads to downregulation of PI(3)P-binding proteins and impairment of autophagy, resulting in increased sensitivity to ionizing radiation and earlier hatching.\",\n      \"method\": \"Fam83f knockout zebrafish, live imaging/subcellular localization of overexpressed protein in HEK293T, C-terminal deletion mutagenesis, transcriptomic analysis, ionizing radiation sensitivity assay\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo with transcriptomic readout and localization mutagenesis, single lab\",\n      \"pmids\": [\"39437839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM83F interacts with KIF23 in NSCLC cells. CAF-derived exosomes transfer FAM83F protein to NSCLC cells, and overexpression of KIF23 attenuates the suppressive effects of FAM83F-deficient exosomes on NSCLC cell malignancy and radiosensitivity.\",\n      \"method\": \"Co-immunoprecipitation (FAM83F–KIF23), exosome transfer assay, FAM83F knockdown in CAF-derived exosomes, KIF23 overexpression rescue, xenograft tumor formation assay\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for FAM83F–KIF23 interaction, single lab, limited mechanistic follow-up on the interaction itself\",\n      \"pmids\": [\"39867833\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM83F is a farnesylated, plasma membrane-targeted protein that activates canonical Wnt signalling by binding and co-localizing CK1α at the plasma membrane upstream of GSK-3β; it also stabilizes p53 by reducing its ubiquitination and degradation in response to DNA damage, activates MAPK signalling via interaction with BRAF/RAF, is transcriptionally induced by c-Myc, is degraded by IMiDs through CRBN-Cul4A in a CK1α-dependent manner, and localizes to lysosomes via a C-terminal signal sequence where it supports autophagic responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FAM83F is a membrane- and lysosome-targeted signalling scaffold that couples casein kinase 1α (CK1α) to multiple growth-control pathways and influences cell proliferation, survival, and stress responses [#0, #2]. It is farnesylated, which targets a FAM83F–CK1α complex to the plasma membrane; this localization is essential for FAM83F to activate canonical Wnt signalling upstream of GSK-3β, since a farnesyl-deficient mutant redirects the complex away from the membrane and attenuates Wnt output [#0]. The CK1α association also confers a specific vulnerability: among FAM83 family members, only FAM83F is degraded by immunomodulatory imide drugs via the CRBN-Cul4A E3 ligase, with degradation requiring the CK1α interaction and phenocopying genetic FAM83F loss by removing CK1α from the membrane and attenuating Wnt signalling [#1]. Independently of Wnt, FAM83F stabilizes p53 by reducing its ubiquitination and proteasomal degradation following DNA damage, thereby promoting p53 target-gene transcription and restraining proliferation [#2], and it activates MAPK signalling through physical interaction with BRAF/RAF [#3]. FAM83F is transcriptionally induced by c-Myc and drives Wnt/β-catenin-dependent proliferation and glycolysis [#4], and is also post-transcriptionally repressed by miR-143 [#5]. A C-terminal signal sequence directs FAM83F to the lysosome, where it supports autophagy and modulates sensitivity to ionizing radiation [#6].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a layer of post-transcriptional control over FAM83F and linked its abundance to a proliferative phenotype, framing it as a cancer-relevant effector.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter and miR-143 gain/loss-of-function with proliferation, migration, invasion, and cell-cycle assays in esophageal squamous cell carcinoma cells\",\n      \"pmids\": [\"26758433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the molecular function of the FAM83F protein itself\", \"No mechanism connecting FAM83F level to the proliferative output\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the first direct molecular activity of FAM83F — stabilizing p53 by limiting its ubiquitination — assigning it a role in the DNA-damage response.\",\n      \"evidence\": \"Co-IP and ubiquitination assays with FAM83F overexpression/knockdown, zebrafish embryo overexpression, and p53 target-gene transcription readouts\",\n      \"pmids\": [\"30692643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FAM83F reduces p53 ubiquitination (direct vs. via an E3/DUB) not resolved\", \"Relationship to FAM83F's other signalling roles unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked FAM83F to RAS/MAPK signalling via BRAF/RAF binding and showed it can drive dedifferentiation and chemoresistance, broadening its pathway connectivity beyond p53.\",\n      \"evidence\": \"Stable PCCL3 overexpression, co-IP with BRAF/RAF, gene-expression, migration, and apoptosis assays in thyroid follicular cells\",\n      \"pmids\": [\"30881348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of BRAF/RAF interaction not dissected\", \"Single overexpression model in one cell type\", \"No structural or mutational mapping of the interaction\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the core mechanism: farnesylation targets a FAM83F–CK1α complex to the plasma membrane to activate canonical Wnt signalling upstream of GSK-3β.\",\n      \"evidence\": \"Co-localization, co-IP, CRISPR farnesyl-deficient mutant, Xenopus axis-duplication assay, and GSK-3-inhibition rescue in colorectal cancer cells\",\n      \"pmids\": [\"33361109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How membrane-localized CK1α activates Wnt mechanistically not fully defined\", \"Relationship between this Wnt role and the p53/MAPK roles unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed FAM83F is a CK1α-dependent, IMiD-responsive degron target unique among FAM83 proteins, providing a pharmacological route to suppress its Wnt activity.\",\n      \"evidence\": \"IMiD treatment with CRBN-Cul4A degradation assays, Western blot, Wnt reporter, and subcellular fractionation in colorectal cancer cells\",\n      \"pmids\": [\"33361334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CRBN recognition of FAM83F–CK1α not defined\", \"Whether IMiD degradation affects p53/MAPK roles not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed FAM83F downstream of c-Myc transcriptionally and confirmed Wnt/β-catenin-dependent control of proliferation and glycolysis in vivo.\",\n      \"evidence\": \"ChIP of c-Myc at the FAM83F promoter, knockdown/overexpression, XAV939 rescue, glycolysis assays, and xenograft model in cervical cancer\",\n      \"pmids\": [\"38104106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether c-Myc induction operates in non-cancer contexts unknown\", \"Direct metabolic targets of FAM83F not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a second subcellular pool of FAM83F at the lysosome, dependent on a C-terminal signal, and tied it to autophagy and radiation sensitivity.\",\n      \"evidence\": \"fam83f knockout zebrafish with transcriptomics, overexpression localization and C-terminal deletion in HEK293T, and ionizing-radiation assays\",\n      \"pmids\": [\"39437839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which lysosomal FAM83F supports PI(3)P-binding proteins/autophagy unknown\", \"Relationship between lysosomal and plasma-membrane pools unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified KIF23 as a FAM83F interactor in an exosome-mediated stromal-to-tumor transfer context, hinting at intercellular signalling roles.\",\n      \"evidence\": \"Co-IP of FAM83F–KIF23, CAF-derived exosome transfer, KIF23 overexpression rescue, and xenograft assays in NSCLC\",\n      \"pmids\": [\"39867833\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation of the FAM83F–KIF23 interaction\", \"Functional consequence of the interaction at the molecular level undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FAM83F's distinct activities — plasma-membrane CK1α/Wnt scaffolding, p53 stabilization, MAPK activation, and lysosomal autophagy support — are integrated and partitioned in a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking the membrane and lysosomal pools\", \"Whether p53 stabilization and Wnt activation are mechanistically connected is unknown\", \"No structural characterization of FAM83F or its complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CSNK1A1\", \"TP53\", \"BRAF\", \"RAF1\", \"KIF23\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}