{"gene":"SBF2","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2003,"finding":"SBF2 (MTMR13) was identified as a pseudophosphatase member of the myotubularin family; disease-causing nonsense mutations in MTMR13 were found in two consanguineous families with CMT4B2, establishing it as the causative gene for this demyelinating neuropathy with myelin outfoldings.","method":"Homozygosity mapping, mutation identification (nonsense mutations), genetic linkage to chromosome 11p15","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mapping and mutation identification replicated in two independent families, co-segregation confirmed, replicated by independent lab (PMID:12554688)","pmids":["12687498","12554688"],"is_preprint":false},{"year":2003,"finding":"SBF2 encodes a large novel protein belonging to the pseudo-phosphatase branch of myotubularins; an in-frame deletion of SBF2 exons 11 and 12 disrupts an N-terminal domain conserved across species, establishing loss-of-function as the disease mechanism in CMT4B2.","method":"Homozygosity mapping, molecular analysis of SBF2 gene (exon deletion identified), expression analysis in peripheral nervous system tissues","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutation co-segregation in affected family, expression in PNS confirmed, independent replication of SBF2 as CMT4B2 gene","pmids":["12554688"],"is_preprint":false},{"year":2005,"finding":"Endogenous MTMR2 and MTMR13/SBF2 physically associate in human embryonic kidney 293 cells; this interaction is mediated by coiled-coil sequences present in each protein. MTMR13 is a predominantly membrane-associated protein, and its membrane association is mediated by the segment containing the pseudophosphatase domain. MTMR2 and MTMR13 co-fractionate in both a light membrane fraction and a cytosolic fraction.","method":"Co-immunoprecipitation of endogenous proteins, subcellular fractionation, fluorescence microscopy, deletion/domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — endogenous Co-IP, subcellular fractionation, and domain mapping in one study with multiple orthogonal methods","pmids":["15998640"],"is_preprint":false},{"year":2007,"finding":"MTMR13/SBF2 forms a tetrameric complex with MTMR2, and this interaction strongly increases the enzymatic phosphatase activity of MTMR2 (which dephosphorylates PtdIns 3-phosphate and PtdIns 3,5-bisphosphate). Mtmr13/Sbf2-deficient mice develop myelin outfoldings and infoldings with decreased motor performance, reproducing CMT4B2 pathological hallmarks.","method":"Generation of Mtmr13/Sbf2-deficient mice, nerve morphology, electrophysiology, biochemical characterization of protein complex and enzymatic activity","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo knockout model with defined phenotype, biochemical demonstration of complex and activity enhancement, replicated by independent lab (PMID:18349142)","pmids":["17855448"],"is_preprint":false},{"year":2008,"finding":"Loss of Mtmr13 in mice leads to a peripheral neuropathy with myelin outfoldings and infoldings predominantly at the paranode, reduced nerve conduction velocity, and axon loss. Mtmr2 protein levels are decreased by approximately 50% in Mtmr13-deficient sciatic nerves, indicating that Mtmr13 stabilizes Mtmr2.","method":"Knockout mouse model (Mtmr13-/- mice), nerve conduction velocity measurements, electron microscopy, western blotting for Mtmr2 levels","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined cellular and molecular phenotype, multiple orthogonal methods, replicated across labs","pmids":["18349142"],"is_preprint":false},{"year":2011,"finding":"Overexpression of Mtmr2 prevents degradation of the epidermal growth factor receptor (EGFR) and leads to sustained Akt activation. Mtmr13/Sbf2 counteracts the blockage of EGFR degradation (without affecting prolonged Akt activation), indicating that MTMR2 and MTMR13/SBF2 regulate EGFR sorting and downstream AKT signaling.","method":"Overexpression in cell lines, western blotting for EGFR and phospho-AKT, signaling pathway analysis in Mtmr2 and Mtmr13/Sbf2 mouse mutants","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression and mouse mutant analysis, single lab, two complementary methods but limited mechanistic resolution for MTMR13 specifically","pmids":["19912440"],"is_preprint":false},{"year":2012,"finding":"Drosophila Sbf (ortholog of MTMR13) functions as a guanine nucleotide exchange factor (GEF) that activates Rab21 GTPase. Sbf coordinates PI(3)P turnover (by dynamically interacting with class II PI 3-kinase and stably recruiting Mtm/MTMR2) and Rab21 activation at PI(3)P endosomes. Together, Sbf, Mtm, and Rab21 control macrophage protrusion formation through an endosomal trafficking pathway.","method":"Genetic knockdown in Drosophila macrophages, epistasis analysis, live imaging, PI(3)P reporter assays, GEF activity assay for Rab21","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — GEF activity demonstrated biochemically, genetic epistasis, multiple orthogonal methods in one