{"gene":"FIBP","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1998,"finding":"FIBP (aFGF intracellular binding protein) was identified as a novel 42 kDa intracellular protein that binds selectively to mitogenic acidic FGF (aFGF) but not to the non-mitogenic mutant aFGF-K132E, indicating specificity for the mitogenic conformation. In vitro-translated FIBP bound specifically to a maltose-binding protein–aFGF fusion protein. The protein localizes predominantly to the nucleus and, to a lesser extent, to mitochondria and other cytoplasmic membranes, including post-translational association with microsomes.","method":"Yeast two-hybrid screen, in vitro binding assay (MBP-aFGF pulldown), cell-free translation + microsome association, immunoblot, fluorescence microscopy","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (yeast two-hybrid, in vitro pulldown with mutant specificity control, microsome association, subcellular localization by immunoblot and fluorescence microscopy) in a single foundational study","pmids":["9806903"],"is_preprint":false},{"year":2000,"finding":"The human FIBP gene spans >5 kb, comprises ten exons and nine introns, and maps to chromosome 11q13.1. Two splice variants exist in different tissues. Functional promoter analysis with a luciferase reporter system localized strong transcriptional activity to within 600 bp of the 5′ flanking region. Comparative analysis showed FIBP is evolutionarily conserved across human, mouse, and Drosophila.","method":"Genomic mapping, splice variant cloning and sequencing, luciferase reporter assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter functional assay plus genomic characterization, single lab, two methods","pmids":["11104667"],"is_preprint":false},{"year":2003,"finding":"A Drosophila FIBP homologue (DrFIBP) was cloned and characterized; it shares conserved structural architecture with human FIBP. DrFIBP is expressed during embryonic, larval, and adult stages and is spatially expressed in the developing tracheal system and ventral midline cells — two known sites of FGF signaling — as determined by whole-mount embryo immunostaining.","method":"Cloning, comparative sequence analysis, RT-PCR, whole-mount embryo immunostaining","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct spatial localization by immunostaining in Drosophila ortholog, linking FIBP to FGF signaling sites; single lab","pmids":["12801646"],"is_preprint":false},{"year":2008,"finding":"RNA interference-mediated inhibition of FIBP in bovine granulosa cells in vitro inhibited estradiol production, suggesting FIBP promotes estradiol biosynthesis in granulosa cells of regressing subordinate follicles.","method":"RNA interference (RNAi) knockdown in primary granulosa cells, estradiol production assay","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct loss-of-function with defined cellular phenotype (estradiol output), single lab, single method","pmids":["18285519"],"is_preprint":false},{"year":2014,"finding":"FIBP was identified as a novel CDK5-binding partner in non-neuronal cells. FIBP, CDK5, and KIAA0528 form a stable trimeric complex, with KIAA0528 and FIBP both required for the assembly and stability of the complex. Depletion of FIBP (or CDK5 or KIAA0528) in breast cancer cells impaired cell proliferation and decreased migration.","method":"Proteomic CDK family interactome (AP-MS with SAINT analysis), Co-IP validation, siRNA knockdown with proliferation and migration assays","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry interactome plus functional KD phenotype, single lab, two orthogonal approaches","pmids":["25096995"],"is_preprint":false},{"year":2016,"finding":"A homozygous nonsense FIBP variant in a patient caused FIBP mRNA degradation (likely NMD) and resulted in increased proliferation capacity of the patient's fibroblasts compared with controls, linking FIBP loss-of-function to enhanced cell proliferation in the context of an overgrowth syndrome.","method":"Exome sequencing, RT-PCR (cDNA degradation), in vitro cellular proliferation assay","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function (nonsense mutation with mRNA degradation confirmed) plus cellular proliferation assay; single patient/lab but two orthogonal readouts","pmids":["26660953"],"is_preprint":false},{"year":2016,"finding":"An in-frame insertion in FIBP (p.H59LN) in three affected siblings with an overgrowth syndrome caused increased proliferation capacity in patient skin fibroblasts compared to controls. In situ hybridization in mouse embryos detected Fibp expression most notably in the brain, suggesting a role in cognitive development.","method":"Whole-genome genotyping, whole-exome sequencing, in vitro cellular proliferation assay, in situ hybridization in mouse embryos","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with proliferation assay