{"gene":"OSTF1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1998,"finding":"OSTF1 (OSF/SH3P2) was identified as a novel intracellular protein containing an SH3 domain and ankyrin repeats, produced by osteoclasts, that indirectly stimulates osteoclast formation and bone resorption via conditioned media; recombinant OSF was shown to bind c-Src with high affinity, suggesting involvement in Src-mediated signal transduction.","method":"Expression cloning, transfection of 293 cells, conditioned media assay for osteoclast-like cell formation, fetal rat long bone resorption assay, in situ hybridization, immunoblot, recombinant protein binding assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cloning with multiple orthogonal assays (conditioned media, bone resorption, c-Src binding), single lab","pmids":["10092216"],"is_preprint":false},{"year":2004,"finding":"SH3P2 (OSTF1) was identified as a novel Cbl-interacting protein and substrate of tyrosine kinase Src; a specific polyproline motif in Cbl mediates binding of both SH3P2 and Src, and these two proteins mutually sequester each other from monomeric Cbl. In adherent cells, SH3P2 associates with Cbl and filamentous actin and localizes to focal contacts in fibroblasts and to the apical part of podosome rings in differentiated osteoclasts.","method":"Co-immunoprecipitation, pulldown assays, mutagenesis of Cbl polyproline motif, immunofluorescence localization","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and subcellular localization with functional context, single lab, two orthogonal methods","pmids":["15135048"],"is_preprint":false},{"year":2011,"finding":"SH3P2 (OSTF1) functions as a negative regulator of cell motility; overexpression inhibits and RNAi-mediated depletion enhances motility in tumor cell lines. RSK (ribosomal S6 kinase) phosphorylates SH3P2 at Ser202 in an ERK-pathway-dependent manner, and this phosphorylation inhibits SH3P2's ability to suppress cell motility. Expression of unphosphorylatable SH3P2(S202A) inhibited tumor cell motility, establishing Ser202 phosphorylation as a key regulatory switch.","method":"Functional expression cloning, overexpression/RNAi in HeLa S3 and tumor cell lines, cell motility assay, site-directed mutagenesis (S202A), kinase inhibitor experiments (BI-D1870, PD184352), phosphorylation assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — loss-of-function, gain-of-function, site-directed mutagenesis, pharmacological inhibition, and specific phosphorylation mapping in one study with multiple orthogonal methods","pmids":["21501342"],"is_preprint":false},{"year":2017,"finding":"Genetic knockout of Ostf1 in mice (exons 3 and 4 replaced by LacZ) resulted in increased trabecular bone mass in long bones, confirming a role for OSTF1 in bone development and osteoclast regulation in vivo. LacZ reporter staining showed widespread expression in vasculature of most organs and multiple cell types in adult and embryonic tissues.","method":"Knockout mouse model, X-Gal staining, bone phenotyping (micro-CT/histology implied), SHIRPA behavioral testing","journal":"Mammalian genome : official journal of the International Mammalian Genome Society","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined skeletal phenotype (increased trabecular mass), replicated with expression mapping","pmids":["28936620"],"is_preprint":false},{"year":2018,"finding":"OSTF1 was identified as a novel binding partner of RP2 (retinitis pigmentosa 2 protein); this interaction is abolished by a human pathogenic RP2 mutation. Structure-based mapping pinpointed the binding interface to a conserved surface cluster spanning both C- and N-terminal domains of RP2, distinct from the ARL3-binding site. RP2 is a positive regulator of cell motility in vitro and recruits OSTF1 to the cell membrane, preventing OSTF1 from interacting with the migration regulator Myo1E.","method":"Co-immunoprecipitation, pulldown assays, structure-based interface mapping, pathogenic mutation analysis, cell motility assay, subcellular localization (membrane fractionation/imaging)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structure-based interface mapping, pathogenic mutation validation, reciprocal binding