rigorous study, functionally validated in vivo","pmids":["22648168"],"is_preprint":false},{"year":2015,"finding":"Starvation induces Sbf/MTMR13 GEF activity and RAB21 activation. MTMR13 is required for RAB21 activation, VAMP8 interaction, and VAMP8 endolysosomal trafficking; depletion of Sbf/MTMR13 or Rab21 blocks endolysosomal trafficking of VAMP8 (a SNARE required for autophagosome-lysosome fusion), thereby blocking starvation-induced autophagy.","method":"RNAi knockdown in Drosophila and mammalian cells, GEF activity assays, co-immunoprecipitation (MTMR13-VAMP8 interaction), fluorescence microscopy of VAMP8 trafficking, autophagy flux assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical GEF activity assay, Co-IP for binding partner identification, functional rescue experiments, multiple orthogonal methods","pmids":["25648148"],"is_preprint":false},{"year":2013,"finding":"A missense mutation (c.659C>G, p.Thr220Arg) in the DENN domain of SBF2 was identified in patients with severe thrombocytopenia, suggesting the DENN domain mediates putative association with Rab GTPases important for vesicle transport and membrane trafficking.","method":"Whole-exome sequencing, Sanger sequencing validation, family segregation analysis","journal":"Journal of thrombosis and thrombolysis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single case genetic identification, no direct biochemical validation of DENN domain function in this study","pmids":["23334996"],"is_preprint":false},{"year":2018,"finding":"In an in vitro SC-DRG explant model of CMT4B2, Mtmr13-/- Schwann cells develop myelin outfoldings, and Mtmr13 deficiency reduces Mtmr2 levels, further supporting Mtmr13's role in stabilizing Mtmr2. Overexpression of MTMR2 in Mtmr13-/- SC-DRGs moderately reduced myelin outfoldings, indicating that reduced PI 3-phosphatase activity contributes to the phenotype. Loss of vacuolar protein sorting 34 (Vps34) or PI3K-C2β in Mtmr13-/- mice had no impact on myelin outfoldings.","method":"Schwann cell-DRG explant culture from Mtmr13-/- mice, MTMR2 overexpression, double knockout mice (Mtmr13-/- x Vps34-/- and Mtmr13-/- x PI3K-C2β-/-), electron microscopy","journal":"ASN neuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro model with genetic rescue (MTMR2 OE), double KO epistasis, single lab but multiple orthogonal genetic approaches","pmids":["30419760"],"is_preprint":false},{"year":2022,"finding":"Mtmr2 is required to maintain wild-type levels of both Mtmr5 and Mtmr13 in mouse peripheral nerves, suggesting these factors function in discrete protein complexes with Mtmr2. Genetic elimination of both Mtmr5 and Mtmr13 in mice leads to perinatal lethality, indicating partial functional redundancy during embryogenesis. Loss of Mtmr5 causes axon radial sorting defects without CMT4B2-like myelin outfoldings, distinguishing the roles of Mtmr5 and Mtmr13 in the PNS.","method":"Double knockout mice (Mtmr5-/- x Mtmr13-/-), western blotting for protein levels, nerve morphology by electron microscopy, quantification of myelinated axons","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic models with defined phenotypes, multiple orthogonal methods, single lab","pmids":["34718573"],"is_preprint":false},{"year":2006,"finding":"Overexpressed epitope-tagged Sbf2 shows cytoplasmic distribution in cells. Sbf2 mRNA is broadly expressed across tissues including peripheral nervous system, and the murine Sbf2 protein shares high amino acid identity with human SBF2.","method":"Overexpression of epitope-tagged protein with fluorescence microscopy, in situ hybridization, Northern blot, RT-PCR","journal":"Gene expression patterns : GEP","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression localization experiment without functional consequence, single lab","pmids":["16750429"],"is_preprint":false},{"year":2015,"finding":"siRNA-mediated silencing of SBF2 in pancreatic cancer PANC-1 cells inhibited proliferation and promoted apoptosis, accompanied by decreased phospho-SMAD-2 and phospho-SMAD-3 and increased SMAD-7, suggesting SBF2 modulates TGF-β/SMAD signaling.","method":"siRNA knockdown, MTT proliferation assay, flow cytometry apoptosis assay, western blotting for TGF-β/SMAD pathway components","journal":"Technology in cancer research & treatment","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single KD experiment with pathway readout, no direct mechanistic link established, single lab single method per endpoint","pmids":["25882882"],"is_preprint":false},{"year":2022,"finding":"SBF2 knockdown in iPSC-derived sensory neurons exacerbated paclitaxel-induced changes to cell viability and neurite outgrowth while attenuating paclitaxel-induced sodium current inhibition, providing functional evidence that SBF2 modulates taxane-induced neuronal damage.","method":"Ex vivo model: SBF2 knockdown in iPSC-derived sensory neurons, cell viability assays, neurite outgrowth measurement, electrophysiology (sodium current recording), gene expression analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ex