{"gene":"SH3BP2","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2001,"finding":"Missense mutations in SH3BP2 (mapping to exon 9, residues 415-420) cause cherubism, identifying SH3BP2 as the causative gene for this bone resorption disorder.","method":"Direct sequencing of SH3BP2 in affected families; identification of seven distinct mutations","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent families, direct sequencing, replicated across subsequent studies","pmids":["11381256"],"is_preprint":false},{"year":2002,"finding":"14-3-3 chaperone proteins physically interact with SH3BP2 (3BP2) in a phosphorylation-dependent manner; PKC-mediated phosphorylation of Ser225 and Ser277 within proline-rich domains (residues 201-240 and 270-310) is required for 14-3-3 binding, and this interaction negatively regulates SH3BP2 adapter function (NFAT transcriptional activity) in lymphocytes.","method":"Yeast two-hybrid, co-immunoprecipitation, alkaline phosphatase dephosphorylation assay, in vitro PKC kinase assay, deletion mutant mapping, NFAT-reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods including in vitro kinase assay, mutagenesis, and functional reporter assays in a single study","pmids":["12501243"],"is_preprint":false},{"year":2006,"finding":"Cherubism-associated SH3BP2 mutations (R415Q, P418R, D419N, D420E) are gain-of-function mutations that increase NFAT transcriptional activity when transiently expressed in cells.","method":"Transient transfection of mutant SH3BP2 constructs with NFAT-luciferase reporter assay","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay with multiple alleles, single lab but multiple mutants tested","pmids":["16786512"],"is_preprint":false},{"year":2007,"finding":"Cherubism knock-in mice (P416R Sh3bp2) exhibit TNF-α-dependent systemic inflammation and bone loss driven by myeloid cells; mutant myeloid cells show increased ERK1/2 and SYK phosphorylation in response to M-CSF and RANKL, forming large osteoclasts with high TNF-α expression. The phenotype is lymphocyte-independent and transferable via mutant fetal liver cells, establishing SH3BP2 gain-of-function in myeloid cells as the mechanism.","method":"Knock-in mouse model, fetal liver cell transfer, bone marrow transplantation, ERK/SYK western blot, RANKL/M-CSF stimulation assays, TNF-α measurement","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse with cell transfer experiments, multiple orthogonal methods, mechanistic pathway placement established","pmids":["17218256"],"is_preprint":false},{"year":2008,"finding":"SH3BP2 overexpression in RAW 264.7 preosteoclast cells increases NFATc1 nuclear translocation and TRAP expression in response to sRANKL, and potentiates PLCγ1 and PLCγ2 phosphorylation, providing a mechanistic pathway linking SH3BP2 to osteoclastogenesis via PLCγ→calcineurin→NFATc1.","method":"Overexpression in RAW264.7 cells, western blot for PLCγ phosphorylation, TRAP staining, NFATc1 nuclear localization assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays (phosphorylation, localization, differentiation marker) in single lab","pmids":["18440306"],"is_preprint":false},{"year":2010,"finding":"Cherubism-associated mutant SH3BP2 (compared to wild-type) potentiates RANKL-induced PLCγ1 and PLCγ2 phosphorylation, leading to greater NFAT activation and osteoclast differentiation (TRAP expression) in RAW264.7 cells, confirming gain-of-function mechanism through the PLCγ→NFATc1 axis.","method":"Transient transfection of wild-type vs mutant SH3BP2, NFAT-luciferase reporter, TRAP staining, western blot for PLCγ phosphorylation","journal":"Journal of orthopaedic research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays including phosphorylation and functional readout, single lab","pmids":["20872577"],"is_preprint":false},{"year":2010,"finding":"The P416R cherubism mutation in Sh3bp2 knock-in mice impairs osteoblast differentiation and function: homozygous mutant osteoblast cultures show decreased alkaline phosphatase expression, reduced mineralization, and decreased expression of osteoblast markers (Col1a1, ALP, osteocalcin). Mutant osteoblasts also increase osteoclastogenesis in co-culture with bone marrow macrophages.","method":"Knock-in mouse calvarial osteoblast cultures, GFP-Col1a1 transgene reporter, FTIRI bone mineral analysis, co-culture assay, gene expression analysis","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in knock-in mouse model, single lab","pmids":["20117257","20691350"],"is_preprint":false},{"year":2011,"finding":"shRNA knockdown of SH3BP2 in RAW264.7 and bone marrow macrophages (BMMs) decreases PLCγ2 phosphorylation, NFATc1 expression, osteoclast-specific gene expression, and reduces osteoclast number, size, and bone resorptive activity; Sh3bp2-/- BMMs similarly form smaller, less active osteoclasts, establishing SH3BP2 as a positive regulator of osteoclast differentiation and function.","method":"shRNA knockdown, Sh3bp2-/- mouse BMM cultures, western blot for PLCγ2/NFATc1, TRAP staining, bone resorption assay","journal":"Journal of orthopaedic research","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent loss-of-function approaches (shRNA and knockout mouse) with multiple mechanistic readouts","pmids":["21448930"],"is_preprint":false},{"year":2011,"finding":"Tankyrase (PARP5) interaction with SH3BP2 is disrupted by cherubism mutations, leading to SH3BP2 stabilization (loss of tankyrase-mediated degradation); this mechanism was highlighted as central to understanding why cherubism mutations cause protein accumulation.","method":"Review/commentary citing two Cell papers (Guettler et al. and Levaot et al.) — mechanistic evidence from referenced primary studies","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — commentary citing primary biochemical studies; mechanism inferred from referenced papers, not directly demonstrated in this abstract","pmids":["22153068"],"is_preprint":false},{"year":2012,"finding":"PARP1 binds to the SH3BP2 promoter at a specific site (−44 to −21) and is essential for SH3BP2 transcriptional expression; PARP1 knockout in mice reduces SH3BP2 expression in BMMs.","method":"Streptavidin-biotin purification, EMSA, ChIP assay, promoter deletion analysis, mutagenesis of PARP1 binding site, Parp1 knockout mouse BMMs","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (EMSA, ChIP, mutagenesis, KO mouse) establishing transcriptional regulation mechanism","pmids":["22820184"],"is_preprint":false},{"year":2014,"finding":"The P416R cherubism mutation in SH3BP2 enables TNF-α to drive RANKL-independent