and in vivo expression evidence; single lab, two orthogonal methods","pmids":["27183861"],"is_preprint":false},{"year":2018,"finding":"FIBP knockdown in colorectal cancer stem cells inhibited proliferation, enhanced chemotherapy sensitivity, and reduced stemness markers in vitro and in vivo. Mechanistically, FIBP bound to GSK3β and inhibited its phosphorylation at Tyr216, thereby activating β-catenin/TCF/cyclin D1 signaling. Additional GSK3β knockdown reversed FIBP-silencing-induced inhibition of proliferation. FIBP also regulated stemness via methylation activity dependent on GSK3β but independent of β-catenin.","method":"shRNA knockdown, Co-IP (FIBP–GSK3β interaction), phosphorylation assay, RNA-seq + GSEA, in vivo xenograft, GSK3β rescue knockdown, DNA methylation profiling","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including direct protein interaction (Co-IP), phosphorylation measurement, genetic epistasis rescue, and in vivo validation in a single rigorous study","pmids":["30275459"],"is_preprint":false},{"year":2022,"finding":"FIBP knockdown in murine and human CD8+ T cells significantly enhanced T cell-mediated cancer killing in in vitro co-culture assays. Fibp knockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 melanoma model. Mechanistically, Fibp knockout T cells exhibited reduced cholesterol metabolism, which was identified as the pathway through which FIBP inhibits effector T cell function.","method":"CRISPR/Cas9 knockout in murine and human CD8+ T cells, in vitro tumor co-culture killing assay, in vivo adoptive cell transfer (B16 tumor model), cholesterol metabolism profiling","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic knockout in two species (mouse and human), in vitro and in vivo orthogonal functional assays, metabolic pathway identification; multiple methods in one rigorous study","pmids":["35501486"],"is_preprint":false},{"year":2023,"finding":"FIBP interacts with transcription factor STAT3 to enhance its transcriptional activity, leading to induced expression of the downstream target gene EME1. Depletion of FIBP inhibited lung adenocarcinoma progression and radioresistance in vitro and in vivo, and the biological effects of FIBP were partially dependent on EME1.","method":"Co-IP (FIBP–STAT3 interaction), STAT3 transcriptional activity assay, EME1 expression analysis, FIBP knockdown in vitro and in vivo, EME1 rescue experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue and in vivo data; single lab but multiple methods","pmids":["37564211"],"is_preprint":false},{"year":2025,"finding":"USP5 was found to interact with a protein complex containing FIBP, C2CD5, and CDK5, as identified by co-immunoprecipitation coupled with mass spectrometry in AML cells, confirming FIBP participates in this multi-protein complex.","method":"Co-immunoprecipitation coupled with mass spectrometry","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS identification, no specific functional follow-up on FIBP's role in the complex, single lab","pmids":["41344512"],"is_preprint":false}],"current_model":"FIBP is an evolutionarily conserved intracellular protein that binds selectively to mitogenic aFGF/FGF1, localizes predominantly to the nucleus and cytoplasmic membranes, and functions as a modulator of FGF signaling-dependent cell proliferation; it forms a stable trimeric complex with CDK5 and KIAA0528 required for cell growth and migration, binds GSK3β to inhibit its Tyr216 phosphorylation thereby activating β-catenin/cyclin D1 signaling and regulating DNA methylation-dependent stemness, interacts with STAT3 to enhance its transcriptional activity and induce EME1 expression driving radioresistance, and negatively regulates effector CD8+ T cell function through promotion of cholesterol metabolism."},"narrative":{"mechanistic_narrative":"FIBP is an evolutionarily conserved intracellular protein, originally identified as a selective binding partner for mitogenic acidic FGF (FGF1) that distinguishes the mitogenic conformation from a non-mitogenic mutant, and it localizes predominantly to the nucleus with additional association to mitochondria and cytoplasmic membranes [PMID:9806903]. Across multiple cancer contexts FIBP acts as a positive modulator of proliferation and stemness: it binds GSK3β and blocks its Tyr216 phosphorylation to activate β-catenin/TCF/cyclin D1 signaling and to control DNA-methylation–dependent stemness in colorectal cancer stem cells [PMID:30275459], and it interacts with STAT3 to enhance its transcriptional activity and induce EME1, driving lung adenocarcinoma progression and radioresistance [PMID:37564211]. FIBP is also a stable subunit of a CDK5–KIAA0528 trimeric complex whose assembly requires FIBP and that supports cancer cell proliferation and migration [PMID:25096995]. Beyond tumor-cell-intrinsic roles, FIBP restrains effector CD8+ T cell function by promoting cholesterol metabolism, such that its loss potentiates anti-tumor T cell killing [PMID:35501486]. Consistent with a growth-restraining role in normal tissue, loss-of-function FIBP variants in human overgrowth syndromes increase the proliferative capacity of patient fibroblasts [PMID:26660953, PMID:27183861].","teleology":[{"year":1998,"claim":"Established FIBP as a discrete intracellular protein that reads the mitogenic state of acidic FGF, providing the first molecular link between FIBP and FGF-dependent proliferation.","evidence":"Yeast two-hybrid screen and in vitro MBP-aFGF pulldown with a non-mitogenic mutant control, plus subcellular localization by immunoblot and fluorescence microscopy","pmids":["9806903"],"confidence":"High","gaps":["No structure of the FIBP–aFGF interface","Functional consequence of aFGF binding for downstream signaling not tested","Nuclear versus membrane pools not functionally distinguished"]},{"year":2000,"claim":"Defined the human FIBP gene structure, chromosomal location, splice variants, and an active promoter, framing FIBP as a regulated, conserved locus.","evidence":"Genomic mapping, splice variant cloning, and luciferase promoter reporter assay","pmids":["11104667"],"confidence":"Medium","gaps":["Tissue-specific roles of the two splice variants unresolved","Transcription factors driving the promoter not identified"]},{"year":2003,"claim":"Showed the FIBP ortholog is spatially expressed at canonical FGF-signaling sites in Drosophila, reinforcing a conserved developmental link to FGF biology.","evidence":"Cloning, RT-PCR, and whole-mount embryo immunostaining of DrFIBP","pmids":["12801646"],"confidence":"Medium","gaps":["No genetic perturbation of DrFIBP to test FGF pathway requirement","Spatial expression does not establish a mechanistic role"]},{"year":2008,"claim":"Provided first loss-of-function evidence that FIBP supports a defined cellular output, here estradiol biosynthesis in granulosa cells.","evidence":"RNAi knockdown in primary bovine granulosa cells with estradiol production readout","pmids":["18285519"],"confidence":"Medium","gaps":["Mechanism linking FIBP to steroidogenesis not defined","Single method, single cell type"]},{"year":2014,"claim":"Identified FIBP as an assembly-required subunit of a CDK5–KIAA0528 trimeric complex in non-neuronal cells and tied it to proliferation and migration.","evidence":"AP-MS interactome with SAINT, Co-IP validation, and siRNA knockdown proliferation/migration assays in breast cancer cells","pmids":["25096995"],"confidence":"Medium","gaps":["Catalytic or substrate role of the complex not defined","How FIBP stabilizes the complex structurally unknown"]},{"year":2016,"claim":"Linked human FIBP loss-of-function to an overgrowth phenotype, indicating FIBP normally restrains proliferation in vivo.","evidence":"Exome/genome sequencing of patients (nonsense and in-frame insertion variants), confirmed mRNA degradation, fibroblast proliferation assays, and mouse embryo in situ hybridization","pmids":["26660953","27183861"],"confidence":"Medium","gaps":["Mechanism connecting FIBP loss to fibroblast hyperproliferation not resolved","Brain expression role in cognitive phenotype untested functionally"]},{"year":2018,"claim":"Defined a concrete signaling mechanism: FIBP binds GSK3β to suppress its Tyr216 phosphorylation, activating β-catenin/cyclin D1 and separately controlling methylation-dependent stemness.","evidence":"shRNA knockdown, FIBP–GSK3β Co-IP, phosphorylation assay, RNA-seq/GSEA, GSK3β epistasis rescue, DNA methylation profiling, and xenografts in colorectal cancer stem cells","pmids":["30275459"],"confidence":"High","gaps":["Whether FIBP directly possesses methyltransferase activity or recruits one is unclear","Relationship between the GSK3β axis and the CDK5 complex not integrated"]},{"year":2022,"claim":"Revealed a cell-extrinsic immunoregulatory role: FIBP limits effector CD8+ T cell anti-tumor function via cholesterol metabolism, identifying it as an actionable immunotherapy target.","evidence":"CRISPR/Cas9 knockout in murine and human CD8+ T cells, tumor co-culture killing, in vivo adoptive transfer in B16 melanoma, and cholesterol metabolism profiling","pmids":["35501486"],"confidence":"High","gaps":["Molecular step by which FIBP controls cholesterol metabolism unknown","Whether the FGF/GSK3β/CDK5 activities operate in T cells untested"]},{"year":2023,"claim":"Added a transcriptional mechanism: FIBP enhances STAT3 activity to induce EME1, driving tumor progression and radioresistance.","evidence":"Reciprocal FIBP–STAT3 Co-IP, STAT3 transcriptional activity and EME1 expression assays, FIBP knockdown in vitro/in vivo, and EME1 rescue in lung adenocarcinoma","pmids":["37564211"],"confidence":"Medium","gaps":["Whether FIBP binds STAT3 directly or via a complex not resolved","How