{"gene":"FKBP15","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2008,"finding":"WAFL (FKBP15) associates with early endosomes via its central coiled-coil domain, interacts with WASP-interacting protein (WIP) and actin, and links to both microtubule and actin filament systems. RNAi depletion of WAFL results in delayed transport of endosomal cargo, indicating a role in early endosome transport at the transition between microfilament-based and microtubule-based movement.","method":"RNAi depletion, co-immunoprecipitation, fluorescence microscopy, functional endosomal transport assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with defined cargo transport phenotype, plus binding partner identification by co-IP, single lab with two orthogonal methods","pmids":["19121306"],"is_preprint":false},{"year":2012,"finding":"The Fam21 'tail' domain of the WASH complex binds directly to FKBP15, mediating membrane association of FKBP15. This interaction was identified as necessary for targeting FKBP15 to endosomes.","method":"Pulldown assays, co-immunoprecipitation, cell fractionation, overexpression of Fam21 tail domain","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional overexpression in a single lab, two orthogonal methods","pmids":["22070227"],"is_preprint":false},{"year":2010,"finding":"WAFL (FKBP15) interacts with KIAA0196 and KIAA1033, both of which bind to the alpha-appendage of the adaptor protein complex 2 (AP2), an interaction hub for accessory proteins in clathrin-mediated endocytosis. The specific interaction between WAFL and KIAA0196 was confirmed by co-immunoprecipitation in HCT-116 cells.","method":"Immunoprecipitation and mass spectrometry, co-immunoprecipitation with specific antibodies","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed by mass spectrometry and reciprocal co-IP in two cell lines, single lab","pmids":["20376207"],"is_preprint":false},{"year":2008,"finding":"WAFL (FKBP15) is a new gene with sequence homology to the WASP family of actin regulators and is differentially expressed (upregulated) in the inflamed colonic mucosa of ulcerative colitis patients but not in Crohn's disease. In vitro monocyte differentiation experiments suggested WAFL participates in innate immune functions.","method":"Subtractive suppression hybridization, Northern blot, immunohistochemistry, immunocytochemistry, in vitro monocyte differentiation, real-time RT-PCR","journal":"International journal of colorectal disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — primarily expression-level characterization with limited mechanistic follow-up; single lab","pmids":["18654788"],"is_preprint":false},{"year":2006,"finding":"FKBP133 (mouse ortholog of FKBP15/KIAA0674) contains a WH1 (Wiskott-Aldrich syndrome protein homology region 1) domain and an FKBP motif. It localizes to axonal shafts and co-localizes with F-actin in growth cones of DRG neurons. Overexpression increases filopodium number; deletion of the WH1 domain reduces growth cone size and filopodium number. Overexpression confers resistance to Semaphorin-3A-induced growth cone collapse, indicating the WH1 domain modulates growth cone morphology.","method":"Immunofluorescence localization, overexpression and deletion-mutant transfection in DRG neurons, morphometric analysis of growth cones and filopodia, Semaphorin-3A collapse assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mutagenesis combined with functional neuronal assays (filopodium counting, collapse assay), single lab with multiple orthogonal readouts","pmids":["16756961"],"is_preprint":false},{"year":2016,"finding":"Knockdown of FKBP15 selectively inhibited recycling of wild-type ß1-adrenergic receptor (ß1-AR) from endosomes to the plasma membrane but had no effect on ß2-AR recycling, placing FKBP15 in a FAM21C-dependent endosomal sorting pathway specific to ß1-AR trafficking.","method":"siRNA knockdown of FKBP15, receptor recycling assays, flow cytometry","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — specific knockdown phenotype with receptor-selective functional readout, single lab, single method","pmids":["27816670"],"is_preprint":false},{"year":2023,"finding":"Overexpression of FKBP15 significantly inhibited the osteogenesis of dental follicle stem cells (DFSCs) by restricting actin cytoskeleton organization, placing FKBP15 downstream of the miR-7974/FTO axis in a pathway regulating RUNX2-independent osteogenic differentiation.","method":"Overexpression in DFSCs, osteogenesis assay (calcium deposition, osteogenic gene expression), actin cytoskeleton staining, miRNA profiling, transcriptome sequencing","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with specific cellular phenotype (osteogenesis, actin organization), pathway placement by miRNA/m6A axis, single lab with multiple orthogonal assays","pmids":["38003310"],"is_preprint":false},{"year":2026,"finding":"Phosphoproteomic analysis identified FKBP15 phosphorylation at S320 as significantly altered in breast cancer lymph node metastasis, and upstream kinase PRKCB was identified as relevant; targeted inhibition of PRKCB suppressed breast cancer cell proliferation and metastasis. FKBP15-S320 phosphorylation was also correlated with PD-L1 immune checkpoint expression.","method":"Quantitative phosphoproteomics (paired primary tumor/lymph node), cell experiments with PRKCB silencing, correlation with PD-L1 expression","journal":"Protein & cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — phosphosite identified by mass spectrometry with functional validation via kinase silencing, but specific role of FKBP15-S320 not directly tested; single study","pmids":["41527309"],"is_preprint":false}],"current_model":"FKBP15 (also known as WAFL, FKBP133, KIAA0674) is a large FKBP-domain and WH1-domain-containing protein that localizes to early endosomes via its coiled-coil domain and is recruited there through direct binding to the Fam21 tail of the WASH complex; it associates with actin (via WIP) and microtubules to regulate early endosome transport, and its WH1 domain modulates neuronal growth cone morphology and filopodium formation, while its endosomal function supports selective recycling of the ß1-adrenergic receptor to the plasma membrane."},"narrative":{"mechanistic_narrative":"FKBP15 (WAFL, FKBP133, KIAA0674) is a multidomain FKBP- and WH1-domain protein that functions in endosomal membrane trafficking by coupling the actin and microtubule cytoskeletal systems at the early endosome [PMID:19121306]. It associates with early endosomes through its central coiled-coil domain and is recruited to membranes by direct binding to the Fam21 tail of the WASH complex; loss of this interaction abolishes its endosomal targeting [PMID:19121306, PMID:22070227]. Once positioned on the endosome, FKBP15 interacts with WASP-interacting protein (WIP) and actin and links to both microfilament and microtubule systems, and its depletion delays endosomal cargo transport at the transition between actin- and microtubule-based movement [PMID:19121306]. It engages additional endocytic machinery, interacting with KIAA0196 and KIAA1033, which connect to the AP2 adaptor of clathrin-mediated endocytosis [PMID:20376207], and it operates within a FAM21C-dependent sorting route that selectively recycles the ß1-adrenergic receptor to the plasma membrane without affecting ß2-AR [PMID:27816670]. Beyond endosomes, the WH1 domain of FKBP15 modulates the actin cytoskeleton in other contexts: it shapes neuronal growth cone morphology and filopodium formation and confers resistance to Semaphorin-3A-induced growth cone collapse [PMID:16756961], and FKBP15 overexpression restricts actin organization to inhibit osteogenic differentiation of dental follicle stem cells [PMID:38003310]. The unifying mechanistic theme is regulation of actin/microtubule-dependent membrane and cytoskeletal dynamics; despite its FKBP motif, no prolyl-isomerase enzymatic activity has been characterized in the available corpus.","teleology":[{"year":2006,"claim":"Established that the FKBP15 ortholog carries a WH1 domain that actively shapes the actin cytoskeleton, framing the protein as an actin-regulatory factor rather than a passive FKBP enzyme.","evidence":"Immunofluorescence, domain-deletion mutagenesis, filopodium morphometry, and Semaphorin-3A collapse assays in mouse DRG neurons","pmids":["16756961"],"confidence":"Medium","gaps":["Molecular mechanism by which the WH1 domain promotes filopodium formation not defined","Binding partners of the WH1 domain in neurons not identified","Whether the FKBP motif contributes to this activity untested"]},{"year":2008,"claim":"Defined the endosomal trafficking role of FKBP15 by showing it bridges actin and microtubule systems at early endosomes, explaining how its loss delays cargo transport.","evidence":"RNAi depletion with cargo transport assays plus co-IP of WIP/actin and microscopy in cultured cells","pmids":["19121306"],"confidence":"Medium","gaps":["Direct vs indirect nature of actin/microtubule