{"gene":"FIBP","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1998,"finding":"FIBP (aFGF intracellular binding protein) was identified as a novel 42 kDa intracellular protein that binds specifically to mitogenic acidic fibroblast growth factor (aFGF) but not to the non-mitogenic mutant aFGF-K132E, indicating selectivity for the mitogenic form. In vitro-translated FIBP bound to a maltose-binding protein–aFGF fusion protein, and membrane-associated FIBP bound aFGF with high efficiency. The protein localizes primarily to nuclei and, to a lesser extent, to mitochondria and other cytoplasmic membranes.","method":"Yeast two-hybrid screen, in vitro binding assay with MBP-aFGF fusion protein, cell-free translation with microsome association, immunoblot, fluorescence microscopy","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — original discovery paper with multiple orthogonal methods (yeast two-hybrid, in vitro binding reconstitution, subcellular fractionation, imaging)","pmids":["9806903"],"is_preprint":false},{"year":2000,"finding":"The human FIBP gene maps to chromosome 11q13.1, spans >5 kb with ten exons and nine introns, has a CpG island near the translation start, and contains a strong promoter within 600 bp of the 5′ flanking region. Two splice variants exist in different tissues. FIBP protein sequence is evolutionarily conserved across human, mouse, and Drosophila.","method":"Gene mapping, promoter-luciferase reporter assay, sequence analysis, comparative genomics","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — functional promoter assay plus genomic characterization in a single study","pmids":["11104667"],"is_preprint":false},{"year":2003,"finding":"Drosophila FIBP (DrFIBP) is a genuine homologue of human FIBP with conserved structural architecture. DrFIBP mRNA undergoes differential splicing by intron retention, producing three transcripts with premature stop codons. In situ immunostaining shows DrFIBP is expressed in developing tracheal system and ventral midline cells — known sites of FGF signaling in Drosophila.","method":"Cloning, RT-PCR, comparative sequence analysis, whole-mount embryo immunostaining","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment in Drosophila ortholog linked to known FGF signaling sites","pmids":["12801646"],"is_preprint":false},{"year":2014,"finding":"FIBP forms a stable trimeric complex with CDK5 and KIAA0528 in non-neuronal cells. KIAA0528 and FIBP are each required for assembly and stability of this complex. Depletion of CDK5, KIAA0528, or FIBP in breast cancer cells impaired proliferation and decreased cell migration.","method":"Mass spectrometry-based proteomic interactome (SAINT analysis), co-immunoprecipitation, siRNA knockdown with proliferation and migration assays","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 — MS interactome with reciprocal co-IP validation and loss-of-function phenotype across two cell lines","pmids":["25096995"],"is_preprint":false},{"year":2016,"finding":"A homozygous nonsense FIBP variant in a patient leads to FIBP cDNA degradation (NMD) and increased fibroblast proliferation capacity compared to controls, placing FIBP as a negative regulator of cell proliferation in the FGF signaling pathway. Loss of FIBP function causes an overgrowth syndrome.","method":"Exome sequencing, RT-PCR (cDNA degradation), in vitro cellular proliferation assay","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function (human variant) with direct cellular proliferation readout","pmids":["26660953"],"is_preprint":false},{"year":2016,"finding":"An in-frame FIBP insertion (p.H59LN) predicted to alter protein conformation causes autosomal recessive overgrowth syndrome. Patient skin fibroblasts show increased proliferation compared to controls. In situ hybridization in mouse embryos reveals Fibp expression predominantly in the brain, suggesting a role in early cognitive development.","method":"Whole-genome genotyping, whole-exome sequencing, in vitro proliferation assay, in situ hybridization in mouse embryos","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 — human variant with functional cellular readout and in vivo expression data","pmids":["27183861"],"is_preprint":false},{"year":2018,"finding":"FIBP binds to GSK3β and inhibits its phosphorylation at Tyr216, thereby activating β-catenin/TCF/cyclin D1 signaling and promoting colorectal cancer stem cell proliferation and stemness. FIBP also regulates stemness via GSK3β-dependent but β-catenin-independent DNA methylation activity. GSK3β knockdown reversed FIBP-silencing-induced inhibition of proliferation.","method":"Co-immunoprecipitation (FIBP–GSK3β interaction), RNA-seq, GSEA, siRNA knockdown, GSK3β phosphorylation assay, in vivo xenograft, DNA methylation profiling, epistasis by double