assays, and functional motility assay in one study with multiple orthogonal methods","pmids":["29361551"],"is_preprint":false},{"year":2020,"finding":"SH3P2 (OSTF1) suppresses osteoclast differentiation by controlling the membrane localization of myosin 1E (Myo1E). RANKL stimulation induces SH3P2 dephosphorylation, which increases association of Myo1E with SH3P2, thereby preventing Myo1E localization to the plasma membrane. SH3P2 knockout mice displayed decreased femoral trabecular bone mass and enhanced osteoclast localization on tibial trabecular bone surface, and SH3P2-KO bone marrow-derived macrophages showed enhanced osteoclast differentiation (multinuclearity) in response to M-CSF and RANKL.","method":"SH3P2 knockout mice, cell fractionation (membrane fraction), co-immunoprecipitation, osteoclast differentiation assay (M-CSF/RANKL), Myo1E knockdown, bone histology","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined bone phenotype, mechanistic dissection via dephosphorylation/co-IP/membrane fractionation, and Myo1E knockdown rescue, multiple orthogonal methods in single study","pmids":["32916757"],"is_preprint":false},{"year":2024,"finding":"OSTF1 knockdown in chondrocytes mitigated IL-1β-induced apoptosis (reduced cleaved caspase-3 and cleaved PARP), inflammation, and extracellular matrix degradation by inhibiting the NF-κB signaling pathway; transcriptomic analysis revealed 18 differentially expressed genes in OSTF1-silenced chondrocytes overlapping with NF-κB downstream targets.","method":"RNAi/siRNA knockdown, IL-1β-stimulated chondrocyte model, OA rat model (ACLT), western blot, RNA-seq transcriptomic analysis, bioinformatics","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined cellular phenotype and pathway placement (NF-κB), single lab, pathway assignment partly bioinformatic","pmids":["38699012"],"is_preprint":false}],"current_model":"OSTF1 (SH3P2/OSF) is an intracellular SH3-domain-containing protein that functions as a negative regulator of cell motility and osteoclast differentiation: it suppresses cell migration and is inactivated by RSK-mediated phosphorylation at Ser202 downstream of the ERK pathway; it interacts with c-Src (via its SH3 domain), with Cbl at focal contacts and podosome rings, and with RP2 (which recruits OSTF1 to the cell membrane to sequester it from the motility regulator Myo1E); upon RANKL-induced dephosphorylation, OSTF1 binds Myo1E and prevents its membrane localization, thereby suppressing osteoclast cell-to-cell fusion and differentiation — consistent with Ostf1-knockout mice showing increased trabecular bone mass and enhanced osteoclastogenesis."},"narrative":{"mechanistic_narrative":"OSTF1 (SH3P2/OSF) is an intracellular SH3-domain-containing adaptor protein that acts as a negative regulator of cell motility and osteoclast differentiation [PMID:21501342, PMID:32916757]. It engages the actin-coupled signaling machinery through its SH3 domain, binding c-Src with high affinity and associating with Cbl at a specific polyproline motif, where c-Src and OSTF1 mutually compete for monomeric Cbl; in adherent cells it localizes with filamentous actin at focal contacts in fibroblasts and at the apical podosome rings of osteoclasts [PMID:10092216, PMID:15135048]. OSTF1's suppressive activity is gated by ERK-pathway signaling: RSK phosphorylates OSTF1 at Ser202, and this phosphorylation relieves its inhibition of cell motility, whereas the non-phosphorylatable S202A mutant constitutively suppresses tumor cell migration [PMID:21501342]. In osteoclasts, RANKL stimulation drives OSTF1 dephosphorylation, increasing its binding to myosin 1E (Myo1E) and preventing Myo1E from reaching the plasma membrane, thereby restraining osteoclast differentiation and cell fusion [PMID:32916757]; the motility regulator RP2 counteracts this by recruiting OSTF1 to the membrane and sequestering it from Myo1E, an interaction abolished by a pathogenic RP2 mutation [PMID:29361551]. Consistent with this restraining role in bone, Ostf1-knockout mice display altered trabecular bone mass and enhanced osteoclastogenesis [PMID:28936620, PMID:32916757]. OSTF1 also modulates IL-1β-induced chondrocyte apoptosis, inflammation, and extracellular matrix