nuclear FIBP coordinates STAT3 versus GSK3β axes unknown"]},{"year":2025,"claim":"Extended the CDK5–FIBP complex inventory by placing USP5 and C2CD5 within it in AML cells.","evidence":"Co-immunoprecipitation coupled with mass spectrometry in AML cells","pmids":["41344512"],"confidence":"Low","gaps":["Single Co-IP/MS without functional follow-up on FIBP's role in the complex","Whether USP5 acts on FIBP stability untested"]},{"year":null,"claim":"It remains unknown how FIBP's distinct activities — aFGF binding, the CDK5 complex, GSK3β/β-catenin signaling, STAT3 transactivation, and cholesterol metabolism — are unified into a single biochemical function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No defined catalytic activity for FIBP itself","No structural model integrating its multiple partners","Relationship between nuclear and membrane-associated pools unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8]}],"complexes":["FIBP-CDK5-KIAA0528 trimeric complex"],"partners":["FGF1","CDK5","KIAA0528","GSK3B","STAT3","USP5","C2CD5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43427","full_name":"Acidic fibroblast growth factor intracellular-binding protein","aliases":["FGF-1 intracellular-binding protein"],"length_aa":364,"mass_kda":41.9,"function":"May be involved in mitogenic function of FGF1. May mediate with IER2 FGF-signaling in the establishment of laterality in the embryo (By similarity)","subcellular_location":"Nucleus; Endomembrane system","url":"https://www.uniprot.org/uniprotkb/O43427/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FIBP","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FIBP","total_profiled":1310},"omim":[{"mim_id":"617107","title":"THAUVIN-ROBINET-FAIVRE SYNDROME; TROFAS","url":"https://www.omim.org/entry/617107"},{"mim_id":"608296","title":"FIBROBLAST GROWTH FACTOR, ACIDIC, INTRACELLULAR BINDING PROTEIN; FIBP","url":"https://www.omim.org/entry/608296"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FIBP"},"hgnc":{"alias_symbol":["FGFIBP"],"prev_symbol":[]},"alphafold":{"accession":"O43427","domains":[{"cath_id":"-","chopping":"16-96","consensus_level":"high","plddt":93.679,"start":16,"end":96},{"cath_id":"-","chopping":"100-213","consensus_level":"high","plddt":94.9835,"start":100,"end":213},{"cath_id":"1.10.490","chopping":"234-360","consensus_level":"high","plddt":96.4889,"start":234,"end":360}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43427","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43427-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43427-F1-predicted_aligned_error_v6.png","plddt_mean":91.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FIBP","jax_strain_url":"https://www.jax.org/strain/search?query=FIBP"},"sequence":{"accession":"O43427","fasta_url":"https://rest.uniprot.org/uniprotkb/O43427.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43427/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43427"}},"corpus_meta":[{"pmid":"35931864","id":"PMC_35931864","title":"Genetics 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In vitro-translated FIBP bound specifically to a maltose-binding protein–aFGF fusion protein. The protein localizes predominantly to the nucleus and, to a lesser extent, to mitochondria and other cytoplasmic membranes, including post-translational association with microsomes.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay (MBP-aFGF pulldown), cell-free translation + microsome association, immunoblot, fluorescence microscopy\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (yeast two-hybrid, in vitro pulldown with mutant specificity control, microsome association, subcellular localization by immunoblot and fluorescence microscopy) in a single foundational study\",\n      \"pmids\": [\"9806903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human FIBP gene spans >5 kb, comprises ten exons and nine introns, and maps to chromosome 11q13.1. Two splice variants exist in different tissues. Functional promoter analysis with a luciferase reporter system localized strong transcriptional activity to within 600 bp of the 5′ flanking region. Comparative analysis showed FIBP is evolutionarily conserved across human, mouse, and Drosophila.\",\n      \"method\": \"Genomic mapping, splice variant cloning and sequencing, luciferase reporter assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter functional assay plus genomic characterization, single lab, two methods\",\n      \"pmids\": [\"11104667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A Drosophila FIBP homologue (DrFIBP) was cloned and characterized; it shares conserved structural architecture with human FIBP. DrFIBP is expressed during embryonic, larval, and adult stages and is spatially expressed in the developing tracheal system and ventral midline cells — two known sites of FGF signaling — as determined by whole-mount embryo immunostaining.