osteoclastogenesis in BMMs via SYK and PLCγ2 phosphorylation leading to increased NFATc1 nuclear translocation; heterozygous mutant mice show exacerbated bone loss in TNF-α calvarial injection and hTNFtg models. SH3BP2 knockdown in RAW264.7 cells reduces TNF-α-induced osteoclast formation.","method":"Knock-in mouse BMM cultures, western blot for SYK/PLCγ2, NFATc1 nuclear localization, calvarial TNF-α injection model, hTNFtg mouse model, shRNA knockdown","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vitro and in vivo models, mechanistic pathway (SYK→PLCγ2→NFATc1) established with orthogonal methods","pmids":["24916406"],"is_preprint":false},{"year":2014,"finding":"SH3BP2 gain-of-function (P416R) augments inflammation and bone loss in collagen-induced arthritis through increased macrophage TNF-α production and enhanced RANKL-induced osteoclastogenesis with increased NFATc1 nuclear localization; lymphocyte responses (proliferation, IFN-γ, IL-17, anti-CII antibodies) were not significantly different between wild-type and mutant mice.","method":"CIA mouse model, paw swelling assessment, micro-CT, histology, cytokine gene expression, BMM culture for TNF-α and osteoclastogenesis, NFATc1 nuclear localization, lymph node cell culture","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo and in vitro readouts with mechanistic pathway placement, single lab","pmids":["25144740"],"is_preprint":false},{"year":2019,"finding":"Tankyrase (PARP5) catalyzes ADP-ribosylation of SH3BP2, targeting it for degradation; pharmacological tankyrase inhibition in mice stabilizes SH3BP2 leading to increased osteoclast formation and bone loss, establishing tankyrase as a negative regulator of SH3BP2 protein levels and osteoclastogenesis.","method":"Tankyrase inhibitor treatment in mice, micro-CT bone analysis, osteoclast formation assays — reviewed mechanistic data from primary studies","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological model with mechanistic follow-up; review article summarizing primary experimental evidence","pmids":["30813388"],"is_preprint":false},{"year":2019,"finding":"SH3BP2 functions through a SH3BP2-SYK signaling axis to regulate the bone-resorbing function (not differentiation) of osteoclasts in periodontitis; conditional knockout of SH3BP2 and SYK in myeloid cells (LysM-Cre) reduces alveolar bone loss without affecting inflammatory cytokine expression or osteoclast induction.","method":"Sh3bp2-/- mice, conditional myeloid knockout (LysM-Cre), ligature-induced periodontitis model, micro-CT, SYK inhibitor (GS-9973), in vitro mineral resorption assay","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus pharmacological inhibition, in vivo and in vitro, with specific mechanistic dissection of resorption vs. differentiation","pmids":["31613396"],"is_preprint":false},{"year":2018,"finding":"SH3BP2 silencing in GIST cell lines downregulates oncogenic KIT and PDGFRA expression and reduces microphthalmia-associated transcription factor (MITF) levels; reconstitution of both SH3BP2 and MITF rescues cell viability, placing SH3BP2 upstream of MITF in regulating KIT/PDGFRA expression in GISTs.","method":"shRNA silencing in GIST cell lines, western blot, overexpression rescue experiment, in vivo xenograft tumor growth assay, migration assay","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with rescue experiment establishing pathway position, single lab","pmids":["29885053"],"is_preprint":false},{"year":2020,"finding":"SH3BP2 gain-of-function (homozygous P416R) drives RANKL-independent osteoclastogenesis in vivo; Sh3bp2 knock-in mice develop TRAP-positive, cathepsin K-positive multinucleated osteoclasts spontaneously even in the absence of RANKL (Rankl-/- background), with elevated serum TNF-α as the likely driver.","method":"Sh3bp2 KI × Rankl-/- double mutant mouse model, TRAP staining, cathepsin K staining, micro-CT bone analysis, osteoclast marker gene expression, serum TRAP5b and TNF-α measurement","journal":"Bone reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-mutant mouse genetic epistasis clearly establishing RANKL-independent osteoclastogenesis downstream of SH3BP2","pmids":["32258251"],"is_preprint":false},{"year":2021,"finding":"SH3BP2 deficiency suppresses dendritic cell differentiation in vitro and reduces the number of dendritic cells in spleens of lupus-prone mice; B cell-specific SH3BP2 deficiency does not rescue lupus phenotypes, indicating the relevant SH3BP2 function in lupus is not B cell-intrinsic.","method":"SH3BP2-deficient mouse on Fas lupus background, flow cytometry of lymphocyte subsets, B cell-specific conditional KO, in vitro dendritic cell differentiation assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional and global KO with in vitro and in vivo mechanistic readouts, single lab","pmids":["33920631"],"is_preprint":false},{"year":2024,"finding":"SH3BP2 forms a signalosome complex with PLCγ2 and VAV2 (Rho-GEF) in human podocytes, as shown by co-immunoprecipitation; downstream signaling through MyD88, TRIF, and NFATc1 is upregulated in SH3BP2-associated nephrotic syndrome.","method":"Co-immunoprecipitation of SH3BP2 with PLCγ2 and VAV2 in human podocytes, Sh3bp2 KI/KI transgenic mouse model (albuminuria measurement)","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP in human podocytes supported by in vivo gain-of-function mouse model data","pmids":["38127456"],"is_preprint":false},{"year":2024,"finding":"SH3BP2 silencing inhibits microglia activation and neuroinflammation via the JAK/STAT signaling pathway; silencing decreases phosphorylation of JAK and STAT in LPS-stimulated microglia and improves neurological outcomes in spinal cord injury rat models.","method":"Lentiviral shSH3BP2 injection in SCI rat model, LPS-stimulated BV2 and primary microglia, western blot for p-JAK/p-STAT, qRT-PCR, immunofluorescence, behavioral assays","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with in vitro mechanistic validation, single lab, pathway placement via JAK/STAT","pmids":["39546158"],"is_preprint":false},{"year":2021,"finding":"TLR2/4-mediated inflammation in the jaw triggers cherubism-like bone expansion specifically in Sh3bp2 gain-of-function mice; ablation of Tlr2/4 signaling or neutrophil depletion (anti-Ly6G) ameliorates jawbone expansion, placing SH3BP2 gain-of-function downstream of pathogen-associated molecular pattern (PAMP)-induced TLR signaling in jawbone lesion development.","method":"Sh3bp2 KI mouse pulp exposure model, Tlr2/4 knockout genetic epistasis, anti-Ly6G neutrophil depletion, histology, cytokine expression, micro-CT","journal":"JBMR plus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with TLR pathway and pharmacological depletion in in vivo model, single lab","pmids":["35079675"],"is_preprint":false}],"current_model":"SH3BP2 is a scaffold/adaptor protein that positively regulates osteoclastogenesis and inflammatory signaling in myeloid cells by acting upstream of SYK→PLCγ2→calcineurin→NFATc1; its protein stability is controlled by tankyrase (PARP5)-mediated ADP-ribosylation and degradation, its transcription is driven by PARP1, and its adapter function is negatively regulated by phosphorylation-dependent 14-3-3 binding; gain-of-function cherubism mutations (predominantly in exon 9) disrupt tankyrase-mediated degradation, stabilize the protein, and enhance TNF-α production and RANKL- or TNF-α-driven osteoclast formation through increased SYK and PLCγ2 phosphorylation and NFATc1 nuclear translocation, driving systemic autoinflammation and bone destruction."