{"gene":"SH3GLB1","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2001,"finding":"Bif-1 (SH3GLB1) was identified as a novel Bax-binding protein via yeast two-hybrid cloning. It contains an SH3 domain near its C-terminus and interacts with Bax as confirmed by coimmunoprecipitation and immunofluorescence. Overexpression of Bif-1 promotes Bax conformational change, caspase activation, and apoptotic cell death in FL5.12 cells following IL-3 deprivation.","method":"Yeast two-hybrid, coimmunoprecipitation, immunofluorescence, overexpression in FL5.12 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, immunofluorescence, functional overexpression assay) in a single rigorous study; foundational paper replicated by subsequent work","pmids":["11259440"],"is_preprint":false},{"year":2005,"finding":"Endogenous Bif-1 is required for conformational change of both Bax and Bak, cytochrome c release, and caspase-3 activation during intrinsic apoptosis. Bif-1 heterodimerizes with Bax on mitochondria in intact cells, and this interaction is enhanced by apoptosis induction and precedes Bax conformational change. While Bif-1 did not directly interact with Bak, it plays a regulatory role in Bak activation.","method":"RNAi knockdown in HeLa cells, Bif-1 knockout MEFs, coimmunoprecipitation, apoptosis assays (cytochrome c release, caspase-3 activation), soft-agar and nude-mouse tumorigenesis assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi and genetic KO with defined apoptotic phenotype, multiple orthogonal methods, replicated across cell types","pmids":["16227588"],"is_preprint":false},{"year":2007,"finding":"Bif-1 interacts with Beclin 1 through UVRAG and functions as a positive mediator of the class III PI3-kinase (PI3KC3/VPS34). Both the BAR and SH3 domains are required for Bif-1 to activate PI3KC3 and induce autophagosome formation, while the SH3 domain alone is sufficient for binding to UVRAG. Upon nutrient deprivation, Bif-1 localizes to autophagosomes co-localizing with Atg5 and LC3. Loss of Bif-1 suppresses autophagosome formation and promotes spontaneous tumor development in mice.","method":"Coimmunoprecipitation, domain-deletion mutants, siRNA knockdown, immunofluorescence colocalization, Bif-1 knockout mouse tumorigenesis assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, genetic KO with in vivo tumor phenotype, multiple orthogonal approaches in a single high-impact study","pmids":["17891140"],"is_preprint":false},{"year":2008,"finding":"Bif-1 N-BAR domain stimulates BAX-driven mitochondrial outer membrane permeabilization (MOMP) and BAX conformational activation in a reconstituted system with purified proteins and MOM-like liposomes. This process requires physical interaction between Bif-1 N-BAR and BAX and the presence of cardiolipin. Large-scale membrane morphological rearrangements induced by Bif-1 N-BAR could be separated from functional BAX activation. DLP1/Drp1 caused global morphological changes in MOM-like liposomes but did not stimulate BAX-permeabilizing function.","method":"In vitro reconstitution with purified proteins and MOM-like liposomes, domain mutagenesis (N-BAR domain), cardiolipin-dependence assay, MOMP measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins plus mutagenesis, single lab but multiple orthogonal biochemical methods","pmids":["19074440"],"is_preprint":false},{"year":2008,"finding":"c-Src kinase binds to Bif-1 and directly phosphorylates it on tyrosine 80. Src phosphorylation of Bif-1 suppresses its interaction with Bax, inhibiting Bax activation during anoikis. Apoptotic stimuli repress this phosphorylation event.","method":"Kinase assay, site-directed mutagenesis (Y80), coimmunoprecipitation, anoikis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct kinase assay with mutagenesis identifying specific phosphorylation site, Co-IP confirmation of functional consequence, single lab with multiple methods","pmids":["18474606"],"is_preprint":false},{"year":2010,"finding":"A specific PI3K-III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 (but not ATG14L) regulates both receptor degradation and cytokinesis. UVRAG and BIF-1 localize strongly to the midbody, supporting an unanticipated role of BIF-1 in cytokinesis.","method":"siRNA-mediated depletion of individual subunits, high-content microscopy-based assays for receptor degradation and cytokinesis, immunofluorescence