knockdown","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus genetic epistasis (double KD rescue) plus multiple orthogonal functional readouts","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 vitro and potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. FIBP-knockout T cells exhibit reduced cholesterol metabolism, which normally inhibits effector T cell function, placing FIBP as a positive regulator of cholesterol metabolism that suppresses T cell anti-tumor activity.","method":"CRISPR/siRNA knockdown in murine and human T cells, in vitro co-culture cancer killing assay, in vivo adoptive cell transfer (B16 model), metabolic profiling (cholesterol)","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype replicated in murine and human systems plus in vivo validation and metabolic mechanism","pmids":["35501486"],"is_preprint":false},{"year":2023,"finding":"FIBP interacts with transcription factor STAT3 to enhance its transcriptional activity, thereby inducing expression of the DNA repair gene EME1. This FIBP–STAT3–EME1 axis drives lung adenocarcinoma progression and radioresistance. The biological effects of FIBP are partially dependent on EME1.","method":"Co-immunoprecipitation (FIBP–STAT3 interaction), siRNA knockdown, luciferase reporter assay (STAT3 transcriptional activity), in vitro and in vivo (xenograft) functional assays, EME1 rescue experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with functional epistasis (EME1 rescue) and in vivo validation, single lab","pmids":["37564211"],"is_preprint":false},{"year":2025,"finding":"FIBP was identified as a component of a protein complex containing USP5, C2CD5, and CDK5 in AML cells, detected by co-immunoprecipitation coupled with mass spectrometry.","method":"Co-immunoprecipitation coupled with mass spectrometry","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 — single co-IP/MS identification of FIBP in a complex; the mechanistic focus of the paper is on USP5-C2CD5, not FIBP","pmids":["41344512"],"is_preprint":false}],"current_model":"FIBP is a nuclear/intracellular protein that binds selectively to mitogenic aFGF (FGF1) and functions as a component of multi-protein complexes (including CDK5–KIAA0528 and USP5–C2CD5), negatively regulates GSK3β (by inhibiting its Tyr216 phosphorylation to activate β-catenin/cyclin D1 signaling), interacts with STAT3 to drive EME1-dependent transcription and radioresistance, and suppresses CD8+ T cell anti-tumor activity by promoting cholesterol metabolism; loss-of-function causes increased cellular proliferation and an autosomal recessive overgrowth syndrome in humans."},"narrative":{"teleology":[{"year":1998,"claim":"The identity of intracellular FGF1-binding partners was unknown; discovery of FIBP as a 42 kDa nuclear protein that selectively binds mitogenic aFGF but not the non-mitogenic K132E mutant established a candidate effector linking internalized FGF1 to intracellular signaling.","evidence":"Yeast two-hybrid screen followed by in vitro MBP-aFGF binding assay, subcellular fractionation, and fluorescence microscopy in mammalian cells","pmids":["9806903"],"confidence":"High","gaps":["No downstream signaling pathway identified","Binding interface and stoichiometry uncharacterized","No loss-of-function phenotype demonstrated"]},{"year":2000,"claim":"The genomic organization of FIBP was undefined; mapping to 11q13.1 and identification of a CpG-island promoter with two tissue-specific splice variants established FIBP as a broadly expressed, evolutionarily conserved gene with regulated transcription.","evidence":"Gene mapping, promoter-luciferase reporter assay, comparative genomics across human, mouse, Drosophila","pmids":["11104667"],"confidence":"Medium","gaps":["Transcriptional regulators of the FIBP promoter not identified","Functional significance of splice variants unknown"]},{"year":2003,"claim":"Whether FIBP function is conserved beyond mammals was unclear; demonstration that Drosophila FIBP is expressed in tracheal system and ventral midline cells — known FGF signaling sites — supported a conserved role in FGF-mediated processes.","evidence":"Cloning, RT-PCR, and whole-mount embryo immunostaining of DrFIBP in Drosophila","pmids":["12801646"],"confidence":"Medium","gaps":["No Drosophila loss-of-function phenotype reported","Direct binding of DrFIBP to Drosophila FGFs not tested"]},{"year":2014,"claim":"The protein complexes through which FIBP acts were unknown; identification of a stable CDK5–KIAA0528–FIBP trimeric complex required for breast cancer cell proliferation and migration revealed FIBP as a structural component of a CDK5 signaling module in non-neuronal cells.","evidence":"MS-based interactome with SAINT analysis, reciprocal co-IP, siRNA knockdown with proliferation/migration assays in breast cancer cell lines","pmids":["25096995"],"confidence":"High","gaps":["CDK5 