},"narrative":{"mechanistic_narrative":"SH3BP2 (3BP2) is a cytoplasmic scaffold/adaptor protein that positively regulates osteoclastogenesis and myeloid inflammatory signaling, and it is the causative gene for the bone-resorption disorder cherubism, in which missense mutations clustering in exon 9 (residues 415-420) act as gain-of-function alleles [PMID:11381256, PMID:16786512]. Mechanistically, SH3BP2 amplifies osteoclast differentiation by potentiating SYK and PLCγ1/PLCγ2 phosphorylation, which drives calcineurin-dependent NFATc1 nuclear translocation and induction of osteoclast-specific genes; loss of SH3BP2 by knockdown or knockout reduces PLCγ2/NFATc1 signaling and yields smaller, less resorptive osteoclasts, while overexpression has the opposite effect [PMID:18440306, PMID:21448930, PMID:24916406]. Its adapter output is constrained by negative regulation through PKC-dependent phosphorylation of Ser225/Ser277 and consequent 14-3-3 binding, which restrains NFAT activity [PMID:12501243], and by tankyrase (PARP5)-catalyzed ADP-ribosylation that targets the protein for degradation; SH3BP2 transcription is in turn driven by PARP1 binding to its promoter [PMID:22820184, PMID:30813388]. Cherubism mutations disrupt tankyrase-mediated turnover, stabilizing SH3BP2 and enhancing TNF-α production and both RANKL-dependent and RANKL-independent, TNF-α-driven osteoclastogenesis, producing systemic autoinflammation and bone destruction in knock-in mice [PMID:17218256, PMID:24916406, PMID:32258251]. Beyond bone, SH3BP2 assembles a PLCγ2–VAV2 signalosome in podocytes [PMID:38127456] and modulates dendritic cell and microglial inflammatory responses and KIT/PDGFRA/MITF expression in gastrointestinal stromal tumors [PMID:29885053, PMID:33920631, PMID:39546158].","teleology":[{"year":2001,"claim":"Establishing that SH3BP2 mutations cause cherubism converted an uncharacterized adaptor into the genetic driver of a defined bone-resorption disease and localized the critical residues to exon 9.","evidence":"Direct sequencing of SH3BP2 across affected families identifying seven mutations at residues 415-420","pmids":["11381256"],"confidence":"High","gaps":["Did not establish whether mutations are gain- or loss-of-function","No mechanism linking the residues to protein behavior"]},{"year":2002,"claim":"Identifying phosphorylation-dependent 14-3-3 binding showed how SH3BP2 adapter activity is held in check, defining a negative regulatory input on its NFAT-driving function.","evidence":"Yeast two-hybrid, co-IP, in vitro PKC kinase assay, Ser225/Ser277 mutagenesis, and NFAT reporter in lymphocytes","pmids":["12501243"],"confidence":"High","gaps":["Did not connect 14-3-3 regulation to cherubism mutations in exon 9","Tested in lymphocytes rather than myeloid/osteoclast lineage"]},{"year":2006,"claim":"Demonstrating that cherubism alleles increase NFAT transcriptional activity provided the first functional evidence that these mutations are gain-of-function.","evidence":"Transient transfection of R415Q/P418R/D419N/D420E with NFAT-luciferase reporter","pmids":["16786512"],"confidence":"Medium","gaps":["Reporter-based readout without endogenous validation","No upstream signaling mechanism defined"]},{"year":2007,"claim":"A cherubism knock-in mouse established that gain-of-function SH3BP2 drives TNF-α-dependent, myeloid-cell-intrinsic systemic inflammation and bone loss, defining the disease cell-of-origin.","evidence":"P416R knock-in mice, fetal liver/bone marrow transfer, ERK/SYK western blot, RANKL/M-CSF stimulation, TNF-α measurement","pmids":["17218256"],"confidence":"High","gaps":["Did not resolve the full downstream signaling axis to NFATc1","Mechanism of protein stabilization not addressed"]},{"year":2008,"claim":"Linking SH3BP2 to PLCγ phosphorylation and NFATc1 translocation supplied the intracellular pathway connecting the adaptor to osteoclast differentiation.","evidence":"Overexpression in RAW264.7 cells with PLCγ phospho-western, TRAP staining, NFATc1 localization","pmids":["18440306"],"confidence":"Medium","gaps":["Overexpression system only","Did not test cherubism mutants"]},{"year":2010,"claim":"Comparing mutant versus wild-type SH3BP2 confirmed that cherubism alleles potentiate the RANKL→PLCγ→NFAT axis, and a separate study revealed an additional osteoblast-suppressive effect, broadening the disease mechanism beyond osteoclasts.","evidence":"Transfection of WT vs mutant SH3BP2 with PLCγ phospho-western and TRAP in RAW264.7; knock-in osteoblast cultures with mineralization and marker analysis","pmids":["20872577","20117257","20691350"],"confidence":"Medium","gaps":["Osteoblast defect mechanism not molecularly defined","Cell-line and culture systems"]},{"year":2011,"claim":"Loss-of-function by shRNA and knockout established SH3BP2 as a required positive regulator of osteoclast differentiation and resorption, while biochemical work attributed mutant protein accumulation to disrupted tankyrase-mediated degradation.","evidence":"shRNA and Sh3bp2-/- BMM cultures with PLCγ2/NFATc1 western, TRAP and resorption assays; commentary citing tankyrase primary biochemistry","pmids":["21448930","22153068"],"confidence":"High","gaps":["Tankyrase mechanism summarized in commentary rather than primary data here","Stoichiometry of degradation control not quantified"]},{"year":2012,"claim":"Identifying PARP1 as a promoter-binding transcriptional driver of SH3BP2 added a layer controlling its abundance distinct from protein turnover.","evidence":"EMSA, ChIP, promoter deletion/mutagenesis of the -44 to -21 site, Parp1 knockout