degradation through the NF-κB pathway [PMID:38699012].","teleology":[{"year":1998,"claim":"Established OSTF1 as an osteoclast-derived intracellular SH3/ankyrin-repeat protein that influences osteoclast formation and binds c-Src, placing it in Src-mediated signaling.","evidence":"Expression cloning with conditioned-media osteoclast formation and bone resorption assays plus recombinant c-Src binding","pmids":["10092216"],"confidence":"Medium","gaps":["Stimulatory effect was indirect via conditioned media, not a defined molecular mechanism","Direct cellular role of the c-Src interaction not resolved"]},{"year":2004,"claim":"Defined OSTF1's physical partnerships, showing it binds Cbl through a polyproline motif shared with Src and localizes to actin-rich focal contacts and podosome rings.","evidence":"Reciprocal Co-IP, pulldowns, Cbl polyproline mutagenesis, and immunofluorescence in fibroblasts and osteoclasts","pmids":["15135048"],"confidence":"Medium","gaps":["Functional consequence of the Cbl/Src competition not established","Single lab, no structural detail of the interface"]},{"year":2011,"claim":"Identified OSTF1 as a negative regulator of cell motility and uncovered the regulatory switch: RSK phosphorylation of Ser202 downstream of ERK inactivates its motility-suppressing function.","evidence":"Gain/loss-of-function in HeLa S3 and tumor lines, S202A mutagenesis, RSK/MEK kinase inhibitors, and phosphorylation mapping","pmids":["21501342"],"confidence":"High","gaps":["Downstream effector through which OSTF1 suppresses motility not yet identified","Phosphatase reversing Ser202 not defined"]},{"year":2017,"claim":"Provided in vivo confirmation that OSTF1 regulates bone, with knockout mice showing altered trabecular bone mass and broad vascular/tissue expression.","evidence":"Ostf1 LacZ-knockout mouse with bone phenotyping and X-Gal expression mapping","pmids":["28936620"],"confidence":"High","gaps":["Cellular mechanism linking OSTF1 loss to bone phenotype not dissected here","Functional relevance of widespread vascular expression unexplored"]},{"year":2018,"claim":"Connected OSTF1 to RP2 and Myo1E, showing RP2 recruits OSTF1 to the membrane to sequester it from the motility regulator Myo1E, with a disease-relevant interface.","evidence":"Co-IP, pulldowns, structure-based interface mapping, pathogenic RP2 mutation analysis, and motility assays","pmids":["29361551"],"confidence":"High","gaps":["Physiological consequences of the RP2–OSTF1 axis in retinal tissue not addressed","How RP2 binding and Myo1E binding are spatially coordinated unclear"]},{"year":2020,"claim":"Defined the osteoclast mechanism: RANKL-induced OSTF1 dephosphorylation enhances Myo1E binding, blocking Myo1E membrane localization to suppress osteoclast differentiation.","evidence":"Knockout mice, membrane fractionation, Co-IP, Myo1E knockdown rescue, and M-CSF/RANKL osteoclast differentiation assays","pmids":["32916757"],"confidence":"High","gaps":["Identity of the RANKL-activated phosphatase acting on OSTF1 not established","How Myo1E membrane localization promotes osteoclast fusion mechanistically unresolved"]},{"year":2024,"claim":"Extended OSTF1 function to chondrocytes, where its knockdown blunts IL-1β-driven apoptosis, inflammation, and matrix degradation via NF-κB.","evidence":"siRNA knockdown in IL-1β-stimulated chondrocytes, OA rat ACLT model, western blot, and RNA-seq","pmids":["38699012"],"confidence":"Medium","gaps":["NF-κB pathway placement is partly bioinformatic, lacking direct mechanistic linkage","Whether the SH3/Myo1E/Cbl axis operates in chondrocytes is untested"]},{"year":null,"claim":"The phosphatase that dephosphorylates OSTF1 Ser202 downstream of RANKL, and the unifying molecular pathway connecting its motility, osteoclast, and NF-κB roles, remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified phosphatase reversing Ser202","No structural model of OSTF1's SH3 domain bound to its partners","Mechanistic integration across cell types not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[],"complexes":[],"partners":["SRC","CBL","RP2","MYO1E","RPS6KA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92882","full_name":"Osteoclast-stimulating factor 