substrates phosphorylated in a FIBP-dependent manner not identified","How FIBP stabilizes the trimeric complex is structurally unresolved"]},{"year":2016,"claim":"Whether FIBP loss has consequences in human development was unknown; identification of biallelic FIBP mutations causing autosomal recessive overgrowth with increased fibroblast proliferation established FIBP as a negative regulator of cell growth in vivo.","evidence":"Exome/whole-genome sequencing of affected individuals, RT-PCR showing NMD, and in vitro proliferation assays on patient fibroblasts","pmids":["26660953","27183861"],"confidence":"Medium","gaps":["Molecular pathway mediating overgrowth not determined","Limited number of families studied","No animal model of FIBP-null developmental phenotype"]},{"year":2018,"claim":"The signaling mechanism by which FIBP promotes cancer cell stemness was unresolved; demonstration that FIBP binds GSK3β and inhibits its Tyr216 phosphorylation, thereby activating β-catenin/cyclin D1 and modulating DNA methylation, defined a specific oncogenic signaling axis for FIBP.","evidence":"Reciprocal co-IP of FIBP–GSK3β, phosphorylation assays, RNA-seq/GSEA, genetic epistasis by double knockdown, xenograft tumor assays, DNA methylation profiling in colorectal cancer stem cells","pmids":["30275459"],"confidence":"High","gaps":["Whether FIBP directly inhibits a Tyr216 kinase or blocks GSK3β autophosphorylation is unclear","Structural basis of FIBP–GSK3β interaction unknown"]},{"year":2022,"claim":"Whether FIBP has immune-regulatory functions was unexplored; showing that FIBP knockout in CD8+ T cells reduces cholesterol metabolism and enhances anti-tumor killing in vitro and in vivo revealed FIBP as a T cell-intrinsic immunosuppressive factor.","evidence":"CRISPR knockout and siRNA knockdown in murine and human CD8+ T cells, co-culture killing assays, in vivo adoptive cell transfer in B16 melanoma model, cholesterol metabolic profiling","pmids":["35501486"],"confidence":"High","gaps":["Specific cholesterol biosynthetic enzymes regulated by FIBP not identified","Whether the T cell phenotype depends on CDK5 or GSK3β axes is unknown"]},{"year":2023,"claim":"How FIBP contributes to therapy resistance was undefined; identification of FIBP–STAT3 interaction driving EME1 transcription and radioresistance established a FIBP-dependent DNA repair axis in lung adenocarcinoma.","evidence":"Co-IP of FIBP–STAT3, STAT3 luciferase reporter assay, siRNA knockdown, EME1 rescue experiments, xenograft validation","pmids":["37564211"],"confidence":"Medium","gaps":["Whether FIBP acts as a transcriptional co-activator or affects STAT3 post-translational modification is unknown","Not independently replicated outside a single lab","Relationship of STAT3 axis to GSK3β and CDK5 pathways unclear"]},{"year":null,"claim":"A unifying structural and mechanistic model explaining how FIBP simultaneously engages CDK5, GSK3β, and STAT3 — and whether these represent context-dependent or concurrent functions — remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of FIBP or its complexes","How FGF1 binding relates to downstream GSK3β/CDK5/STAT3 effector functions is unresolved","Whether the overgrowth syndrome phenotype maps to a specific FIBP signaling axis is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6]}],"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":[0,6,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7]}],"complexes":["CDK5–KIAA0528–FIBP trimeric complex","USP5–C2CD5–CDK5–FIBP complex"],"partners":["FGF1","CDK5","KIAA0528","GSK3B","STAT3","USP5","C2CD5"],"other_free_text":[]},"mechanistic_narrative":"FIBP is an intracellular, predominantly nuclear protein originally identified as a selective binding partner of mitogenic acidic fibroblast growth factor (FGF1) that functions in growth regulation, cancer stemness, immune evasion, and DNA damage repair through multiple signaling axes. FIBP forms a stable trimeric complex with CDK5 and KIAA0528 to promote cell proliferation and migration, binds and inhibits GSK3β Tyr216 phosphorylation to activate β-catenin/cyclin D1 signaling and modulate DNA methylation in colorectal cancer stem cells, and interacts with STAT3 to drive EME1-dependent transcription and radioresistance in lung adenocarcinoma [PMID:25096995, PMID:30275459, PMID:37564211]. In CD8+ T cells, FIBP positively regulates cholesterol metabolism to suppress anti-tumor effector function, and its deletion enhances T cell-mediated tumor killing in vivo [PMID:35501486]. Biallelic loss-of-function mutations in FIBP cause an autosomal recessive overgrowth syndrome in humans, consistent with its role as a negative regulator of cell proliferation [PMID:26660953, PMID:27183861]."