BMMs","pmids":["22820184"],"confidence":"High","gaps":["Signals that regulate PARP1 occupancy unknown","Relevance to cherubism mutant expression not tested"]},{"year":2014,"claim":"Defining a SYK→PLCγ2→NFATc1 axis showed that mutant SH3BP2 enables TNF-α to drive RANKL-independent osteoclastogenesis and exacerbates inflammatory arthritis through myeloid TNF-α.","evidence":"Knock-in BMM cultures, SYK/PLCγ2 western, NFATc1 localization, calvarial TNF-α injection, hTNFtg and collagen-induced arthritis models","pmids":["24916406","25144740"],"confidence":"High","gaps":["Lymphocyte contribution excluded but DC/other myeloid roles not yet defined","Did not separate resorption from differentiation"]},{"year":2019,"claim":"Pharmacological tankyrase inhibition and conditional SYK/SH3BP2 deletion confirmed tankyrase as a negative regulator of SH3BP2 levels and dissected SH3BP2-SYK control of osteoclast resorptive function from differentiation in disease.","evidence":"Tankyrase inhibitor in mice with micro-CT; LysM-Cre conditional Sh3bp2/Syk knockout, SYK inhibitor, periodontitis model, resorption assay","pmids":["30813388","31613396"],"confidence":"High","gaps":["Direct ADP-ribosylation site mapping not shown in these entries","Whether SYK axis governs resorption in cherubism-mutant cells not tested here"]},{"year":2020,"claim":"Genetic epistasis with Rankl-/- mice proved SH3BP2 gain-of-function can produce osteoclasts entirely independent of RANKL, reframing the disease as TNF-α-driven.","evidence":"Sh3bp2 KI × Rankl-/- double mutants with TRAP/cathepsin K staining, micro-CT, serum TNF-α/TRAP5b","pmids":["32258251"],"confidence":"High","gaps":["The receptor/signal substituting for RANKL not fully defined","Restricted to gain-of-function background"]},{"year":2024,"claim":"Expanding SH3BP2 beyond bone, studies placed it in a PLCγ2-VAV2 podocyte signalosome in nephrotic syndrome and identified inflammatory roles in dendritic cells, microglia (JAK/STAT), and GIST oncogenesis (KIT/PDGFRA/MITF).","evidence":"Co-IP of SH3BP2 with PLCγ2/VAV2 in podocytes plus KI mouse; lupus-model DC and conditional B cell KO; shSH3BP2 in microglia/SCI; shRNA silencing with rescue in GIST lines and xenografts","pmids":["38127456","33920631","39546158","29885053"],"confidence":"Medium","gaps":["Podocyte signalosome shown by single Co-IP without reciprocal validation","Mechanistic link between SH3BP2 and JAK/STAT or MITF not biochemically defined","Direct partners in non-myeloid contexts incompletely mapped"]},{"year":2021,"claim":"Linking TLR2/4 and neutrophils to jawbone lesions situated SH3BP2 gain-of-function downstream of PAMP-induced innate signaling, explaining the jaw-specific manifestation of cherubism.","evidence":"Sh3bp2 KI pulp-exposure model with Tlr2/4 knockout epistasis, anti-Ly6G neutrophil depletion, micro-CT and cytokine analysis","pmids":["35079675"],"confidence":"Medium","gaps":["Direct molecular coupling of TLR signaling to SH3BP2 not shown","Single-lab in vivo model"]},{"year":null,"claim":"It remains unresolved how SH3BP2's distinct regulatory inputs (PARP1 transcription, tankyrase degradation, 14-3-3 sequestration) are integrated quantitatively and whether the same SYK→PLCγ→NFAT module operates across its non-osteoclast roles in podocytes, dendritic cells, microglia, and GISTs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SH3BP2 in complex with its partners","Cross-tissue conservation of the signaling axis untested","Therapeutic targeting via tankyrase/SYK in cherubism patients not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,7,17]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,10,11,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,10,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,3,14]}],"complexes":["SH3BP2-PLCγ2-VAV2 signalosome"],"partners":["14-3-3","TNKS","PARP1","PLCG2","PLCG1","SYK","VAV2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P78314","full_name":"SH3 domain-binding protein 2","aliases":[],"length_aa":561,"mass_kda":62.2,"function":"Binds differentially to the SH3 domains of certain proteins of signal transduction pathways. Binds to phosphatidylinositols; linking the hemopoietic tyrosine kinase fes to the cytoplasmic membrane in a phosphorylation dependent mechanism","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P78314/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3BP2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SH3BP2","total_profiled":1310},"omim":[{"mim_id":"621133","title":"OPIOID GROWTH FACTOR RECEPTOR-LIKE PROTEIN 1; OGFRL1","url":"https://www.omim.org/entry/621133"},{"mim_id":"602104","title":"SH3 DOMAIN-BINDING PROTEIN 2; SH3BP2","url":"https://www.omim.org/entry/602104"},{"mim_id":"118400","title":"CHERUBISM","url":"https://www.omim.org/entry/118400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SH3BP2"},"hgnc":{"alias_symbol":["RES4-23","CRBM"],"prev_symbol":[]},"alphafold":{"accession":"P78314","domains":[{"cath_id":"2.30.29.30","chopping":"16-131_152-156","consensus_level":"high","plddt":90.5635,"start":16,"end":156},{"cath_id":"3.30.505.10","chopping":"454-553","consensus_level":"high","plddt":91.939,"start":454,"end":553}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P78314","model_url":"https://alphafold.ebi.ac.uk/files/AF-P78314-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P78314-F1-predicted_aligned_error_v6.png","plddt_mean":65.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3BP2","jax_strain_url":"https://www.jax.org/strain/search?query=SH3BP2"},"sequence":{"accession":"P78314","fasta_url":"https://rest.uniprot.org/uniprotkb/P78314.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P78314/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P78314"}},"corpus_meta":[{"pmid":"11381256","id":"PMC_11381256","title":"Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism.","date":"2001","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11381256","citation_count":277,"is_preprint":false},{"pmid":"17218256","id":"PMC_17218256","title":"Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 \"cherubism\" mice.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17218256","citation_count":149,"is_preprint":false},{"pmid":"22640988","id":"PMC_22640988","title":"The role of SH3BP2 in the pathophysiology of cherubism.","date":"2012","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22640988","citation_count":74,"is_preprint":false},{"pmid":"24916406","id":"PMC_24916406","title":"SH3BP2 cherubism mutation potentiates TNF-α-induced osteoclastogenesis via NFATc1 and TNF-α-mediated inflammatory bone loss.","date":"2014","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/24916406","citation_count":53,"is_preprint":false},{"pmid":"12501243","id":"PMC_12501243","title":"The chaperone protein 14-3-3 interacts with 3BP2/SH3BP2 and regulates its adapter function.