\",\n      \"method\": \"Cloning, comparative sequence analysis, RT-PCR, whole-mount embryo immunostaining\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct spatial localization by immunostaining in Drosophila ortholog, linking FIBP to FGF signaling sites; single lab\",\n      \"pmids\": [\"12801646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RNA interference-mediated inhibition of FIBP in bovine granulosa cells in vitro inhibited estradiol production, suggesting FIBP promotes estradiol biosynthesis in granulosa cells of regressing subordinate follicles.\",\n      \"method\": \"RNA interference (RNAi) knockdown in primary granulosa cells, estradiol production assay\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct loss-of-function with defined cellular phenotype (estradiol output), single lab, single method\",\n      \"pmids\": [\"18285519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FIBP was identified as a novel CDK5-binding partner in non-neuronal cells. FIBP, CDK5, and KIAA0528 form a stable trimeric complex, with KIAA0528 and FIBP both required for the assembly and stability of the complex. Depletion of FIBP (or CDK5 or KIAA0528) in breast cancer cells impaired cell proliferation and decreased migration.\",\n      \"method\": \"Proteomic CDK family interactome (AP-MS with SAINT analysis), Co-IP validation, siRNA knockdown with proliferation and migration assays\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry interactome plus functional KD phenotype, single lab, two orthogonal approaches\",\n      \"pmids\": [\"25096995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A homozygous nonsense FIBP variant in a patient caused FIBP mRNA degradation (likely NMD) and resulted in increased proliferation capacity of the patient's fibroblasts compared with controls, linking FIBP loss-of-function to enhanced cell proliferation in the context of an overgrowth syndrome.\",\n      \"method\": \"Exome sequencing, RT-PCR (cDNA degradation), in vitro cellular proliferation assay\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function (nonsense mutation with mRNA degradation confirmed) plus cellular proliferation assay; single patient/lab but two orthogonal readouts\",\n      \"pmids\": [\"26660953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An in-frame insertion in FIBP (p.H59LN) in three affected siblings with an overgrowth syndrome caused increased proliferation capacity in patient skin fibroblasts compared to controls. In situ hybridization in mouse embryos detected Fibp expression most notably in the brain, suggesting a role in cognitive development.\",\n      \"method\": \"Whole-genome genotyping, whole-exome sequencing, in vitro cellular proliferation assay, in situ hybridization in mouse embryos\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with proliferation assay and in vivo expression evidence; single lab, two orthogonal methods\",\n      \"pmids\": [\"27183861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FIBP knockdown in colorectal cancer stem cells inhibited proliferation, enhanced chemotherapy sensitivity, and reduced stemness markers in vitro and in vivo. Mechanistically, FIBP bound to GSK3β and inhibited its phosphorylation at Tyr216, thereby activating β-catenin/TCF/cyclin D1 signaling. Additional GSK3β knockdown reversed FIBP-silencing-induced inhibition of proliferation. FIBP also regulated stemness via methylation activity dependent on GSK3β but independent of β-catenin.\",\n      \"method\": \"shRNA knockdown, Co-IP (FIBP–GSK3β interaction), phosphorylation assay, RNA-seq + GSEA, in vivo xenograft, GSK3β rescue knockdown, DNA methylation profiling\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including direct protein interaction (Co-IP), phosphorylation measurement, genetic epistasis rescue, and in vivo validation in a single rigorous study\",\n      \"pmids\": [\"30275459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FIBP knockdown in murine and human CD8+ T cells significantly enhanced T cell-mediated cancer killing in in vitro co-culture assays. Fibp knockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 melanoma model. Mechanistically, Fibp knockout T cells exhibited reduced cholesterol metabolism, which was identified as the pathway through which FIBP inhibits effector T cell function.\",\n      \"method\": \"CRISPR/Cas9 knockout in murine and human CD8+ T cells, in vitro tumor co-culture killing assay, in vivo adoptive cell transfer (B16 tumor model), cholesterol metabolism profiling\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic knockout in two species (mouse and human), in vitro and in vivo orthogonal functional assays, metabolic pathway identification; multiple methods in one rigorous study\",\n      \"pmids\": [\"35501486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FIBP interacts with transcription factor STAT3 to enhance its transcriptional activity, leading to induced expression of the downstream target gene EME1. Depletion of FIBP inhibited lung adenocarcinoma progression and radioresistance in vitro and in vivo, and the biological effects of FIBP were partially dependent on EME1.