links not resolved","Identity of cargo affected beyond bulk endosomal transport unspecified"]},{"year":2008,"claim":"Linked FKBP15 expression to inflamed colonic mucosa and innate immune function, raising a disease-associated expression context.","evidence":"Subtractive hybridization, Northern blot, immunohistochemistry, and in vitro monocyte differentiation from ulcerative colitis tissue","pmids":["18654788"],"confidence":"Low","gaps":["Expression-level correlation only with no mechanistic link to inflammation","Causal role in immune function untested"]},{"year":2010,"claim":"Connected FKBP15 to the clathrin endocytic machinery by identifying its interaction with KIAA0196 and KIAA1033, which dock onto the AP2 adaptor hub.","evidence":"IP-mass spectrometry and reciprocal co-IP in HCT-116 cells","pmids":["20376207"],"confidence":"Medium","gaps":["Functional consequence of the AP2-linked interactions not tested","Whether binding is direct or scaffolded unknown"]},{"year":2012,"claim":"Identified the molecular basis of FKBP15 membrane recruitment by showing the Fam21 WASH-complex tail binds it directly and targets it to endosomes.","evidence":"Pulldown, reciprocal co-IP, cell fractionation, and Fam21-tail overexpression","pmids":["22070227"],"confidence":"Medium","gaps":["Binding interface/structure on FKBP15 not mapped","Regulation of the Fam21–FKBP15 interaction unknown"]},{"year":2016,"claim":"Demonstrated cargo selectivity of the FKBP15 endosomal pathway, showing it specifically supports ß1-adrenergic receptor recycling within a FAM21C-dependent route.","evidence":"siRNA knockdown with receptor recycling assays and flow cytometry","pmids":["27816670"],"confidence":"Medium","gaps":["Basis for ß1- vs ß2-AR selectivity not explained","Single-method functional readout"]},{"year":2023,"claim":"Extended FKBP15 actin-regulatory function to stem cell differentiation, placing it downstream of a miR-7974/FTO axis where it restricts actin organization and inhibits osteogenesis.","evidence":"Overexpression in dental follicle stem cells with osteogenesis assays, actin staining, miRNA profiling, and transcriptomics","pmids":["38003310"],"confidence":"Medium","gaps":["Direct molecular effector of actin restriction not identified","RUNX2-independent mechanism not fully defined"]},{"year":2026,"claim":"Flagged a phosphoregulatory event by identifying FKBP15-S320 as a PRKCB-linked phosphosite altered in breast cancer metastasis and correlated with PD-L1.","evidence":"Quantitative phosphoproteomics of paired tumor/lymph node samples with PRKCB silencing","pmids":["41527309"],"confidence":"Low","gaps":["Functional role of S320 phosphorylation not directly tested","Whether PRKCB phosphorylates FKBP15 directly unconfirmed","Causal link to metastasis/PD-L1 not established"]},{"year":null,"claim":"Whether the FKBP motif of FKBP15 confers prolyl-isomerase or chaperone activity, and how that relates to its cytoskeletal and trafficking roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No enzymatic activity assigned to the FKBP domain in the corpus","No structural model of the full-length protein","Substrate of any catalytic activity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5]}],"complexes":[],"partners":["FAM21C","WIPF1","KIAA0196","KIAA1033"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T1M5","full_name":"FK506-binding protein 15","aliases":["133 kDa FK506-binding protein","133 kDa FKBP","FKBP-133","WASP- and FKBP-like protein","WAFL"],"length_aa":1219,"mass_kda":133.6,"function":"May be involved in the cytoskeletal organization of neuronal growth cones. Seems to be inactive as a PPIase (By similarity). Involved in the transport of early endosomes at the level of transition between microfilament-based and microtubule-based movement","subcellular_location":"Cytoplasm; Cell projection, axon; Early endosome","url":"https://www.uniprot.org/uniprotkb/Q5T1M5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FKBP15","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DNAJC13","stoichiometry":10.0},{"gene":"VPS35","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FKBP15","total_profiled":1310},"omim":[{"mim_id":"617398","title":"FK506-BINDING PROTEIN 15; FKBP15","url":"https://www.omim.org/entry/617398"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FKBP15"},"hgnc":{"alias_symbol":["PPP1R76","FKBP133","WAFL"],"prev_symbol":["KIAA0674"]},"alphafold":{"accession":"Q5T1M5","domains":[{"cath_id":"2.30.29.30","chopping":"72-177","consensus_level":"medium","plddt":93.3234,"start":72,"end":177},{"cath_id":"3.10.50.40","chopping":"178-291","consensus_level":"medium","plddt":85.776,"start":178,"end":291},{"cath_id":"1.20.5","chopping":"577-706","consensus_level":"medium","plddt":95.0776,"start":577,"end":706}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T1M5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T1M5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T1M5-F1-predicted_aligned_error_v6.png","plddt_mean":63.