vivo neuronal model with electrophysiology and multiple functional readouts, single lab","pmids":["34986146"],"is_preprint":false}],"current_model":"SBF2/MTMR13 is a catalytically inactive pseudophosphatase (lacking the essential Cys and Arg residues) that contains a DENN domain and functions as a guanine nucleotide exchange factor (GEF) for RAB21, physically associates with and stabilizes the active PI(3)P/PI(3,5)P2 phosphatase MTMR2 via coiled-coil interactions to enhance its enzymatic activity, localizes predominantly to membranes via its pseudophosphatase domain, and coordinates PI(3)P turnover with RAB21-mediated endosomal trafficking to regulate autophagosome-lysosome fusion, EGFR sorting/AKT signaling, and Schwann cell myelination; loss-of-function mutations cause CMT4B2 peripheral neuropathy with myelin outfoldings."},"narrative":{"mechanistic_narrative":"SBF2 (MTMR13) is a large pseudophosphatase of the myotubularin family that coordinates phosphoinositide turnover with RAB-mediated endosomal trafficking [PMID:12687498, PMID:12554688, PMID:22648168]. It physically associates with the active PI(3)P/PI(3,5)P2 phosphatase MTMR2 through coiled-coil sequences, forming a tetrameric complex that strongly enhances MTMR2 catalytic activity, and it stabilizes MTMR2 protein in vivo, where loss of MTMR13 reduces MTMR2 levels by roughly half [PMID:15998640, PMID:17855448, PMID:18349142]. Through its DENN domain SBF2 acts as a guanine nucleotide exchange factor that activates RAB21, dynamically engaging class II PI 3-kinase and stably recruiting MTMR2 at PI(3)P-positive endosomes to couple lipid turnover with RAB21 activation [PMID:22648168]. This activity is induced by starvation and drives RAB21-dependent endolysosomal trafficking of the SNARE VAMP8, required for autophagosome-lysosome fusion and starvation-induced autophagy [PMID:25648148], and it regulates EGFR sorting and downstream AKT signaling together with MTMR2 [PMID:19912440]. In peripheral nerve, SBF2/MTMR2 function sustains Schwann cell myelination; loss-of-function mutations in SBF2 cause CMT4B2 demyelinating peripheral neuropathy with myelin outfoldings, a phenotype reproduced in Mtmr13-deficient mice and Schwann cell explants and partially rescued by MTMR2 overexpression [PMID:12687498, PMID:12554688, PMID:17855448, PMID:30419760].","teleology":[{"year":2003,"claim":"Established SBF2/MTMR13 as a disease gene by linking loss-of-function mutations to CMT4B2, framing the protein as a myotubularin-family pseudophosphatase critical for myelin integrity.","evidence":"Homozygosity mapping and nonsense/exon-deletion mutation identification in consanguineous CMT4B2 families","pmids":["12687498","12554688"],"confidence":"High","gaps":["Did not define the biochemical function of the pseudophosphatase domain","No molecular partner or pathway identified at this stage"]},{"year":2005,"claim":"Identified the physical basis of SBF2 function by showing endogenous association with the active phosphatase MTMR2 and membrane targeting via the pseudophosphatase domain.","evidence":"Endogenous Co-IP, subcellular fractionation, and domain-mapping fluorescence microscopy in HEK293 cells","pmids":["15998640"],"confidence":"High","gaps":["Did not establish a functional consequence of the interaction for MTMR2 activity","Membrane identity not resolved"]},{"year":2007,"claim":"Showed the interaction is functionally consequential, with MTMR13 forming a tetrameric complex that enhances MTMR2 phosphatase activity, and reproduced CMT4B2 pathology in knockout mice.","evidence":"Mtmr13-deficient mice with nerve morphology and electrophysiology plus biochemical complex/activity assays","pmids":["17855448"],"confidence":"High","gaps":["Did not address how enhanced phosphatase activity affects specific trafficking events","Stoichiometry of the complex in vivo not defined"]},{"year":2008,"claim":"Defined a stabilization mechanism by demonstrating that MTMR13 maintains MTMR2 protein levels in nerve, linking pseudophosphatase loss to reduced active phosphatase.","evidence":"Mtmr13-/- mice with nerve conduction velocity, electron microscopy, and western blotting of Mtmr2","pmids":["18349142"],"confidence":"High","gaps":["Mechanism of stabilization (degradation pathway) not identified","Phosphoinositide substrate changes in vivo not measured"]},{"year":2011,"claim":"Connected the MTMR2/MTMR13 module to receptor trafficking by showing it regulates EGFR degradation and AKT signaling.","evidence":"Overexpression and mouse mutant analysis with EGFR and phospho-AKT western blotting","pmids":["19912440"],"confidence":"Medium","gaps":["MTMR13-specific contribution mechanistically limited","Did not link EGFR sorting defect to myelin phenotype"]},{"year":2012,"claim":"Revealed the second enzymatic arm of SBF2 by demonstrating DENN-domain GEF activity toward RAB21, coupling PI(3)P turnover with RAB21 activation at endosomes.","evidence":"Drosophila macrophage genetics, epistasis, live imaging, PI(3)P reporters, and Rab21 GEF