\",\n      \"method\": \"Co-IP (FIBP–STAT3 interaction), STAT3 transcriptional activity assay, EME1 expression analysis, FIBP knockdown in vitro and in vivo, EME1 rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue and in vivo data; single lab but multiple methods\",\n      \"pmids\": [\"37564211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP5 was found to interact with a protein complex containing FIBP, C2CD5, and CDK5, as identified by co-immunoprecipitation coupled with mass spectrometry in AML cells, confirming FIBP participates in this multi-protein complex.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS identification, no specific functional follow-up on FIBP's role in the complex, single lab\",\n      \"pmids\": [\"41344512\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FIBP is an evolutionarily conserved intracellular protein that binds selectively to mitogenic aFGF/FGF1, localizes predominantly to the nucleus and cytoplasmic membranes, and functions as a modulator of FGF signaling-dependent cell proliferation; it forms a stable trimeric complex with CDK5 and KIAA0528 required for cell growth and migration, binds GSK3β to inhibit its Tyr216 phosphorylation thereby activating β-catenin/cyclin D1 signaling and regulating DNA methylation-dependent stemness, interacts with STAT3 to enhance its transcriptional activity and induce EME1 expression driving radioresistance, and negatively regulates effector CD8+ T cell function through promotion of cholesterol metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FIBP is an evolutionarily conserved intracellular protein, originally identified as a selective binding partner for mitogenic acidic FGF (FGF1) that distinguishes the mitogenic conformation from a non-mitogenic mutant, and it localizes predominantly to the nucleus with additional association to mitochondria and cytoplasmic membranes [#0]. Across multiple cancer contexts FIBP acts as a positive modulator of proliferation and stemness: it binds GSK3\\u03b2 and blocks its Tyr216 phosphorylation to activate \\u03b2-catenin/TCF/cyclin D1 signaling and to control DNA-methylation\\u2013dependent stemness in colorectal cancer stem cells [#7], and it interacts with STAT3 to enhance its transcriptional activity and induce EME1, driving lung adenocarcinoma progression and radioresistance [#9]. FIBP is also a stable subunit of a CDK5\\u2013KIAA0528 trimeric complex whose assembly requires FIBP and that supports cancer cell proliferation and migration [#4]. Beyond tumor-cell-intrinsic roles, FIBP restrains effector CD8+ T cell function by promoting cholesterol metabolism, such that its loss potentiates anti-tumor T cell killing [#8]. Consistent with a growth-restraining role in normal tissue, loss-of-function FIBP variants in human overgrowth syndromes increase the proliferative capacity of patient fibroblasts [#5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established FIBP as a discrete intracellular protein that reads the mitogenic state of acidic FGF, providing the first molecular link between FIBP and FGF-dependent proliferation.\",\n      \"evidence\": \"Yeast two-hybrid screen and in vitro MBP-aFGF pulldown with a non-mitogenic mutant control, plus subcellular localization by immunoblot and fluorescence microscopy\",\n      \"pmids\": [\"9806903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the FIBP\\u2013aFGF interface\",\n        \"Functional consequence of aFGF binding for downstream signaling not tested\",\n        \"Nuclear versus membrane pools not functionally distinguished\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the human FIBP gene structure, chromosomal location, splice variants, and an active promoter, framing FIBP as a regulated, conserved locus.\",\n      \"evidence\": \"Genomic mapping, splice variant cloning, and luciferase promoter reporter assay\",\n      \"pmids\": [\"11104667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Tissue-specific roles of the two splice variants unresolved\",\n        \"Transcription factors driving the promoter not identified\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed the FIBP ortholog is spatially expressed at canonical FGF-signaling sites in Drosophila, reinforcing a conserved developmental link to FGF biology.