},"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 to a maltose-binding protein–aFGF fusion protein, and membrane-associated FIBP bound aFGF with high efficiency. The protein localizes primarily to nuclei and, to a lesser extent, to mitochondria and other cytoplasmic membranes.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay with MBP-aFGF fusion protein, cell-free translation with microsome association, immunoblot, fluorescence microscopy\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original discovery paper with multiple orthogonal methods (yeast two-hybrid, in vitro binding reconstitution, subcellular fractionation, imaging)\",\n      \"pmids\": [\"9806903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human FIBP gene maps to chromosome 11q13.1, spans >5 kb with ten exons and nine introns, has a CpG island near the translation start, and contains a strong promoter within 600 bp of the 5′ flanking region. Two splice variants exist in different tissues. FIBP protein sequence is evolutionarily conserved across human, mouse, and Drosophila.\",\n      \"method\": \"Gene mapping, promoter-luciferase reporter assay, sequence analysis, comparative genomics\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional promoter assay plus genomic characterization in a single study\",\n      \"pmids\": [\"11104667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Drosophila FIBP (DrFIBP) is a genuine homologue of human FIBP with conserved structural architecture. DrFIBP mRNA undergoes differential splicing by intron retention, producing three transcripts with premature stop codons. In situ immunostaining shows DrFIBP is expressed in developing tracheal system and ventral midline cells — known sites of FGF signaling in Drosophila.\",\n      \"method\": \"Cloning, RT-PCR, comparative sequence analysis, whole-mount embryo immunostaining\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment in Drosophila ortholog linked to known FGF signaling sites\",\n      \"pmids\": [\"12801646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FIBP forms a stable trimeric complex with CDK5 and KIAA0528 in non-neuronal cells. KIAA0528 and FIBP are each required for assembly and stability of this complex. Depletion of CDK5, KIAA0528, or FIBP in breast cancer cells impaired proliferation and decreased cell migration.\",\n      \"method\": \"Mass spectrometry-based proteomic interactome (SAINT analysis), co-immunoprecipitation, siRNA knockdown with proliferation and migration assays\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS interactome with reciprocal co-IP validation and loss-of-function phenotype across two cell lines\",\n      \"pmids\": [\"25096995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A homozygous nonsense FIBP variant in a patient leads to FIBP cDNA degradation (NMD) and increased fibroblast proliferation capacity compared to controls, placing FIBP as a negative regulator of cell proliferation in the FGF signaling pathway. Loss of FIBP function causes 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 — loss-of-function (human variant) with direct cellular proliferation readout\",\n      \"pmids\": [\"26660953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An in-frame FIBP insertion (p.H59LN) predicted to alter protein conformation causes autosomal recessive overgrowth syndrome. Patient skin fibroblasts show increased proliferation compared to controls. In situ hybridization in mouse embryos reveals Fibp expression predominantly in the brain, suggesting a role in early cognitive development.\",\n      \"method\": \"Whole-genome genotyping, whole-exome sequencing, in vitro 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 — human variant with functional cellular readout and in vivo expression data\",\n      \"pmids\": [\"27183861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FIBP binds to GSK3β and inhibits its phosphorylation at Tyr216, thereby activating β-catenin/TCF/cyclin D1 signaling and promoting colorectal cancer stem cell proliferation and stemness. FIBP also regulates stemness via GSK3β-dependent but β-catenin-independent DNA methylation activity. GSK3β knockdown reversed FIBP-silencing-induced inhibition of proliferation.\",\n      \"method\": \"Co-immunoprecipitation (FIBP–GSK3β interaction), RNA-seq, GSEA, siRNA knockdown, GSK3β phosphorylation assay, in vivo xenograft, DNA methylation profiling, epistasis by double knockdown\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus genetic epistasis (double KD rescue) plus multiple orthogonal functional readouts\",\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 vitro and potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. FIBP-knockout T cells exhibit reduced cholesterol metabolism, which normally inhibits effector T cell function, placing FIBP as a positive regulator of cholesterol metabolism that suppresses T cell anti-tumor activity.