localization to midbody","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific cellular phenotype readout and localization data; single lab, two orthogonal approaches","pmids":["20643123"],"is_preprint":false},{"year":2010,"finding":"GSK-3β inhibition results in elevation of Bif-1 protein levels, and silencing Bif-1 abrogates the GSK-3β-inhibition-induced autophagic response and necrotic cell death under serum starvation. This places Bif-1 downstream of GSK-3β in regulating autophagy and cell survival.","method":"GSK-3β chemical inhibitors and siRNA, Bif-1 siRNA silencing, cell death assays (morphology and biochemical markers), western blotting","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via siRNA, two orthogonal GSK-3β inhibition methods, single lab","pmids":["20159967"],"is_preprint":false},{"year":2011,"finding":"Bif-1 is required for Atg9 trafficking and fission of Golgi membranes during autophagy induction. Upon starvation, Atg9-positive membranes undergo tubulation and fragmentation to produce punctate structures positive for Rab5, Atg16L, and LC3. Loss of Bif-1 suppresses starvation-induced Golgi membrane fission and peripheral redistribution of Atg9. Bif-1 mutants lacking functional N-BAR domain regions (membrane binding/bending) fail to restore Golgi fission, Atg9 foci, and autophagosome formation in Bif-1-deficient cells.","method":"Loss-of-function (siRNA/KO), N-BAR domain mutants, live-cell fluorescence microscopy of Atg9 trafficking, Golgi morphology assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis combined with KO rescue and live imaging; multiple orthogonal approaches, builds on replicated biology","pmids":["21068542"],"is_preprint":false},{"year":2012,"finding":"Bif-1 promotes EGFR endocytic degradation in breast cancer cells. Loss of Bif-1 delays EGFR degradation, sequesters internalized EGF in Rab5-positive endosomes, impairs Rab7 recruitment and activation, and alters intracellular pH and acidic vesicle localization. This results in sustained Erk1/2 activation and increased EGF-stimulated chemotactic cell migration.","method":"siRNA knockdown, EGFR degradation assay, Rab5/Rab7 colocalization by immunofluorescence, Erk1/2 activation by western blot, chemotaxis assay, EGFR inhibitor (gefitinib) rescue","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype, multiple pathway readouts, pharmacological rescue, single lab","pmids":["22785202"],"is_preprint":false},{"year":2013,"finding":"Bif-1 is indispensable for autophagy-dependent clearance of damaged mitochondria (mitophagy). Loss of Bif-1 causes accumulation of ER-associated immature autophagosomes and suppresses autophagosome maturation. At the premalignant stage, allelic loss of Bif-1 increases mitochondrial mass, accumulation of DNA damage, and upregulation of Mcl-1, linking impaired mitophagy to chromosomal instability and apoptosis resistance during Myc-driven lymphomagenesis.","method":"Bif-1 KO/haploinsufficient mice with Eμ-Myc transgene, CCCP-treated PARK2-expressing MEFs, electron microscopy of autophagosome morphology, mitochondrial mass assays, immunoblotting for Mcl-1/Bcl-xl, caspase-3 activation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with in vivo phenotype, primary cell assays, multiple orthogonal methods across two papers from same group (PMID 23287860 and 23680845)","pmids":["23287860","23680845"],"is_preprint":false},{"year":2013,"finding":"SH3GLB1 (Bif-1) is present on endo/lysosomal carriers of nicotinic acetylcholine receptors (CHRN) at the neuromuscular junction during fasting-induced muscle atrophy, together with TRIM63 and SQSTM1, and these vesicles are surrounded by the autophagic marker MAP1LC3A in an ATG7-dependent fashion, indicating SH3GLB1 participates in selective autophagy-mediated CHRN turnover.","method":"In vivo mouse studies (denervation, fasting), ATG7 KO, TRIM63 KO, immunofluorescence colocalization, co-precipitation of SQSTM1/LC3-II with CHRN","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mice with defined phenotype, co-precipitation, in vivo imaging; single lab","pmids":["24220501"],"is_preprint":false},{"year":2016,"finding":"Bif-1 interacts with Dynamin 2 (DNM2) and this interaction is enhanced upon nutrient starvation. Bif-1 and DNM2 cooperatively induce the generation of Atg9-containing vesicles from a Rab11-positive reservoir. Inhibition of DNM2 