assay","pmids":["22648168"],"confidence":"High","gaps":["GEF activity demonstrated in Drosophila ortholog; human RAB21 GEF assay not shown here","Structural basis of nucleotide exchange unresolved"]},{"year":2015,"claim":"Placed SBF2 GEF activity in autophagy by showing starvation-induced RAB21 activation drives VAMP8 endolysosomal trafficking required for autophagosome-lysosome fusion.","evidence":"RNAi in Drosophila and mammalian cells, GEF assays, MTMR13-VAMP8 Co-IP, VAMP8 trafficking imaging, autophagy flux","pmids":["25648148"],"confidence":"High","gaps":["Direct vs indirect nature of the MTMR13-VAMP8 interaction not resolved","Relevance to Schwann cell pathology not tested"]},{"year":2018,"claim":"Tested causality of phosphatase loss for myelin pathology, showing MTMR2 overexpression partially rescues outfoldings while excluding VPS34 and PI3K-C2β as the relevant kinases in this context.","evidence":"Mtmr13-/- Schwann cell-DRG explants with MTMR2 overexpression and Mtmr13/Vps34 and Mtmr13/PI3K-C2β double knockouts","pmids":["30419760"],"confidence":"Medium","gaps":["Only partial rescue indicates additional MTMR13 functions beyond MTMR2 stabilization","PI(3)P-generating kinase responsible for the phenotype not identified"]},{"year":2022,"claim":"Distinguished MTMR13 from the paralog MTMR5 within MTMR2 complexes, establishing partial redundancy and non-overlapping PNS roles.","evidence":"Mtmr5/Mtmr13 double knockout mice, western blotting, and nerve electron microscopy","pmids":["34718573"],"confidence":"Medium","gaps":["Molecular basis of redundancy during embryogenesis not defined","Whether MTMR5 and MTMR13 form mutually exclusive complexes not directly shown"]},{"year":2022,"claim":"Extended SBF2 relevance to neuronal injury by showing it modulates taxane-induced damage in sensory neurons.","evidence":"SBF2 knockdown in iPSC-derived sensory neurons with viability, neurite outgrowth, and sodium current recordings","pmids":["34986146"],"confidence":"Medium","gaps":["Molecular pathway linking SBF2 to sodium current and viability not defined","Connection to the MTMR2/RAB21 axis not established"]},{"year":null,"claim":"How SBF2's dual roles as MTMR2-stabilizing pseudophosphatase and RAB21 GEF are integrated at endosomal membranes to control myelination, and the structural basis of these activities, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the SBF2-MTMR2 complex or DENN-RAB21 interface","Direct human RAB21 GEF kinetics not reported","Causal link between autophagy/VAMP8 trafficking defects and Schwann cell pathology untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]}],"complexes":["MTMR2-MTMR13 tetrameric complex"],"partners":["MTMR2","RAB21","VAMP8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86WG5","full_name":"Myotubularin-related protein 13","aliases":["Inactive phosphatidylinositol 3-phosphatase 13","SET-binding factor 2"],"length_aa":1849,"mass_kda":208.5,"function":"Guanine nucleotide exchange factor (GEF) which activates RAB21 and possibly RAB28 (PubMed:20937701, PubMed:25648148). Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form (PubMed:20937701, PubMed:25648148). In response to starvation-induced autophagy, activates RAB21 which in turn binds to and regulates SNARE protein VAMP8 endolysosomal transport required for SNARE-mediated autophagosome-lysosome fusion (PubMed:25648148). Acts as an adapter for the phosphatase MTMR2 (By similarity). Increases MTMR2 catalytic activity towards phosphatidylinositol 3,5-bisphosphate and to a lesser extent towards phosphatidylinositol 3-phosphate (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, perinuclear region; Membrane; Endosome membrane; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/Q86WG5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SBF2","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":"MTMR1","stoichiometry":0.2},{"gene":"MTMR2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SBF2","total_profiled":1310},"omim":[{"mim_id":"607697","title":"SET-BINDING FACTOR 2; SBF2","url":"https://www.omim.org/entry/607697"},{"mim_id":"606255","title":"STATURE AS A QUANTITATIVE TRAIT","url":"https://www.omim.org/entry/606255"},{"mim_id":"604563","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4B2; CMT4B2","url":"https://www.omim.org/entry/604563"},{"mim_id":"603560","title":"SET-BINDING FACTOR 1; SBF1","url":"https://www.omim.org/entry/603560"},{"mim_id":"313900","title":"THROMBOCYTOPENIA 1; THC1","url":"https://www.omim.org/entry/313900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Intermediate filaments","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SBF2"},"hgnc":{"alias_symbol":["KIAA1766","MTMR13","DENND7B"],"prev_symbol":["CMT4B2"]},"alphafold":{"accession":"Q86WG5","domains":[{"cath_id":"3.30.450.200","chopping":"3-92_113-187_476-497","consensus_level":"high","plddt":82.9704,"start":3,"end":497},{"cath_id":"3.40.50.11500","chopping":"198-333_348-467","consensus_level":"medium","plddt":87.7109,"start":198,"end":467},{"cath_id":"-","chopping":"670-688_714-765_813-868","consensus_level":"medium","plddt":83.2944,"start":670,"end":868},{"cath_id":"2.30.29.30","chopping":"885-1005","consensus_level":"high","plddt":80.8363,"start":885,"end":1005},{"cath_id":"-","chopping":"1191-1202_1341-1584","consensus_level":"high","plddt":87.7351,"start":1191,"end":1584},{"cath_id":"2.30.29.30","chopping":"1747-1849","consensus_level":"high","plddt":87.3448,"start":1747,"end":1849},{"cath_id":"1.25.40","chopping":"547-665","consensus_level":"high","plddt":83.2465,"start":547,"end":665}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WG5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WG5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WG5-F1-predicted_aligned_error_v6.png","plddt_mean":73.