1","aliases":[],"length_aa":214,"mass_kda":23.8,"function":"Induces bone resorption, acting probably through a signaling cascade which results in the secretion of factor(s) enhancing osteoclast formation and activity","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q92882/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OSTF1","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":"MYO1E","stoichiometry":10.0},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/OSTF1","total_profiled":1310},"omim":[{"mim_id":"617724","title":"TSC22 DOMAIN FAMILY, MEMBER 2; TSC22D2","url":"https://www.omim.org/entry/617724"},{"mim_id":"612865","title":"PHOSPHATIDYLINOSITOL 4-PHOSPHATE-5-KINASE-LIKE 1; PIP5KL1","url":"https://www.omim.org/entry/612865"},{"mim_id":"611914","title":"TSC22 DOMAIN FAMILY, MEMBER 4; TSC22D4","url":"https://www.omim.org/entry/611914"},{"mim_id":"610180","title":"OSTEOCLAST-STIMULATING FACTOR 1; OSTF1","url":"https://www.omim.org/entry/610180"},{"mim_id":"607751","title":"TASTE RECEPTOR, TYPE 2, MEMBER 38; TAS2R38","url":"https://www.omim.org/entry/607751"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OSTF1"},"hgnc":{"alias_symbol":["SH3P2","OSF","bA235O14.1"],"prev_symbol":[]},"alphafold":{"accession":"Q92882","domains":[{"cath_id":"2.30.30.40","chopping":"14-71","consensus_level":"high","plddt":95.8624,"start":14,"end":71},{"cath_id":"1.25.40.20","chopping":"75-205","consensus_level":"high","plddt":94.6619,"start":75,"end":205}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92882","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92882-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92882-F1-predicted_aligned_error_v6.png","plddt_mean":90.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OSTF1","jax_strain_url":"https://www.jax.org/strain/search?query=OSTF1"},"sequence":{"accession":"Q92882","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92882.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92882/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92882"}},"corpus_meta":[{"pmid":"32826876","id":"PMC_32826876","title":"The 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(OSF-2) in the cytoadherence phenomena mediated by malaria parasites.","date":"2025","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40433670","citation_count":1,"is_preprint":false},{"pmid":"42100191","id":"PMC_42100191","title":"Prolactin, cortisol, and extracellular osmolality regulate cftr, ostf1, and sgk1 in tilapia ionocytes.","date":"2026","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/42100191","citation_count":0,"is_preprint":false},{"pmid":"24941748","id":"PMC_24941748","title":"[Expression and bioactivity of OSF-1 in Pichia pastoris].","date":"2014","source":"Sheng wu gong cheng xue bao = Chinese journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/24941748","citation_count":0,"is_preprint":false},{"pmid":"35150031","id":"PMC_35150031","title":"Tyrosine sulphation of CXCR4 induces the migration of fibroblast in OSF.","date":"2022","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/35150031","citation_count":0,"is_preprint":false},{"pmid":"41488299","id":"PMC_41488299","title":"Effect of periostin (OSF-2) on phagocytosis of Plasmodium-infected erythrocytes.","date":"2025","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41488299","citation_count":0,"is_preprint":false},{"pmid":"40580027","id":"PMC_40580027","title":"miR-134-3p Deficiency-Induced Methionine Metabolism Promotes Fibrosis via SLC25A33 in OSF.","date":"2025","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40580027","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23890,"output_tokens":2305,"usd":0.053123,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9347,"output_tokens":2841,"usd":0.05888,"stage2_stop_reason":"end_turn"},"total_usd":0.112003,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"OSTF1 (OSF/SH3P2) was identified as a novel intracellular protein containing an SH3 domain and ankyrin repeats, produced by osteoclasts, that indirectly stimulates osteoclast formation and bone resorption via conditioned media; recombinant OSF was shown to bind c-Src with high affinity, suggesting involvement in Src-mediated signal transduction.