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FKBP15","jax_strain_url":"https://www.jax.org/strain/search?query=FKBP15"},"sequence":{"accession":"Q5T1M5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T1M5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T1M5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T1M5"}},"corpus_meta":[{"pmid":"22070227","id":"PMC_22070227","title":"Recruitment 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RNAi depletion of WAFL results in delayed transport of endosomal cargo, indicating a role in early endosome transport at the transition between microfilament-based and microtubule-based movement.\",\n      \"method\": \"RNAi depletion, co-immunoprecipitation, fluorescence microscopy, functional endosomal transport assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with defined cargo transport phenotype, plus binding partner identification by co-IP, single lab with two orthogonal methods\",\n      \"pmids\": [\"19121306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The Fam21 'tail' domain of the WASH complex binds directly to FKBP15, mediating membrane association of FKBP15. This interaction was identified as necessary for targeting FKBP15 to endosomes.\",\n      \"method\": \"Pulldown assays, co-immunoprecipitation, cell fractionation, overexpression of Fam21 tail domain\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional overexpression in a single lab, two orthogonal methods\",\n      \"pmids\": [\"22070227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WAFL (FKBP15) interacts with KIAA0196 and KIAA1033, both of which bind to the alpha-appendage of the adaptor protein complex 2 (AP2), an interaction hub for accessory proteins in clathrin-mediated endocytosis. The specific interaction between WAFL and KIAA0196 was confirmed by co-immunoprecipitation in HCT-116 cells.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry, co-immunoprecipitation with specific antibodies\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed by mass spectrometry and reciprocal co-IP in two cell lines, single lab\",\n      \"pmids\": [\"20376207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"WAFL (FKBP15) is a new gene with sequence homology to the WASP family of actin regulators and is differentially expressed (upregulated) in the inflamed colonic mucosa of ulcerative colitis patients but not in Crohn's disease. In vitro monocyte differentiation experiments suggested WAFL participates in innate immune functions.\",\n      \"method\": \"Subtractive suppression hybridization, Northern blot, immunohistochemistry, immunocytochemistry, in vitro monocyte differentiation, real-time RT-PCR\",\n      \"journal\": \"International journal of colorectal disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — primarily expression-level characterization with limited mechanistic follow-up; single lab\",\n      \"pmids\": [\"18654788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FKBP133 (mouse ortholog of FKBP15/KIAA0674) contains a WH1 (Wiskott-Aldrich syndrome protein homology region 1) domain and an FKBP motif. It localizes to axonal shafts and co-localizes with F-actin in growth cones of DRG neurons. Overexpression increases filopodium number; deletion of the WH1 domain reduces growth cone size and filopodium number. Overexpression confers resistance to Semaphorin-3A-induced growth cone collapse, indicating the WH1 domain modulates growth cone morphology.\",\n      \"method\": \"Immunofluorescence localization, overexpression and deletion-mutant transfection in DRG neurons, morphometric analysis of growth cones and filopodia, Semaphorin-3A collapse assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mutagenesis combined with functional neuronal assays (filopodium counting, collapse assay), single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"16756961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of FKBP15 selectively inhibited recycling of wild-type ß1-adrenergic receptor (ß1-AR) from endosomes to the plasma membrane but had no effect on ß2-AR recycling, placing FKBP15 in a FAM21C-dependent endosomal sorting pathway specific to ß1-AR trafficking.