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SBF2","jax_strain_url":"https://www.jax.org/strain/search?query=SBF2"},"sequence":{"accession":"Q86WG5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86WG5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86WG5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WG5"}},"corpus_meta":[{"pmid":"12687498","id":"PMC_12687498","title":"Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12687498","citation_count":232,"is_preprint":false},{"pmid":"30992025","id":"PMC_30992025","title":"Exosomal transfer of long non-coding RNA SBF2-AS1 enhances chemoresistance to temozolomide in glioblastoma.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30992025","citation_count":224,"is_preprint":false},{"pmid":"12554688","id":"PMC_12554688","title":"Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15.","date":"2003","source":"Human molecular 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family; disease-causing nonsense mutations in MTMR13 were found in two consanguineous families with CMT4B2, establishing it as the causative gene for this demyelinating neuropathy with myelin outfoldings.\",\n      \"method\": \"Homozygosity mapping, mutation identification (nonsense mutations), genetic linkage to chromosome 11p15\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mapping and mutation identification replicated in two independent families, co-segregation confirmed, replicated by independent lab (PMID:12554688)\",\n      \"pmids\": [\"12687498\", \"12554688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SBF2 encodes a large novel protein belonging to the pseudo-phosphatase branch of myotubularins; an in-frame deletion of SBF2 exons 11 and 12 disrupts an N-terminal domain conserved across species, establishing loss-of-function as the disease mechanism in CMT4B2.\",\n      \"method\": \"Homozygosity mapping, molecular analysis of SBF2 gene (exon deletion identified), expression analysis in peripheral nervous system tissues\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutation co-segregation in affected family, expression in PNS confirmed, independent replication of SBF2 as CMT4B2 gene\",\n      \"pmids\": [\"12554688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Endogenous MTMR2 and MTMR13/SBF2 physically associate in human embryonic kidney 293 cells; this interaction is mediated by coiled-coil sequences present in each protein. MTMR13 is a predominantly membrane-associated protein, and its membrane association is mediated by the segment containing the pseudophosphatase domain. MTMR2 and MTMR13 co-fractionate in both a light membrane fraction and a cytosolic fraction.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, subcellular fractionation, fluorescence microscopy, deletion/domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — endogenous Co-IP, subcellular fractionation, and domain mapping in one study with multiple orthogonal methods\",\n      \"pmids\": [\"15998640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MTMR13/SBF2 forms a tetrameric complex with MTMR2, and this interaction strongly increases the enzymatic phosphatase activity of MTMR2 (which dephosphorylates PtdIns 3-phosphate and PtdIns 3,5-bisphosphate). Mtmr13/Sbf2-deficient mice develop myelin outfoldings and infoldings with decreased motor performance, reproducing CMT4B2 pathological hallmarks.\",\n      \"method\": \"Generation of Mtmr13/Sbf2-deficient mice, nerve morphology, electrophysiology, biochemical characterization of protein complex and enzymatic activity\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo knockout model with defined phenotype, biochemical demonstration of complex and activity enhancement, replicated by independent lab (PMID:18349142)\",\n      \"pmids\": [\"17855448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of Mtmr13 in mice leads to a peripheral neuropathy with myelin outfoldings and infoldings predominantly at the paranode, reduced nerve conduction velocity, and axon loss. Mtmr2 protein levels are decreased by approximately 50% in Mtmr13-deficient sciatic nerves, indicating that Mtmr13 stabilizes Mtmr2.