\",\n      \"method\": \"Expression cloning, transfection of 293 cells, conditioned media assay for osteoclast-like cell formation, fetal rat long bone resorption assay, in situ hybridization, immunoblot, recombinant protein binding assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cloning with multiple orthogonal assays (conditioned media, bone resorption, c-Src binding), single lab\",\n      \"pmids\": [\"10092216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SH3P2 (OSTF1) was identified as a novel Cbl-interacting protein and substrate of tyrosine kinase Src; a specific polyproline motif in Cbl mediates binding of both SH3P2 and Src, and these two proteins mutually sequester each other from monomeric Cbl. In adherent cells, SH3P2 associates with Cbl and filamentous actin and localizes to focal contacts in fibroblasts and to the apical part of podosome rings in differentiated osteoclasts.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, mutagenesis of Cbl polyproline motif, immunofluorescence localization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and subcellular localization with functional context, single lab, two orthogonal methods\",\n      \"pmids\": [\"15135048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SH3P2 (OSTF1) functions as a negative regulator of cell motility; overexpression inhibits and RNAi-mediated depletion enhances motility in tumor cell lines. RSK (ribosomal S6 kinase) phosphorylates SH3P2 at Ser202 in an ERK-pathway-dependent manner, and this phosphorylation inhibits SH3P2's ability to suppress cell motility. Expression of unphosphorylatable SH3P2(S202A) inhibited tumor cell motility, establishing Ser202 phosphorylation as a key regulatory switch.\",\n      \"method\": \"Functional expression cloning, overexpression/RNAi in HeLa S3 and tumor cell lines, cell motility assay, site-directed mutagenesis (S202A), kinase inhibitor experiments (BI-D1870, PD184352), phosphorylation assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — loss-of-function, gain-of-function, site-directed mutagenesis, pharmacological inhibition, and specific phosphorylation mapping in one study with multiple orthogonal methods\",\n      \"pmids\": [\"21501342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Genetic knockout of Ostf1 in mice (exons 3 and 4 replaced by LacZ) resulted in increased trabecular bone mass in long bones, confirming a role for OSTF1 in bone development and osteoclast regulation in vivo. LacZ reporter staining showed widespread expression in vasculature of most organs and multiple cell types in adult and embryonic tissues.\",\n      \"method\": \"Knockout mouse model, X-Gal staining, bone phenotyping (micro-CT/histology implied), SHIRPA behavioral testing\",\n      \"journal\": \"Mammalian genome : official journal of the International Mammalian Genome Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined skeletal phenotype (increased trabecular mass), replicated with expression mapping\",\n      \"pmids\": [\"28936620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OSTF1 was identified as a novel binding partner of RP2 (retinitis pigmentosa 2 protein); this interaction is abolished by a human pathogenic RP2 mutation. Structure-based mapping pinpointed the binding interface to a conserved surface cluster spanning both C- and N-terminal domains of RP2, distinct from the ARL3-binding site. RP2 is a positive regulator of cell motility in vitro and recruits OSTF1 to the cell membrane, preventing OSTF1 from interacting with the migration regulator Myo1E.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, structure-based interface mapping, pathogenic mutation analysis, cell motility assay, subcellular localization (membrane fractionation/imaging)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structure-based interface mapping, pathogenic mutation validation, reciprocal binding assays, and functional motility assay in one study with multiple orthogonal methods\",\n      \"pmids\": [\"29361551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SH3P2 (OSTF1) suppresses osteoclast differentiation by controlling the membrane localization of myosin 1E (Myo1E). RANKL stimulation induces SH3P2 dephosphorylation, which increases association of Myo1E with SH3P2, thereby preventing Myo1E localization to the plasma membrane. SH3P2 knockout mice displayed decreased femoral trabecular bone mass and enhanced osteoclast localization on tibial trabecular bone surface, and SH3P2-KO bone marrow-derived macrophages showed enhanced osteoclast differentiation (multinuclearity) in response to M-CSF and RANKL.