\",\n      \"method\": \"siRNA knockdown of FKBP15, receptor recycling assays, flow cytometry\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — specific knockdown phenotype with receptor-selective functional readout, single lab, single method\",\n      \"pmids\": [\"27816670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Overexpression of FKBP15 significantly inhibited the osteogenesis of dental follicle stem cells (DFSCs) by restricting actin cytoskeleton organization, placing FKBP15 downstream of the miR-7974/FTO axis in a pathway regulating RUNX2-independent osteogenic differentiation.\",\n      \"method\": \"Overexpression in DFSCs, osteogenesis assay (calcium deposition, osteogenic gene expression), actin cytoskeleton staining, miRNA profiling, transcriptome sequencing\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with specific cellular phenotype (osteogenesis, actin organization), pathway placement by miRNA/m6A axis, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"38003310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Phosphoproteomic analysis identified FKBP15 phosphorylation at S320 as significantly altered in breast cancer lymph node metastasis, and upstream kinase PRKCB was identified as relevant; targeted inhibition of PRKCB suppressed breast cancer cell proliferation and metastasis. FKBP15-S320 phosphorylation was also correlated with PD-L1 immune checkpoint expression.\",\n      \"method\": \"Quantitative phosphoproteomics (paired primary tumor/lymph node), cell experiments with PRKCB silencing, correlation with PD-L1 expression\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — phosphosite identified by mass spectrometry with functional validation via kinase silencing, but specific role of FKBP15-S320 not directly tested; single study\",\n      \"pmids\": [\"41527309\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FKBP15 (also known as WAFL, FKBP133, KIAA0674) is a large FKBP-domain and WH1-domain-containing protein that localizes to early endosomes via its coiled-coil domain and is recruited there through direct binding to the Fam21 tail of the WASH complex; it associates with actin (via WIP) and microtubules to regulate early endosome transport, and its WH1 domain modulates neuronal growth cone morphology and filopodium formation, while its endosomal function supports selective recycling of the ß1-adrenergic receptor to the plasma membrane.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FKBP15 (WAFL, FKBP133, KIAA0674) is a multidomain FKBP- and WH1-domain protein that functions in endosomal membrane trafficking by coupling the actin and microtubule cytoskeletal systems at the early endosome [#0]. It associates with early endosomes through its central coiled-coil domain and is recruited to membranes by direct binding to the Fam21 tail of the WASH complex; loss of this interaction abolishes its endosomal targeting [#0, #1]. Once positioned on the endosome, FKBP15 interacts with WASP-interacting protein (WIP) and actin and links to both microfilament and microtubule systems, and its depletion delays endosomal cargo transport at the transition between actin- and microtubule-based movement [#0]. It engages additional endocytic machinery, interacting with KIAA0196 and KIAA1033, which connect to the AP2 adaptor of clathrin-mediated endocytosis [#2], and it operates within a FAM21C-dependent sorting route that selectively recycles the ß1-adrenergic receptor to the plasma membrane without affecting ß2-AR [#5]. Beyond endosomes, the WH1 domain of FKBP15 modulates the actin cytoskeleton in other contexts: it shapes neuronal growth cone morphology and filopodium formation and confers resistance to Semaphorin-3A-induced growth cone collapse [#4], and FKBP15 overexpression restricts actin organization to inhibit osteogenic differentiation of dental follicle stem cells [#6]. The unifying mechanistic theme is regulation of actin/microtubule-dependent membrane and cytoskeletal dynamics; despite its FKBP motif, no prolyl-isomerase enzymatic activity has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that the FKBP15 ortholog carries a WH1 domain that actively shapes the actin cytoskeleton, framing the protein as an actin-regulatory factor rather than a passive FKBP enzyme.