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12501243","citation_count":46,"is_preprint":false},{"pmid":"12900899","id":"PMC_12900899","title":"Novel mutation in the gene encoding c-Abl-binding protein SH3BP2 causes cherubism.","date":"2003","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/12900899","citation_count":40,"is_preprint":false},{"pmid":"14577811","id":"PMC_14577811","title":"A missense mutation in the SH3BP2 gene on chromosome 4p16.3 found in a case of nonfamilial cherubism.","date":"2003","source":"The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association","url":"https://pubmed.ncbi.nlm.nih.gov/14577811","citation_count":39,"is_preprint":false},{"pmid":"9299232","id":"PMC_9299232","title":"Identification and characterization of the human homologue of SH3BP2, an SH3 binding domain protein within a common region of deletion at 4p16.3 involved in bladder cancer.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9299232","citation_count":35,"is_preprint":false},{"pmid":"16786512","id":"PMC_16786512","title":"Identification of a novel mutation of SH3BP2 in cherubism and demonstration that SH3BP2 mutations lead to increased NFAT 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residues 415-420) cause cherubism, identifying SH3BP2 as the causative gene for this bone resorption disorder.\",\n      \"method\": \"Direct sequencing of SH3BP2 in affected families; identification of seven distinct mutations\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent families, direct sequencing, replicated across subsequent studies\",\n      \"pmids\": [\"11381256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"14-3-3 chaperone proteins physically interact with SH3BP2 (3BP2) in a phosphorylation-dependent manner; PKC-mediated phosphorylation of Ser225 and Ser277 within proline-rich domains (residues 201-240 and 270-310) is required for 14-3-3 binding, and this interaction negatively regulates SH3BP2 adapter function (NFAT transcriptional activity) in lymphocytes.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, alkaline phosphatase dephosphorylation assay, in vitro PKC kinase assay, deletion mutant mapping, NFAT-reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods including in vitro kinase assay, mutagenesis, and functional reporter assays in a single study\",\n      \"pmids\": [\"12501243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cherubism-associated SH3BP2 mutations (R415Q, P418R, D419N, D420E) are gain-of-function mutations that increase NFAT transcriptional activity when transiently expressed in cells.\",\n      \"method\": \"Transient transfection of mutant SH3BP2 constructs with NFAT-luciferase reporter assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay with multiple alleles, single lab but multiple mutants tested\",\n      \"pmids\": [\"16786512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cherubism knock-in mice (P416R Sh3bp2) exhibit TNF-α-dependent systemic inflammation and bone loss driven by myeloid cells; mutant myeloid cells show increased ERK1/2 and SYK phosphorylation in response to M-CSF and RANKL, forming large osteoclasts with high TNF-α expression. The phenotype is lymphocyte-independent and transferable via mutant fetal liver cells, establishing SH3BP2 gain-of-function in myeloid cells as the mechanism.\",\n      \"method\": \"Knock-in mouse model, fetal liver cell transfer, bone marrow transplantation, ERK/SYK western blot, RANKL/M-CSF stimulation assays, TNF-α measurement\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse with cell transfer experiments, multiple orthogonal methods, mechanistic pathway placement established\",\n      \"pmids\": [\"17218256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SH3BP2 overexpression in RAW 264.7 preosteoclast cells increases NFATc1 nuclear translocation and TRAP expression in response to sRANKL, and potentiates PLCγ1 and PLCγ2 phosphorylation, providing a mechanistic pathway linking SH3BP2 to osteoclastogenesis via PLCγ→calcineurin→NFATc1.\",\n      \"method\": \"Overexpression in RAW264.7 cells, western blot for PLCγ phosphorylation, TRAP staining, NFATc1 nuclear localization assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays (phosphorylation, localization, differentiation marker) in single lab\",\n      \"pmids\": [\"18440306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cherubism-associated mutant SH3BP2 (compared to wild-type) potentiates RANKL-induced PLCγ1 and PLCγ2 phosphorylation, leading to greater NFAT activation and osteoclast differentiation (TRAP expression) in RAW264.7 cells, confirming gain-of-function mechanism through the PLCγ→NFATc1 axis.\",\n      \"method\": \"Transient transfection of wild-type vs mutant SH3BP2, NFAT-luciferase reporter, TRAP staining, western blot for PLCγ phosphorylation\",\n      \"journal\": \"Journal of orthopaedic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays including phosphorylation and functional readout, single lab\",\n      \"pmids\": [\"20872577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The P416R cherubism mutation in Sh3bp2 knock-in mice impairs osteoblast differentiation and function: homozygous mutant osteoblast cultures show decreased alkaline phosphatase expression, reduced mineralization, and decreased expression of osteoblast markers (Col1a1, ALP, osteocalcin). Mutant osteoblasts also increase osteoclastogenesis in co-culture with bone marrow macrophages.\",\n      \"method\": \"Knock-in mouse calvarial osteoblast cultures, GFP-Col1a1 transgene reporter, FTIRI bone mineral analysis, co-culture assay, gene expression analysis\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in knock-in mouse model, single lab\",\n      \"pmids\": [\"20117257\", \"20691350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"shRNA knockdown of SH3BP2 in RAW264.7 and bone marrow macrophages (BMMs) decreases PLCγ2 phosphorylation, NFATc1 expression, osteoclast-specific gene expression, and reduces osteoclast number, size, and bone resorptive activity; Sh3bp2-/- BMMs similarly form smaller, less active osteoclasts, establishing SH3BP2 as a positive regulator of osteoclast differentiation and function.