GTPase activity causes accumulation of Atg9-positive tubular structures from this reservoir. Atg9 trafficking to the Rab11-positive reservoir is constitutive and independent of Bif-1, but membrane tubulation from the reservoir requires Bif-1.","method":"Coimmunoprecipitation, DNM2 GTPase inhibitor, live-cell fluorescence microscopy, Bif-1 KO rescue experiments, Rab11 colocalization","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, pharmacological inhibition, KO rescue, live imaging; single lab, multiple methods","pmids":["26980706"],"is_preprint":false},{"year":2016,"finding":"Threonine-145 phosphorylation of SH3GLB1 regulates CHRN (nicotinic acetylcholine receptor) endocytic trafficking at neuromuscular junctions. Phosphomimetic T145E mutant slows processing of endocytic CHRN vesicles, while phosphodeficient T145A augments it. Co-expression of RAB5 largely rescued the slow processing induced by T145E. SH3GLB1 phosphomutants alter the expression of RAB5 activity regulators.","method":"Overexpression of T145E/T145A phosphomutants in vivo at mouse NMJs, CHRN vesicle tracking, RAB5 co-expression rescue experiments, immunofluorescence","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphomutant analysis in vivo with defined phenotypic readout and rescue experiment; single lab","pmids":["27715385"],"is_preprint":false},{"year":2016,"finding":"Bif-1 deficiency reduces the basal rate of adipose tissue lipolysis, causes adipocyte hypertrophy, and attenuates fasting/refeeding-induced lipid droplet clearance in the liver, demonstrating a role for Bif-1 in regulating lipid catabolism and preventing obesity. Bif-1 loss also downregulates Atg9a and Lamp1 in adipose tissue.","method":"Bif-1 KO mice (aging and high-fat diet challenge), adipose tissue histology, lipolysis assays, liver lipid droplet clearance assay, western blotting for autophagy-lysosomal proteins","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model with multiple metabolic phenotype readouts; single lab","pmids":["26857140"],"is_preprint":false},{"year":2017,"finding":"Calpain (activated via CAPNS1) enables dynamic flux of Atg9/Bif-1-containing vesicles from Golgi stacks toward the budding autophagosome. CAPNS1 depletion causes Atg9 and Bif-1 to remain in GM130-positive Golgi stacks, prevents Atg9 interaction with Vps34 and transferrin receptor, and causes LC3 body/Rab5 early endosome accumulation. A calpain-cleavage-resistant Bif-1 point mutant causes accumulation of p62 and LC3-II.","method":"CAPNS1 siRNA depletion, calpain-resistant Bif-1 point mutant overexpression, coimmunoprecipitation (Atg9-Vps34), immunofluorescence colocalization of Atg9/Bif-1 with Golgi/LC3 markers","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion, point mutant, Co-IP, imaging; single lab with multiple orthogonal methods","pmids":["28302665"],"is_preprint":false},{"year":2018,"finding":"The RNA splicing factor SRRM4 promotes alternative splicing of the Bif-1 gene, producing neural-specific isoforms Bif-1b and Bif-1c in treatment-induced neuroendocrine prostate cancer. The predominant variant Bif-1a is pro-apoptotic, whereas Bif-1b and Bif-1c are anti-apoptotic in PCa cells under camptothecin and UV treatment.","method":"Transcriptome comparison, SRRM4 overexpression and knockdown, isoform-specific apoptosis assays (camptothecin/UV treatment)","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional isoform-specific apoptosis assays with defined stimuli, splicing factor manipulation; single lab","pmids":["29759485"],"is_preprint":false},{"year":2019,"finding":"Upon cell stress, Bif-1 translocates to mitochondria and binds prohibitin-2 via its C-terminus (specifically requiring tryptophan-344), resulting in disruption of the prohibitin complex and proteolytic inactivation/cleavage of the inner membrane fusion protein OPA1, promoting mitochondrial fragmentation and apoptosis. Bif-1 deficiency inhibits prohibitin complex disruption, OPA1 proteolysis, and mitochondrial fragmentation. In vivo, Bif-1 bound prohibitin-2 during renal ischemia/reperfusion injury, and Bif-1 KO protected against OPA1 proteolysis, fragmentation, and kidney injury.","method":"Coimmunoprecipitation, domain-deletion analysis, W344 point mutant, Bif-1 KO mice (renal ischemia/reperfusion model), MEFs, mitochondrial fractionation, OPA1 proteolysis assays","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — point mutagenesis identifying critical residue, Co-IP, in vitro and in vivo genetic KO with defined mechanistic readouts, multiple orthogonal methods","pmids":["31126972"],"is_preprint":false},{"year":2022,"finding":"SUMO2-mediated SUMOylation of SH3GLB1 at lysine 82 is promoted by ionizing radiation, as shown by co-IP and laser confocal colocalization of SUMO2 and SH3GLB1. IR promotes interactions between SH3GLB1 and mitochondrial membrane proteins MFN1/2, TOM20, and Drp1. SH3GLB1 deficiency inhibits mitophagy activation and restores mitochondrial cristae.","method":"Bioinformatics prediction of SUMOylation site (K82), coimmunoprecipitation, laser confocal microscopy colocalization, SH3GLB1 KO in cardiomyocytes and in vivo IR model","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and colocalization confirming interaction, KO functional phenotype, single lab; SUMOylation site predicted bioinformatically but Co-IP supports interaction","pmids":["35487252"],"is_preprint":false},{"year":2025,"finding":"SH3GLB1 is required for the nuclear localization of the NOTCH2 intracellular domain (N2ICD) and NOTCH2 signaling activation in glioblastoma. Genetic depletion of SH3GLB1 impairs N2ICD nuclear localization, reduces tumorigenic potential, and impairs tumor growth in vivo.","method":"SH3GLB1 genetic depletion, N2ICD nuclear localization assay, in vivo tumor growth assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited methodological detail in abstract, mechanism of N2ICD nuclear localization not fully defined","pmids":["40639082"],"is_preprint":false},{"year":2025,"finding":"Affinity-based protein profiling using a fentanyl-derived probe identified SH3GLB1 (endophilin-B1) as a protein that physically binds fentanyl in vitro across multiple species and tissue types, with molecular docking identifying putative binding sites.","method":"Affinity-based protein profiling with photoaffinity probe, click chemistry, molecular docking","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (affinity probe capture), preprint, no functional validation of the interaction, no mutagenesis or specificity controls described in abstract","pmids":["bio_10.1101_2025.02.20.634605"],"is_preprint":true}],"current_model":"SH3GLB1/Bif-1 is a dual-domain (N-BAR + SH3) membrane-curvature protein that: (1) promotes intrinsic apoptosis by heterodimerizing with Bax on mitochondria (requiring its N-BAR domain and cardiolipin) to drive BAX/BAK conformational change and MOMP, an interaction negatively regulated by c-Src phosphorylation at Y80; (2) activates autophagy by joining the UVRAG–Beclin1–VPS34 PI3K-III complex (via SH3–UVRAG interaction) and driving Golgi membrane fission and Atg9-vesicle generation through a Bif-1–Dynamin2 fission machinery at a Rab11-positive reservoir, with its membrane-binding/bending N-BAR domain essential for this function; (3) regulates mitophagy and mitochondrial inner membrane dynamics by translocating to mitochondria under stress to bind prohibitin-2 (via C-terminal W344), disrupting the prohibitin complex and inducing OPA1 proteolysis and mitochondrial fragmentation; and (4) participates in EGFR endocytic trafficking, lipid catabolism, and selective autophagy of nicotinic acetylcholine receptors at neuromuscular junctions, with T145 phosphorylation modulating the latter process."},"narrative":{"mechanistic_narrative":"SH3GLB1/Bif-1 (endophilin-B1) is a dual-domain membrane-remodeling protein that couples membrane curvature generation to the control of apoptosis, autophagy, and mitochondrial dynamics [PMID:16227588, PMID:17891140]. Through its N-BAR domain it directly stimulates BAX-driven mitochondrial outer membrane permeabilization in a cardiolipin-dependent manner, heterodimerizing with Bax on mitochondria to promote BAX/BAK conformational activation, cytochrome c release, and caspase activation during intrinsic apoptosis [PMID:11259440, PMID:16227588, PMID:19074440]; this pro-apoptotic interaction is suppressed by c-Src-mediated phosphorylation at tyrosine 80 [PMID:18474606]. In autophagy, Bif-1 binds Beclin 1 via UVRAG (through its SH3 domain) to positively regulate the class III PI3-kinase VPS34 complex, while its membrane-binding/bending N-BAR domain drives Golgi membrane fission and the generation of Atg9-containing vesicles from a Rab11-positive reservoir together with Dynamin 2, supporting