\",\n      \"evidence\": \"Immunofluorescence, domain-deletion mutagenesis, filopodium morphometry, and Semaphorin-3A collapse assays in mouse DRG neurons\",\n      \"pmids\": [\"16756961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which the WH1 domain promotes filopodium formation not defined\", \"Binding partners of the WH1 domain in neurons not identified\", \"Whether the FKBP motif contributes to this activity untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the endosomal trafficking role of FKBP15 by showing it bridges actin and microtubule systems at early endosomes, explaining how its loss delays cargo transport.\",\n      \"evidence\": \"RNAi depletion with cargo transport assays plus co-IP of WIP/actin and microscopy in cultured cells\",\n      \"pmids\": [\"19121306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect nature of actin/microtubule links not resolved\", \"Identity of cargo affected beyond bulk endosomal transport unspecified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked FKBP15 expression to inflamed colonic mucosa and innate immune function, raising a disease-associated expression context.\",\n      \"evidence\": \"Subtractive hybridization, Northern blot, immunohistochemistry, and in vitro monocyte differentiation from ulcerative colitis tissue\",\n      \"pmids\": [\"18654788\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression-level correlation only with no mechanistic link to inflammation\", \"Causal role in immune function untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected FKBP15 to the clathrin endocytic machinery by identifying its interaction with KIAA0196 and KIAA1033, which dock onto the AP2 adaptor hub.\",\n      \"evidence\": \"IP-mass spectrometry and reciprocal co-IP in HCT-116 cells\",\n      \"pmids\": [\"20376207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the AP2-linked interactions not tested\", \"Whether binding is direct or scaffolded unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the molecular basis of FKBP15 membrane recruitment by showing the Fam21 WASH-complex tail binds it directly and targets it to endosomes.\",\n      \"evidence\": \"Pulldown, reciprocal co-IP, cell fractionation, and Fam21-tail overexpression\",\n      \"pmids\": [\"22070227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface/structure on FKBP15 not mapped\", \"Regulation of the Fam21–FKBP15 interaction unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated cargo selectivity of the FKBP15 endosomal pathway, showing it specifically supports ß1-adrenergic receptor recycling within a FAM21C-dependent route.\",\n      \"evidence\": \"siRNA knockdown with receptor recycling assays and flow cytometry\",\n      \"pmids\": [\"27816670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for ß1- vs ß2-AR selectivity not explained\", \"Single-method functional readout\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended FKBP15 actin-regulatory function to stem cell differentiation, placing it downstream of a miR-7974/FTO axis where it restricts actin organization and inhibits osteogenesis.\",\n      \"evidence\": \"Overexpression in dental follicle stem cells with osteogenesis assays, actin staining, miRNA profiling, and transcriptomics\",\n      \"pmids\": [\"38003310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular effector of actin restriction not identified\", \"RUNX2-independent mechanism not fully defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Flagged a phosphoregulatory event by identifying FKBP15-S320 as a PRKCB-linked phosphosite altered in breast cancer metastasis and correlated with PD-L1.\",\n      \"evidence\": \"Quantitative phosphoproteomics of paired tumor/lymph node samples with PRKCB silencing\",\n      \"pmids\": [\"41527309\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional role of S320 phosphorylation not directly tested\", \"Whether PRKCB phosphorylates FKBP15 directly unconfirmed\", \"Causal link to metastasis/PD-L1 not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the FKBP motif of FKBP15 confers prolyl-isomerase or chaperone activity, and how that relates to its cytoskeletal and trafficking roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No enzymatic activity assigned to the FKBP domain in the corpus\", \"No structural model of the full-length protein\", \"Substrate of any catalytic activity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FAM21C\", \"WIPF1\", \"KIAA0196\", \"KIAA1033\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}