\",\n      \"method\": \"Knockout mouse model (Mtmr13-/- mice), nerve conduction velocity measurements, electron microscopy, western blotting for Mtmr2 levels\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined cellular and molecular phenotype, multiple orthogonal methods, replicated across labs\",\n      \"pmids\": [\"18349142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of Mtmr2 prevents degradation of the epidermal growth factor receptor (EGFR) and leads to sustained Akt activation. Mtmr13/Sbf2 counteracts the blockage of EGFR degradation (without affecting prolonged Akt activation), indicating that MTMR2 and MTMR13/SBF2 regulate EGFR sorting and downstream AKT signaling.\",\n      \"method\": \"Overexpression in cell lines, western blotting for EGFR and phospho-AKT, signaling pathway analysis in Mtmr2 and Mtmr13/Sbf2 mouse mutants\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression and mouse mutant analysis, single lab, two complementary methods but limited mechanistic resolution for MTMR13 specifically\",\n      \"pmids\": [\"19912440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila Sbf (ortholog of MTMR13) functions as a guanine nucleotide exchange factor (GEF) that activates Rab21 GTPase. Sbf coordinates PI(3)P turnover (by dynamically interacting with class II PI 3-kinase and stably recruiting Mtm/MTMR2) and Rab21 activation at PI(3)P endosomes. Together, Sbf, Mtm, and Rab21 control macrophage protrusion formation through an endosomal trafficking pathway.\",\n      \"method\": \"Genetic knockdown in Drosophila macrophages, epistasis analysis, live imaging, PI(3)P reporter assays, GEF activity assay for Rab21\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — GEF activity demonstrated biochemically, genetic epistasis, multiple orthogonal methods in one rigorous study, functionally validated in vivo\",\n      \"pmids\": [\"22648168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Starvation induces Sbf/MTMR13 GEF activity and RAB21 activation. MTMR13 is required for RAB21 activation, VAMP8 interaction, and VAMP8 endolysosomal trafficking; depletion of Sbf/MTMR13 or Rab21 blocks endolysosomal trafficking of VAMP8 (a SNARE required for autophagosome-lysosome fusion), thereby blocking starvation-induced autophagy.\",\n      \"method\": \"RNAi knockdown in Drosophila and mammalian cells, GEF activity assays, co-immunoprecipitation (MTMR13-VAMP8 interaction), fluorescence microscopy of VAMP8 trafficking, autophagy flux assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical GEF activity assay, Co-IP for binding partner identification, functional rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"25648148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A missense mutation (c.659C>G, p.Thr220Arg) in the DENN domain of SBF2 was identified in patients with severe thrombocytopenia, suggesting the DENN domain mediates putative association with Rab GTPases important for vesicle transport and membrane trafficking.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing validation, family segregation analysis\",\n      \"journal\": \"Journal of thrombosis and thrombolysis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single case genetic identification, no direct biochemical validation of DENN domain function in this study\",\n      \"pmids\": [\"23334996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In an in vitro SC-DRG explant model of CMT4B2, Mtmr13-/- Schwann cells develop myelin outfoldings, and Mtmr13 deficiency reduces Mtmr2 levels, further supporting Mtmr13's role in stabilizing Mtmr2. Overexpression of MTMR2 in Mtmr13-/- SC-DRGs moderately reduced myelin outfoldings, indicating that reduced PI 3-phosphatase activity contributes to the phenotype. Loss of vacuolar protein sorting 34 (Vps34) or PI3K-C2β in Mtmr13-/- mice had no impact on myelin outfoldings.\",\n      \"method\": \"Schwann cell-DRG explant culture from Mtmr13-/- mice, MTMR2 overexpression, double knockout mice (Mtmr13-/- x Vps34-/- and Mtmr13-/- x PI3K-C2β-/-), electron microscopy\",\n      \"journal\": \"ASN neuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro model with genetic rescue (MTMR2 OE), double KO epistasis, single lab but multiple orthogonal genetic approaches\",\n      \"pmids\": [\"30419760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mtmr2 is required to maintain wild-type levels of both Mtmr5 and Mtmr13 in mouse peripheral nerves, suggesting these factors function in discrete protein complexes with Mtmr2. Genetic elimination of both Mtmr5 and Mtmr13 in mice leads to perinatal lethality, indicating partial functional redundancy during embryogenesis. Loss of Mtmr5 causes axon radial sorting defects without CMT4B2-like myelin outfoldings, distinguishing the roles of Mtmr5 and Mtmr13 in the PNS.\",\n      \"method\": \"Double knockout mice (Mtmr5-/- x Mtmr13-/-), western blotting for protein levels, nerve morphology by electron microscopy, quantification of myelinated axons\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic models with defined phenotypes, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34718573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpressed epitope-tagged Sbf2 shows cytoplasmic distribution in cells. Sbf2 mRNA is broadly expressed across tissues including peripheral nervous system, and the murine Sbf2 protein shares high amino acid identity with human SBF2.