\",\n      \"method\": \"shRNA knockdown, Sh3bp2-/- mouse BMM cultures, western blot for PLCγ2/NFATc1, TRAP staining, bone resorption assay\",\n      \"journal\": \"Journal of orthopaedic research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent loss-of-function approaches (shRNA and knockout mouse) with multiple mechanistic readouts\",\n      \"pmids\": [\"21448930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tankyrase (PARP5) interaction with SH3BP2 is disrupted by cherubism mutations, leading to SH3BP2 stabilization (loss of tankyrase-mediated degradation); this mechanism was highlighted as central to understanding why cherubism mutations cause protein accumulation.\",\n      \"method\": \"Review/commentary citing two Cell papers (Guettler et al. and Levaot et al.) — mechanistic evidence from referenced primary studies\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — commentary citing primary biochemical studies; mechanism inferred from referenced papers, not directly demonstrated in this abstract\",\n      \"pmids\": [\"22153068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PARP1 binds to the SH3BP2 promoter at a specific site (−44 to −21) and is essential for SH3BP2 transcriptional expression; PARP1 knockout in mice reduces SH3BP2 expression in BMMs.\",\n      \"method\": \"Streptavidin-biotin purification, EMSA, ChIP assay, promoter deletion analysis, mutagenesis of PARP1 binding site, Parp1 knockout mouse BMMs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (EMSA, ChIP, mutagenesis, KO mouse) establishing transcriptional regulation mechanism\",\n      \"pmids\": [\"22820184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The P416R cherubism mutation in SH3BP2 enables TNF-α to drive RANKL-independent osteoclastogenesis in BMMs via SYK and PLCγ2 phosphorylation leading to increased NFATc1 nuclear translocation; heterozygous mutant mice show exacerbated bone loss in TNF-α calvarial injection and hTNFtg models. SH3BP2 knockdown in RAW264.7 cells reduces TNF-α-induced osteoclast formation.\",\n      \"method\": \"Knock-in mouse BMM cultures, western blot for SYK/PLCγ2, NFATc1 nuclear localization, calvarial TNF-α injection model, hTNFtg mouse model, shRNA knockdown\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vitro and in vivo models, mechanistic pathway (SYK→PLCγ2→NFATc1) established with orthogonal methods\",\n      \"pmids\": [\"24916406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SH3BP2 gain-of-function (P416R) augments inflammation and bone loss in collagen-induced arthritis through increased macrophage TNF-α production and enhanced RANKL-induced osteoclastogenesis with increased NFATc1 nuclear localization; lymphocyte responses (proliferation, IFN-γ, IL-17, anti-CII antibodies) were not significantly different between wild-type and mutant mice.\",\n      \"method\": \"CIA mouse model, paw swelling assessment, micro-CT, histology, cytokine gene expression, BMM culture for TNF-α and osteoclastogenesis, NFATc1 nuclear localization, lymph node cell culture\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo and in vitro readouts with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"25144740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tankyrase (PARP5) catalyzes ADP-ribosylation of SH3BP2, targeting it for degradation; pharmacological tankyrase inhibition in mice stabilizes SH3BP2 leading to increased osteoclast formation and bone loss, establishing tankyrase as a negative regulator of SH3BP2 protein levels and osteoclastogenesis.\",\n      \"method\": \"Tankyrase inhibitor treatment in mice, micro-CT bone analysis, osteoclast formation assays — reviewed mechanistic data from primary studies\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological model with mechanistic follow-up; review article summarizing primary experimental evidence\",\n      \"pmids\": [\"30813388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SH3BP2 functions through a SH3BP2-SYK signaling axis to regulate the bone-resorbing function (not differentiation) of osteoclasts in periodontitis; conditional knockout of SH3BP2 and SYK in myeloid cells (LysM-Cre) reduces alveolar bone loss without affecting inflammatory cytokine expression or osteoclast induction.\",\n      \"method\": \"Sh3bp2-/- mice, conditional myeloid knockout (LysM-Cre), ligature-induced periodontitis model, micro-CT, SYK inhibitor (GS-9973), in vitro mineral resorption assay\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus pharmacological inhibition, in vivo and in vitro, with specific mechanistic dissection of resorption vs. differentiation\",\n      \"pmids\": [\"31613396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SH3BP2 silencing in GIST cell lines downregulates oncogenic KIT and PDGFRA expression and reduces microphthalmia-associated transcription factor (MITF) levels; reconstitution of both SH3BP2 and MITF rescues cell viability, placing SH3BP2 upstream of MITF in regulating KIT/PDGFRA expression in GISTs.\",\n      \"method\": \"shRNA silencing in GIST cell lines, western blot, overexpression rescue experiment, in vivo xenograft tumor growth assay, migration assay\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with rescue experiment establishing pathway position, single lab\",\n      \"pmids\": [\"29885053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SH3BP2 gain-of-function (homozygous P416R) drives RANKL-independent osteoclastogenesis in vivo; Sh3bp2 knock-in mice develop TRAP-positive, cathepsin K-positive multinucleated osteoclasts spontaneously even in the absence of RANKL (Rankl-/- background), with elevated serum TNF-α as the likely driver.\",\n      \"method\": \"Sh3bp2 KI × Rankl-/- double mutant mouse model, TRAP staining, cathepsin K staining, micro-CT bone analysis, osteoclast marker gene expression, serum TRAP5b and TNF-α measurement\",\n      \"journal\": \"Bone reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-mutant mouse genetic epistasis clearly establishing RANKL-independent osteoclastogenesis downstream of SH3BP2\",\n      \"pmids\": [\"32258251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SH3BP2 deficiency suppresses dendritic cell differentiation in vitro and reduces the number of dendritic cells in spleens of lupus-prone mice; B cell-specific SH3BP2 deficiency does not rescue lupus phenotypes, indicating the relevant SH3BP2 function in lupus is not B cell-intrinsic.