\",\n      \"method\": \"SH3P2 knockout mice, cell fractionation (membrane fraction), co-immunoprecipitation, osteoclast differentiation assay (M-CSF/RANKL), Myo1E knockdown, bone histology\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined bone phenotype, mechanistic dissection via dephosphorylation/co-IP/membrane fractionation, and Myo1E knockdown rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"32916757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OSTF1 knockdown in chondrocytes mitigated IL-1β-induced apoptosis (reduced cleaved caspase-3 and cleaved PARP), inflammation, and extracellular matrix degradation by inhibiting the NF-κB signaling pathway; transcriptomic analysis revealed 18 differentially expressed genes in OSTF1-silenced chondrocytes overlapping with NF-κB downstream targets.\",\n      \"method\": \"RNAi/siRNA knockdown, IL-1β-stimulated chondrocyte model, OA rat model (ACLT), western blot, RNA-seq transcriptomic analysis, bioinformatics\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined cellular phenotype and pathway placement (NF-κB), single lab, pathway assignment partly bioinformatic\",\n      \"pmids\": [\"38699012\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OSTF1 (SH3P2/OSF) is an intracellular SH3-domain-containing protein that functions as a negative regulator of cell motility and osteoclast differentiation: it suppresses cell migration and is inactivated by RSK-mediated phosphorylation at Ser202 downstream of the ERK pathway; it interacts with c-Src (via its SH3 domain), with Cbl at focal contacts and podosome rings, and with RP2 (which recruits OSTF1 to the cell membrane to sequester it from the motility regulator Myo1E); upon RANKL-induced dephosphorylation, OSTF1 binds Myo1E and prevents its membrane localization, thereby suppressing osteoclast cell-to-cell fusion and differentiation — consistent with Ostf1-knockout mice showing increased trabecular bone mass and enhanced osteoclastogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OSTF1 (SH3P2/OSF) is an intracellular SH3-domain-containing adaptor protein that acts as a negative regulator of cell motility and osteoclast differentiation [#2, #5]. It engages the actin-coupled signaling machinery through its SH3 domain, binding c-Src with high affinity and associating with Cbl at a specific polyproline motif, where c-Src and OSTF1 mutually compete for monomeric Cbl; in adherent cells it localizes with filamentous actin at focal contacts in fibroblasts and at the apical podosome rings of osteoclasts [#0, #1]. OSTF1's suppressive activity is gated by ERK-pathway signaling: RSK phosphorylates OSTF1 at Ser202, and this phosphorylation relieves its inhibition of cell motility, whereas the non-phosphorylatable S202A mutant constitutively suppresses tumor cell migration [#2]. In osteoclasts, RANKL stimulation drives OSTF1 dephosphorylation, increasing its binding to myosin 1E (Myo1E) and preventing Myo1E from reaching the plasma membrane, thereby restraining osteoclast differentiation and cell fusion [#5]; the motility regulator RP2 counteracts this by recruiting OSTF1 to the membrane and sequestering it from Myo1E, an interaction abolished by a pathogenic RP2 mutation [#4]. Consistent with this restraining role in bone, Ostf1-knockout mice display altered trabecular bone mass and enhanced osteoclastogenesis [#3, #5]. OSTF1 also modulates IL-1\\u03b2-induced chondrocyte apoptosis, inflammation, and extracellular matrix degradation through the NF-\\u03baB pathway [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established OSTF1 as an osteoclast-derived intracellular SH3/ankyrin-repeat protein that influences osteoclast formation and binds c-Src, placing it in Src-mediated signaling.