\",\n      \"method\": \"Overexpression of epitope-tagged protein with fluorescence microscopy, in situ hybridization, Northern blot, RT-PCR\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression localization experiment without functional consequence, single lab\",\n      \"pmids\": [\"16750429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"siRNA-mediated silencing of SBF2 in pancreatic cancer PANC-1 cells inhibited proliferation and promoted apoptosis, accompanied by decreased phospho-SMAD-2 and phospho-SMAD-3 and increased SMAD-7, suggesting SBF2 modulates TGF-β/SMAD signaling.\",\n      \"method\": \"siRNA knockdown, MTT proliferation assay, flow cytometry apoptosis assay, western blotting for TGF-β/SMAD pathway components\",\n      \"journal\": \"Technology in cancer research & treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single KD experiment with pathway readout, no direct mechanistic link established, single lab single method per endpoint\",\n      \"pmids\": [\"25882882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SBF2 knockdown in iPSC-derived sensory neurons exacerbated paclitaxel-induced changes to cell viability and neurite outgrowth while attenuating paclitaxel-induced sodium current inhibition, providing functional evidence that SBF2 modulates taxane-induced neuronal damage.\",\n      \"method\": \"Ex vivo model: SBF2 knockdown in iPSC-derived sensory neurons, cell viability assays, neurite outgrowth measurement, electrophysiology (sodium current recording), gene expression analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ex vivo neuronal model with electrophysiology and multiple functional readouts, single lab\",\n      \"pmids\": [\"34986146\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SBF2/MTMR13 is a catalytically inactive pseudophosphatase (lacking the essential Cys and Arg residues) that contains a DENN domain and functions as a guanine nucleotide exchange factor (GEF) for RAB21, physically associates with and stabilizes the active PI(3)P/PI(3,5)P2 phosphatase MTMR2 via coiled-coil interactions to enhance its enzymatic activity, localizes predominantly to membranes via its pseudophosphatase domain, and coordinates PI(3)P turnover with RAB21-mediated endosomal trafficking to regulate autophagosome-lysosome fusion, EGFR sorting/AKT signaling, and Schwann cell myelination; loss-of-function mutations cause CMT4B2 peripheral neuropathy with myelin outfoldings.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SBF2 (MTMR13) is a large pseudophosphatase of the myotubularin family that coordinates phosphoinositide turnover with RAB-mediated endosomal trafficking [#0, #6]. It physically associates with the active PI(3)P/PI(3,5)P2 phosphatase MTMR2 through coiled-coil sequences, forming a tetrameric complex that strongly enhances MTMR2 catalytic activity, and it stabilizes MTMR2 protein in vivo, where loss of MTMR13 reduces MTMR2 levels by roughly half [#2, #3, #4]. Through its DENN domain SBF2 acts as a guanine nucleotide exchange factor that activates RAB21, dynamically engaging class II PI 3-kinase and stably recruiting MTMR2 at PI(3)P-positive endosomes to couple lipid turnover with RAB21 activation [#6]. This activity is induced by starvation and drives RAB21-dependent endolysosomal trafficking of the SNARE VAMP8, required for autophagosome-lysosome fusion and starvation-induced autophagy [#7], and it regulates EGFR sorting and downstream AKT signaling together with MTMR2 [#5]. In peripheral nerve, SBF2/MTMR2 function sustains Schwann cell myelination; loss-of-function mutations in SBF2 cause CMT4B2 demyelinating peripheral neuropathy with myelin outfoldings, a phenotype reproduced in Mtmr13-deficient mice and Schwann cell explants and partially rescued by MTMR2 overexpression [#0, #3, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established SBF2/MTMR13 as a disease gene by linking loss-of-function mutations to CMT4B2, framing the protein as a myotubularin-family pseudophosphatase critical for myelin integrity.\",\n      \"evidence\": \"Homozygosity mapping and nonsense/exon-deletion mutation identification in consanguineous CMT4B2 families\",\n      \"pmids\": [\"12687498\", \"12554688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical function of the pseudophosphatase domain\", \"No molecular partner or pathway identified at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified the physical basis of SBF2 function by showing endogenous association with the active phosphatase MTMR2 and membrane targeting via the pseudophosphatase domain.