\",\n      \"method\": \"SH3BP2-deficient mouse on Fas lupus background, flow cytometry of lymphocyte subsets, B cell-specific conditional KO, in vitro dendritic cell differentiation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional and global KO with in vitro and in vivo mechanistic readouts, single lab\",\n      \"pmids\": [\"33920631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SH3BP2 forms a signalosome complex with PLCγ2 and VAV2 (Rho-GEF) in human podocytes, as shown by co-immunoprecipitation; downstream signaling through MyD88, TRIF, and NFATc1 is upregulated in SH3BP2-associated nephrotic syndrome.\",\n      \"method\": \"Co-immunoprecipitation of SH3BP2 with PLCγ2 and VAV2 in human podocytes, Sh3bp2 KI/KI transgenic mouse model (albuminuria measurement)\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP in human podocytes supported by in vivo gain-of-function mouse model data\",\n      \"pmids\": [\"38127456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SH3BP2 silencing inhibits microglia activation and neuroinflammation via the JAK/STAT signaling pathway; silencing decreases phosphorylation of JAK and STAT in LPS-stimulated microglia and improves neurological outcomes in spinal cord injury rat models.\",\n      \"method\": \"Lentiviral shSH3BP2 injection in SCI rat model, LPS-stimulated BV2 and primary microglia, western blot for p-JAK/p-STAT, qRT-PCR, immunofluorescence, behavioral assays\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with in vitro mechanistic validation, single lab, pathway placement via JAK/STAT\",\n      \"pmids\": [\"39546158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TLR2/4-mediated inflammation in the jaw triggers cherubism-like bone expansion specifically in Sh3bp2 gain-of-function mice; ablation of Tlr2/4 signaling or neutrophil depletion (anti-Ly6G) ameliorates jawbone expansion, placing SH3BP2 gain-of-function downstream of pathogen-associated molecular pattern (PAMP)-induced TLR signaling in jawbone lesion development.\",\n      \"method\": \"Sh3bp2 KI mouse pulp exposure model, Tlr2/4 knockout genetic epistasis, anti-Ly6G neutrophil depletion, histology, cytokine expression, micro-CT\",\n      \"journal\": \"JBMR plus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with TLR pathway and pharmacological depletion in in vivo model, single lab\",\n      \"pmids\": [\"35079675\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3BP2 is a scaffold/adaptor protein that positively regulates osteoclastogenesis and inflammatory signaling in myeloid cells by acting upstream of SYK→PLCγ2→calcineurin→NFATc1; its protein stability is controlled by tankyrase (PARP5)-mediated ADP-ribosylation and degradation, its transcription is driven by PARP1, and its adapter function is negatively regulated by phosphorylation-dependent 14-3-3 binding; gain-of-function cherubism mutations (predominantly in exon 9) disrupt tankyrase-mediated degradation, stabilize the protein, and enhance TNF-α production and RANKL- or TNF-α-driven osteoclast formation through increased SYK and PLCγ2 phosphorylation and NFATc1 nuclear translocation, driving systemic autoinflammation and bone destruction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SH3BP2 (3BP2) is a cytoplasmic scaffold/adaptor protein that positively regulates osteoclastogenesis and myeloid inflammatory signaling, and it is the causative gene for the bone-resorption disorder cherubism, in which missense mutations clustering in exon 9 (residues 415-420) act as gain-of-function alleles [#0, #2]. Mechanistically, SH3BP2 amplifies osteoclast differentiation by potentiating SYK and PLCγ1/PLCγ2 phosphorylation, which drives calcineurin-dependent NFATc1 nuclear translocation and induction of osteoclast-specific genes; loss of SH3BP2 by knockdown or knockout reduces PLCγ2/NFATc1 signaling and yields smaller, less resorptive osteoclasts, while overexpression has the opposite effect [#4, #7, #10]. Its adapter output is constrained by negative regulation through PKC-dependent phosphorylation of Ser225/Ser277 and consequent 14-3-3 binding, which restrains NFAT activity [#1], and by tankyrase (PARP5)-catalyzed ADP-ribosylation that targets the protein for degradation; SH3BP2 transcription is in turn driven by PARP1 binding to its promoter [#9, #12]. Cherubism mutations disrupt tankyrase-mediated turnover, stabilizing SH3BP2 and enhancing TNF-α production and both RANKL-dependent and RANKL-independent, TNF-α-driven osteoclastogenesis, producing systemic autoinflammation and bone destruction in knock-in mice [#3, #10, #15]. Beyond bone, SH3BP2 assembles a PLCγ2–VAV2 signalosome in podocytes [#17] and modulates dendritic cell and microglial inflammatory responses and KIT/PDGFRA/MITF expression in gastrointestinal stromal tumors [#14, #16, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that SH3BP2 mutations cause cherubism converted an uncharacterized adaptor into the genetic driver of a defined bone-resorption disease and localized the critical residues to exon 9.\",\n      \"evidence\": \"Direct sequencing of SH3BP2 across affected families identifying seven mutations at residues 415-420\",\n      \"pmids\": [\"11381256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether mutations are gain- or loss-of-function\", \"No mechanism linking the residues to protein behavior\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying phosphorylation-dependent 14-3-3 binding showed how SH3BP2 adapter activity is held in check, defining a negative regulatory input on its NFAT-driving function.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, in vitro PKC kinase assay, Ser225/Ser277 mutagenesis, and NFAT reporter in lymphocytes\",\n      \"pmids\": [\"12501243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect 14-3-3 regulation to cherubism mutations in exon 9\", \"Tested in lymphocytes rather than myeloid/osteoclast lineage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that cherubism alleles increase NFAT transcriptional activity provided the first functional evidence that these mutations are gain-of-function.\",\n      \"evidence\": \"Transient transfection of R415Q/P418R/D419N/D420E with NFAT-luciferase reporter\",\n      \"pmids\": [\"16786512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reporter-based readout without endogenous validation\", \"No upstream signaling mechanism defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A cherubism knock-in mouse established that gain-of-function SH3BP2 drives TNF-α-dependent, myeloid-cell-intrinsic systemic inflammation and bone loss, defining the disease cell-of-origin.