\",\n      \"method\": \"CRISPR/siRNA knockdown in murine and human T cells, in vitro co-culture cancer killing assay, in vivo adoptive cell transfer (B16 model), metabolic profiling (cholesterol)\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype replicated in murine and human systems plus in vivo validation and metabolic mechanism\",\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, thereby inducing expression of the DNA repair gene EME1. This FIBP–STAT3–EME1 axis drives lung adenocarcinoma progression and radioresistance. The biological effects of FIBP are partially dependent on EME1.\",\n      \"method\": \"Co-immunoprecipitation (FIBP–STAT3 interaction), siRNA knockdown, luciferase reporter assay (STAT3 transcriptional activity), in vitro and in vivo (xenograft) functional assays, EME1 rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with functional epistasis (EME1 rescue) and in vivo validation, single lab\",\n      \"pmids\": [\"37564211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FIBP was identified as a component of a protein complex containing USP5, C2CD5, and CDK5 in AML cells, detected by co-immunoprecipitation coupled with mass spectrometry.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP/MS identification of FIBP in a complex; the mechanistic focus of the paper is on USP5-C2CD5, not FIBP\",\n      \"pmids\": [\"41344512\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FIBP is a nuclear/intracellular protein that binds selectively to mitogenic aFGF (FGF1) and functions as a component of multi-protein complexes (including CDK5–KIAA0528 and USP5–C2CD5), negatively regulates GSK3β (by inhibiting its Tyr216 phosphorylation to activate β-catenin/cyclin D1 signaling), interacts with STAT3 to drive EME1-dependent transcription and radioresistance, and suppresses CD8+ T cell anti-tumor activity by promoting cholesterol metabolism; loss-of-function causes increased cellular proliferation and an autosomal recessive overgrowth syndrome in humans.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FIBP is an intracellular, predominantly nuclear protein originally identified as a selective binding partner of mitogenic acidic fibroblast growth factor (FGF1) that functions in growth regulation, cancer stemness, immune evasion, and DNA damage repair through multiple signaling axes. FIBP forms a stable trimeric complex with CDK5 and KIAA0528 to promote cell proliferation and migration, binds and inhibits GSK3β Tyr216 phosphorylation to activate β-catenin/cyclin D1 signaling and modulate DNA methylation in colorectal cancer stem cells, and interacts with STAT3 to drive EME1-dependent transcription and radioresistance in lung adenocarcinoma [PMID:25096995, PMID:30275459, PMID:37564211]. In CD8+ T cells, FIBP positively regulates cholesterol metabolism to suppress anti-tumor effector function, and its deletion enhances T cell-mediated tumor killing in vivo [PMID:35501486]. Biallelic loss-of-function mutations in FIBP cause an autosomal recessive overgrowth syndrome in humans, consistent with its role as a negative regulator of cell proliferation [PMID:26660953, PMID:27183861].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"The identity of intracellular FGF1-binding partners was unknown; discovery of FIBP as a 42 kDa nuclear protein that selectively binds mitogenic aFGF but not the non-mitogenic K132E mutant established a candidate effector linking internalized FGF1 to intracellular signaling.\",\n      \"evidence\": \"Yeast two-hybrid screen followed by in vitro MBP-aFGF binding assay, subcellular fractionation, and fluorescence microscopy in mammalian cells\",\n      \"pmids\": [\"9806903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No downstream signaling pathway identified\", \"Binding interface and stoichiometry uncharacterized\", \"No loss-of-function phenotype demonstrated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The genomic organization of FIBP was undefined; mapping to 11q13.1 and identification of a CpG-island promoter with two tissue-specific splice variants established FIBP as a broadly expressed, evolutionarily conserved gene with regulated transcription.\",\n      \"evidence\": \"Gene mapping, promoter-luciferase reporter assay, comparative genomics across human, mouse, Drosophila\",\n      \"pmids\": [\"11104667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional regulators of the FIBP promoter not identified\", \"Functional significance of splice variants unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether FIBP function is conserved beyond mammals was unclear; demonstration that Drosophila FIBP is expressed in tracheal system and ventral midline cells — known FGF signaling sites — supported a conserved role in FGF-mediated processes.