\",\n      \"evidence\": \"Endogenous Co-IP, subcellular fractionation, and domain-mapping fluorescence microscopy in HEK293 cells\",\n      \"pmids\": [\"15998640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish a functional consequence of the interaction for MTMR2 activity\", \"Membrane identity not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed the interaction is functionally consequential, with MTMR13 forming a tetrameric complex that enhances MTMR2 phosphatase activity, and reproduced CMT4B2 pathology in knockout mice.\",\n      \"evidence\": \"Mtmr13-deficient mice with nerve morphology and electrophysiology plus biochemical complex/activity assays\",\n      \"pmids\": [\"17855448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how enhanced phosphatase activity affects specific trafficking events\", \"Stoichiometry of the complex in vivo not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a stabilization mechanism by demonstrating that MTMR13 maintains MTMR2 protein levels in nerve, linking pseudophosphatase loss to reduced active phosphatase.\",\n      \"evidence\": \"Mtmr13-/- mice with nerve conduction velocity, electron microscopy, and western blotting of Mtmr2\",\n      \"pmids\": [\"18349142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of stabilization (degradation pathway) not identified\", \"Phosphoinositide substrate changes in vivo not measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected the MTMR2/MTMR13 module to receptor trafficking by showing it regulates EGFR degradation and AKT signaling.\",\n      \"evidence\": \"Overexpression and mouse mutant analysis with EGFR and phospho-AKT western blotting\",\n      \"pmids\": [\"19912440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MTMR13-specific contribution mechanistically limited\", \"Did not link EGFR sorting defect to myelin phenotype\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed the second enzymatic arm of SBF2 by demonstrating DENN-domain GEF activity toward RAB21, coupling PI(3)P turnover with RAB21 activation at endosomes.\",\n      \"evidence\": \"Drosophila macrophage genetics, epistasis, live imaging, PI(3)P reporters, and Rab21 GEF assay\",\n      \"pmids\": [\"22648168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GEF activity demonstrated in Drosophila ortholog; human RAB21 GEF assay not shown here\", \"Structural basis of nucleotide exchange unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed SBF2 GEF activity in autophagy by showing starvation-induced RAB21 activation drives VAMP8 endolysosomal trafficking required for autophagosome-lysosome fusion.\",\n      \"evidence\": \"RNAi in Drosophila and mammalian cells, GEF assays, MTMR13-VAMP8 Co-IP, VAMP8 trafficking imaging, autophagy flux\",\n      \"pmids\": [\"25648148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of the MTMR13-VAMP8 interaction not resolved\", \"Relevance to Schwann cell pathology not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tested causality of phosphatase loss for myelin pathology, showing MTMR2 overexpression partially rescues outfoldings while excluding VPS34 and PI3K-C2\\u03b2 as the relevant kinases in this context.\",\n      \"evidence\": \"Mtmr13-/- Schwann cell-DRG explants with MTMR2 overexpression and Mtmr13/Vps34 and Mtmr13/PI3K-C2\\u03b2 double knockouts\",\n      \"pmids\": [\"30419760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only partial rescue indicates additional MTMR13 functions beyond MTMR2 stabilization\", \"PI(3)P-generating kinase responsible for the phenotype not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Distinguished MTMR13 from the paralog MTMR5 within MTMR2 complexes, establishing partial redundancy and non-overlapping PNS roles.\",\n      \"evidence\": \"Mtmr5/Mtmr13 double knockout mice, western blotting, and nerve electron microscopy\",\n      \"pmids\": [\"34718573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of redundancy during embryogenesis not defined\", \"Whether MTMR5 and MTMR13 form mutually exclusive complexes not directly shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended SBF2 relevance to neuronal injury by showing it modulates taxane-induced damage in sensory neurons.\",\n      \"evidence\": \"SBF2 knockdown in iPSC-derived sensory neurons with viability, neurite outgrowth, and sodium current recordings\",\n      \"pmids\": [\"34986146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking SBF2 to sodium current and viability not defined\", \"Connection to the MTMR2/RAB21 axis not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SBF2's dual roles as MTMR2-stabilizing pseudophosphatase and RAB21 GEF are integrated at endosomal membranes to control myelination, and the structural basis of these activities, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the SBF2-MTMR2 complex or DENN-RAB21 interface\", \"Direct human RAB21 GEF kinetics not reported\", \"Causal link between autophagy/VAMP8 trafficking defects and Schwann cell pathology untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005085\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"MTMR2-MTMR13 tetrameric complex\"],\n    \"partners\": [\"MTMR2\", \"RAB21\", \"VAMP8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}