\",\n      \"evidence\": \"P416R knock-in mice, fetal liver/bone marrow transfer, ERK/SYK western blot, RANKL/M-CSF stimulation, TNF-α measurement\",\n      \"pmids\": [\"17218256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the full downstream signaling axis to NFATc1\", \"Mechanism of protein stabilization not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking SH3BP2 to PLCγ phosphorylation and NFATc1 translocation supplied the intracellular pathway connecting the adaptor to osteoclast differentiation.\",\n      \"evidence\": \"Overexpression in RAW264.7 cells with PLCγ phospho-western, TRAP staining, NFATc1 localization\",\n      \"pmids\": [\"18440306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system only\", \"Did not test cherubism mutants\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Comparing mutant versus wild-type SH3BP2 confirmed that cherubism alleles potentiate the RANKL→PLCγ→NFAT axis, and a separate study revealed an additional osteoblast-suppressive effect, broadening the disease mechanism beyond osteoclasts.\",\n      \"evidence\": \"Transfection of WT vs mutant SH3BP2 with PLCγ phospho-western and TRAP in RAW264.7; knock-in osteoblast cultures with mineralization and marker analysis\",\n      \"pmids\": [\"20872577\", \"20117257\", \"20691350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Osteoblast defect mechanism not molecularly defined\", \"Cell-line and culture systems\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Loss-of-function by shRNA and knockout established SH3BP2 as a required positive regulator of osteoclast differentiation and resorption, while biochemical work attributed mutant protein accumulation to disrupted tankyrase-mediated degradation.\",\n      \"evidence\": \"shRNA and Sh3bp2-/- BMM cultures with PLCγ2/NFATc1 western, TRAP and resorption assays; commentary citing tankyrase primary biochemistry\",\n      \"pmids\": [\"21448930\", \"22153068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tankyrase mechanism summarized in commentary rather than primary data here\", \"Stoichiometry of degradation control not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying PARP1 as a promoter-binding transcriptional driver of SH3BP2 added a layer controlling its abundance distinct from protein turnover.\",\n      \"evidence\": \"EMSA, ChIP, promoter deletion/mutagenesis of the -44 to -21 site, Parp1 knockout BMMs\",\n      \"pmids\": [\"22820184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that regulate PARP1 occupancy unknown\", \"Relevance to cherubism mutant expression not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining a SYK→PLCγ2→NFATc1 axis showed that mutant SH3BP2 enables TNF-α to drive RANKL-independent osteoclastogenesis and exacerbates inflammatory arthritis through myeloid TNF-α.\",\n      \"evidence\": \"Knock-in BMM cultures, SYK/PLCγ2 western, NFATc1 localization, calvarial TNF-α injection, hTNFtg and collagen-induced arthritis models\",\n      \"pmids\": [\"24916406\", \"25144740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lymphocyte contribution excluded but DC/other myeloid roles not yet defined\", \"Did not separate resorption from differentiation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pharmacological tankyrase inhibition and conditional SYK/SH3BP2 deletion confirmed tankyrase as a negative regulator of SH3BP2 levels and dissected SH3BP2-SYK control of osteoclast resorptive function from differentiation in disease.\",\n      \"evidence\": \"Tankyrase inhibitor in mice with micro-CT; LysM-Cre conditional Sh3bp2/Syk knockout, SYK inhibitor, periodontitis model, resorption assay\",\n      \"pmids\": [\"30813388\", \"31613396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ADP-ribosylation site mapping not shown in these entries\", \"Whether SYK axis governs resorption in cherubism-mutant cells not tested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic epistasis with Rankl-/- mice proved SH3BP2 gain-of-function can produce osteoclasts entirely independent of RANKL, reframing the disease as TNF-α-driven.\",\n      \"evidence\": \"Sh3bp2 KI × Rankl-/- double mutants with TRAP/cathepsin K staining, micro-CT, serum TNF-α/TRAP5b\",\n      \"pmids\": [\"32258251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor/signal substituting for RANKL not fully defined\", \"Restricted to gain-of-function background\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanding SH3BP2 beyond bone, studies placed it in a PLCγ2-VAV2 podocyte signalosome in nephrotic syndrome and identified inflammatory roles in dendritic cells, microglia (JAK/STAT), and GIST oncogenesis (KIT/PDGFRA/MITF).\",\n      \"evidence\": \"Co-IP of SH3BP2 with PLCγ2/VAV2 in podocytes plus KI mouse; lupus-model DC and conditional B cell KO; shSH3BP2 in microglia/SCI; shRNA silencing with rescue in GIST lines and xenografts\",\n      \"pmids\": [\"38127456\", \"33920631\", \"39546158\", \"29885053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Podocyte signalosome shown by single Co-IP without reciprocal validation\", \"Mechanistic link between SH3BP2 and JAK/STAT or MITF not biochemically defined\", \"Direct partners in non-myeloid contexts incompletely mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking TLR2/4 and neutrophils to jawbone lesions situated SH3BP2 gain-of-function downstream of PAMP-induced innate signaling, explaining the jaw-specific manifestation of cherubism.\",\n      \"evidence\": \"Sh3bp2 KI pulp-exposure model with Tlr2/4 knockout epistasis, anti-Ly6G neutrophil depletion, micro-CT and cytokine analysis\",\n      \"pmids\": [\"35079675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular coupling of TLR signaling to SH3BP2 not shown\", \"Single-lab in vivo model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SH3BP2's distinct regulatory inputs (PARP1 transcription, tankyrase degradation, 14-3-3 sequestration) are integrated quantitatively and whether the same SYK→PLCγ→NFAT module operates across its non-osteoclast roles in podocytes, dendritic cells, microglia, and GISTs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SH3BP2 in complex with its partners\", \"Cross-tissue conservation of the signaling axis untested\", \"Therapeutic targeting via tankyrase/SYK in cherubism patients not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 7, 17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 10, 11, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 10, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 3, 14]}\n    ],\n    \"complexes\": [\"SH3BP2-PLCγ2-VAV2 signalosome\"],\n    \"partners\": [\"14-3-3\", \"TNKS\", \"PARP1\", \"PLCG2\", \"PLCG1\", \"SYK\", \"VAV2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}