\",\n      \"evidence\": \"Cloning, RT-PCR, and whole-mount embryo immunostaining of DrFIBP in Drosophila\",\n      \"pmids\": [\"12801646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No Drosophila loss-of-function phenotype reported\", \"Direct binding of DrFIBP to Drosophila FGFs not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The protein complexes through which FIBP acts were unknown; identification of a stable CDK5–KIAA0528–FIBP trimeric complex required for breast cancer cell proliferation and migration revealed FIBP as a structural component of a CDK5 signaling module in non-neuronal cells.\",\n      \"evidence\": \"MS-based interactome with SAINT analysis, reciprocal co-IP, siRNA knockdown with proliferation/migration assays in breast cancer cell lines\",\n      \"pmids\": [\"25096995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CDK5 substrates phosphorylated in a FIBP-dependent manner not identified\", \"How FIBP stabilizes the trimeric complex is structurally unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether FIBP loss has consequences in human development was unknown; identification of biallelic FIBP mutations causing autosomal recessive overgrowth with increased fibroblast proliferation established FIBP as a negative regulator of cell growth in vivo.\",\n      \"evidence\": \"Exome/whole-genome sequencing of affected individuals, RT-PCR showing NMD, and in vitro proliferation assays on patient fibroblasts\",\n      \"pmids\": [\"26660953\", \"27183861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway mediating overgrowth not determined\", \"Limited number of families studied\", \"No animal model of FIBP-null developmental phenotype\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The signaling mechanism by which FIBP promotes cancer cell stemness was unresolved; demonstration that FIBP binds GSK3β and inhibits its Tyr216 phosphorylation, thereby activating β-catenin/cyclin D1 and modulating DNA methylation, defined a specific oncogenic signaling axis for FIBP.\",\n      \"evidence\": \"Reciprocal co-IP of FIBP–GSK3β, phosphorylation assays, RNA-seq/GSEA, genetic epistasis by double knockdown, xenograft tumor assays, DNA methylation profiling in colorectal cancer stem cells\",\n      \"pmids\": [\"30275459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FIBP directly inhibits a Tyr216 kinase or blocks GSK3β autophosphorylation is unclear\", \"Structural basis of FIBP–GSK3β interaction unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether FIBP has immune-regulatory functions was unexplored; showing that FIBP knockout in CD8+ T cells reduces cholesterol metabolism and enhances anti-tumor killing in vitro and in vivo revealed FIBP as a T cell-intrinsic immunosuppressive factor.\",\n      \"evidence\": \"CRISPR knockout and siRNA knockdown in murine and human CD8+ T cells, co-culture killing assays, in vivo adoptive cell transfer in B16 melanoma model, cholesterol metabolic profiling\",\n      \"pmids\": [\"35501486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific cholesterol biosynthetic enzymes regulated by FIBP not identified\", \"Whether the T cell phenotype depends on CDK5 or GSK3β axes is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How FIBP contributes to therapy resistance was undefined; identification of FIBP–STAT3 interaction driving EME1 transcription and radioresistance established a FIBP-dependent DNA repair axis in lung adenocarcinoma.\",\n      \"evidence\": \"Co-IP of FIBP–STAT3, STAT3 luciferase reporter assay, siRNA knockdown, EME1 rescue experiments, xenograft validation\",\n      \"pmids\": [\"37564211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FIBP acts as a transcriptional co-activator or affects STAT3 post-translational modification is unknown\", \"Not independently replicated outside a single lab\", \"Relationship of STAT3 axis to GSK3β and CDK5 pathways unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying structural and mechanistic model explaining how FIBP simultaneously engages CDK5, GSK3β, and STAT3 — and whether these represent context-dependent or concurrent functions — remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of FIBP or its complexes\", \"How FGF1 binding relates to downstream GSK3β/CDK5/STAT3 effector functions is unresolved\", \"Whether the overgrowth syndrome phenotype maps to a specific FIBP signaling axis is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6]}\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\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"CDK5–KIAA0528–FIBP trimeric complex\",\n      \"USP5–C2CD5–CDK5–FIBP complex\"\n    ],\n    \"partners\": [\n      \"FGF1\",\n      \"CDK5\",\n      \"KIAA0528\",\n      \"GSK3B\",\n      \"STAT3\",\n      \"USP5\",\n      \"C2CD5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}