\",\n      \"evidence\": \"Cloning, RT-PCR, and whole-mount embryo immunostaining of DrFIBP\",\n      \"pmids\": [\"12801646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No genetic perturbation of DrFIBP to test FGF pathway requirement\",\n        \"Spatial expression does not establish a mechanistic role\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided first loss-of-function evidence that FIBP supports a defined cellular output, here estradiol biosynthesis in granulosa cells.\",\n      \"evidence\": \"RNAi knockdown in primary bovine granulosa cells with estradiol production readout\",\n      \"pmids\": [\"18285519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking FIBP to steroidogenesis not defined\",\n        \"Single method, single cell type\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified FIBP as an assembly-required subunit of a CDK5\\u2013KIAA0528 trimeric complex in non-neuronal cells and tied it to proliferation and migration.\",\n      \"evidence\": \"AP-MS interactome with SAINT, Co-IP validation, and siRNA knockdown proliferation/migration assays in breast cancer cells\",\n      \"pmids\": [\"25096995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Catalytic or substrate role of the complex not defined\",\n        \"How FIBP stabilizes the complex structurally unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked human FIBP loss-of-function to an overgrowth phenotype, indicating FIBP normally restrains proliferation in vivo.\",\n      \"evidence\": \"Exome/genome sequencing of patients (nonsense and in-frame insertion variants), confirmed mRNA degradation, fibroblast proliferation assays, and mouse embryo in situ hybridization\",\n      \"pmids\": [\"26660953\", \"27183861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting FIBP loss to fibroblast hyperproliferation not resolved\",\n        \"Brain expression role in cognitive phenotype untested functionally\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a concrete signaling mechanism: FIBP binds GSK3\\u03b2 to suppress its Tyr216 phosphorylation, activating \\u03b2-catenin/cyclin D1 and separately controlling methylation-dependent stemness.\",\n      \"evidence\": \"shRNA knockdown, FIBP\\u2013GSK3\\u03b2 Co-IP, phosphorylation assay, RNA-seq/GSEA, GSK3\\u03b2 epistasis rescue, DNA methylation profiling, and xenografts in colorectal cancer stem cells\",\n      \"pmids\": [\"30275459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether FIBP directly possesses methyltransferase activity or recruits one is unclear\",\n        \"Relationship between the GSK3\\u03b2 axis and the CDK5 complex not integrated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a cell-extrinsic immunoregulatory role: FIBP limits effector CD8+ T cell anti-tumor function via cholesterol metabolism, identifying it as an actionable immunotherapy target.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in murine and human CD8+ T cells, tumor co-culture killing, in vivo adoptive transfer in B16 melanoma, and cholesterol metabolism profiling\",\n      \"pmids\": [\"35501486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular step by which FIBP controls cholesterol metabolism unknown\",\n        \"Whether the FGF/GSK3\\u03b2/CDK5 activities operate in T cells untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added a transcriptional mechanism: FIBP enhances STAT3 activity to induce EME1, driving tumor progression and radioresistance.\",\n      \"evidence\": \"Reciprocal FIBP\\u2013STAT3 Co-IP, STAT3 transcriptional activity and EME1 expression assays, FIBP knockdown in vitro/in vivo, and EME1 rescue in lung adenocarcinoma\",\n      \"pmids\": [\"37564211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FIBP binds STAT3 directly or via a complex not resolved\",\n        \"How nuclear FIBP coordinates STAT3 versus GSK3\\u03b2 axes unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the CDK5\\u2013FIBP complex inventory by placing USP5 and C2CD5 within it in AML cells.\",\n      \"evidence\": \"Co-immunoprecipitation coupled with mass spectrometry in AML cells\",\n      \"pmids\": [\"41344512\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single Co-IP/MS without functional follow-up on FIBP's role in the complex\",\n        \"Whether USP5 acts on FIBP stability untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how FIBP's distinct activities \\u2014 aFGF binding, the CDK5 complex, GSK3\\u03b2/\\u03b2-catenin signaling, STAT3 transactivation, and cholesterol metabolism \\u2014 are unified into a single biochemical function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No defined catalytic activity for FIBP itself\",\n        \"No structural model integrating its multiple partners\",\n        \"Relationship between nuclear and membrane-associated pools unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"FIBP-CDK5-KIAA0528 trimeric complex\"],\n    \"partners\": [\"FGF1\", \"CDK5\", \"KIAA0528\", \"GSK3B\", \"STAT3\", \"USP5\", \"C2CD5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}