\",\n      \"evidence\": \"Expression cloning with conditioned-media osteoclast formation and bone resorption assays plus recombinant c-Src binding\",\n      \"pmids\": [\"10092216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stimulatory effect was indirect via conditioned media, not a defined molecular mechanism\", \"Direct cellular role of the c-Src interaction not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined OSTF1's physical partnerships, showing it binds Cbl through a polyproline motif shared with Src and localizes to actin-rich focal contacts and podosome rings.\",\n      \"evidence\": \"Reciprocal Co-IP, pulldowns, Cbl polyproline mutagenesis, and immunofluorescence in fibroblasts and osteoclasts\",\n      \"pmids\": [\"15135048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the Cbl/Src competition not established\", \"Single lab, no structural detail of the interface\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified OSTF1 as a negative regulator of cell motility and uncovered the regulatory switch: RSK phosphorylation of Ser202 downstream of ERK inactivates its motility-suppressing function.\",\n      \"evidence\": \"Gain/loss-of-function in HeLa S3 and tumor lines, S202A mutagenesis, RSK/MEK kinase inhibitors, and phosphorylation mapping\",\n      \"pmids\": [\"21501342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector through which OSTF1 suppresses motility not yet identified\", \"Phosphatase reversing Ser202 not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided in vivo confirmation that OSTF1 regulates bone, with knockout mice showing altered trabecular bone mass and broad vascular/tissue expression.\",\n      \"evidence\": \"Ostf1 LacZ-knockout mouse with bone phenotyping and X-Gal expression mapping\",\n      \"pmids\": [\"28936620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular mechanism linking OSTF1 loss to bone phenotype not dissected here\", \"Functional relevance of widespread vascular expression unexplored\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected OSTF1 to RP2 and Myo1E, showing RP2 recruits OSTF1 to the membrane to sequester it from the motility regulator Myo1E, with a disease-relevant interface.\",\n      \"evidence\": \"Co-IP, pulldowns, structure-based interface mapping, pathogenic RP2 mutation analysis, and motility assays\",\n      \"pmids\": [\"29361551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequences of the RP2\\u2013OSTF1 axis in retinal tissue not addressed\", \"How RP2 binding and Myo1E binding are spatially coordinated unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the osteoclast mechanism: RANKL-induced OSTF1 dephosphorylation enhances Myo1E binding, blocking Myo1E membrane localization to suppress osteoclast differentiation.\",\n      \"evidence\": \"Knockout mice, membrane fractionation, Co-IP, Myo1E knockdown rescue, and M-CSF/RANKL osteoclast differentiation assays\",\n      \"pmids\": [\"32916757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the RANKL-activated phosphatase acting on OSTF1 not established\", \"How Myo1E membrane localization promotes osteoclast fusion mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended OSTF1 function to chondrocytes, where its knockdown blunts IL-1\\u03b2-driven apoptosis, inflammation, and matrix degradation via NF-\\u03baB.\",\n      \"evidence\": \"siRNA knockdown in IL-1\\u03b2-stimulated chondrocytes, OA rat ACLT model, western blot, and RNA-seq\",\n      \"pmids\": [\"38699012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF-\\u03baB pathway placement is partly bioinformatic, lacking direct mechanistic linkage\", \"Whether the SH3/Myo1E/Cbl axis operates in chondrocytes is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The phosphatase that dephosphorylates OSTF1 Ser202 downstream of RANKL, and the unifying molecular pathway connecting its motility, osteoclast, and NF-\\u03baB roles, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified phosphatase reversing Ser202\", \"No structural model of OSTF1's SH3 domain bound to its partners\", \"Mechanistic integration across cell types not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SRC\", \"CBL\", \"RP2\", \"MYO1E\", \"RPS6KA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}