autophagosome formation [PMID:17891140, PMID:21068542, PMID:26980706]. Bif-1 is required for mitophagy and autophagosome maturation [PMID:23287860, PMID:23680845], and under stress it translocates to mitochondria and binds prohibitin-2 via a C-terminal tryptophan-344, disrupting the prohibitin complex to induce OPA1 proteolysis and mitochondrial fragmentation [PMID:31126972]. Beyond these core roles, Bif-1 mediates EGFR endocytic degradation [PMID:22785202], lipid catabolism and lipid-droplet clearance [PMID:26857140], and selective autophagic turnover of nicotinic acetylcholine receptors at the neuromuscular junction, the latter modulated by threonine-145 phosphorylation [PMID:24220501, PMID:27715385]. Its loss promotes tumor development, linking impaired autophagy/mitophagy to genomic instability [PMID:17891140, PMID:23287860, PMID:23680845].","teleology":[{"year":2001,"claim":"Established Bif-1's first molecular identity by showing it is a Bax-binding protein that can drive apoptosis, framing it as a pro-death regulator.","evidence":"Yeast two-hybrid cloning, Co-IP, immunofluorescence, and overexpression in IL-3-deprived FL5.12 cells","pmids":["11259440"],"confidence":"High","gaps":["Did not show endogenous requirement","Mechanism of how Bif-1 promotes Bax conformational change unresolved","Domain requirements not defined"]},{"year":2005,"claim":"Demonstrated that endogenous Bif-1 is genetically required for Bax/Bak activation and MOMP, moving it from a sufficient overexpression effect to a necessary apoptotic mediator with tumor-suppressor implications.","evidence":"RNAi knockdown, Bif-1 KO MEFs, reciprocal Co-IP, apoptosis assays, and tumorigenesis assays","pmids":["16227588"],"confidence":"High","gaps":["Indirect mechanism for Bak activation (no direct binding)","Biochemical mechanism of MOMP stimulation not reconstituted"]},{"year":2007,"claim":"Connected Bif-1 to autophagy by placing it in the UVRAG–Beclin1–VPS34 PI3KC3 complex and assigning distinct domain functions, defining its second major cellular role.","evidence":"Co-IP, domain-deletion mutants, siRNA, colocalization with Atg5/LC3, and KO mouse tumorigenesis","pmids":["17891140"],"confidence":"High","gaps":["How N-BAR membrane activity feeds into PI3KC3 activation not mechanistically resolved","Site of autophagosome nucleation undefined"]},{"year":2008,"claim":"Resolved the biochemistry of Bif-1's pro-apoptotic action, proving the N-BAR domain directly stimulates BAX-mediated MOMP in a cardiolipin-dependent fashion separable from gross membrane remodeling.","evidence":"In vitro reconstitution with purified proteins and MOM-like liposomes plus N-BAR mutagenesis","pmids":["19074440"],"confidence":"High","gaps":["Structural basis of N-BAR–BAX contact not defined","How cardiolipin requirement integrates with curvature generation unclear"]},{"year":2008,"claim":"Identified a phosphoregulatory switch by which c-Src phosphorylation at Y80 disrupts Bif-1–Bax binding, explaining how the apoptotic interaction is gated by survival signaling.","evidence":"Direct kinase assay, Y80 site-directed mutagenesis, Co-IP, and anoikis assay","pmids":["18474606"],"confidence":"High","gaps":["Upstream signals controlling c-Src activity on Bif-1 not mapped","Structural effect of Y80 phosphorylation unknown"]},{"year":2010,"claim":"Extended the Bif-1/UVRAG/VPS34 sub-complex to receptor degradation and cytokinesis, broadening its membrane-trafficking roles beyond autophagosome formation.","evidence":"siRNA depletion of individual subunits with high-content microscopy and midbody localization","pmids":["20643123"],"confidence":"Medium","gaps":["Direct role at midbody vs. indirect effect unresolved","Single lab, two approaches"]},{"year":2010,"claim":"Placed Bif-1 downstream of GSK-3β in an autophagy/cell-survival axis, identifying an upstream regulatory input to Bif-1 levels.","evidence":"GSK-3β chemical and siRNA inhibition with Bif-1 silencing and cell death assays","pmids":["20159967"],"confidence":"Medium","gaps":["Mechanism linking GSK-3β to Bif-1 protein stabilization unknown","Whether regulation is transcriptional or post-translational unclear"]},{"year":2011,"claim":"Defined the membrane-fission mechanism of Bif-1 in autophagy, showing the N-BAR domain is required for starvation-induced Golgi fission and Atg9 vesicle generation.","evidence":"siRNA/KO loss-of-function, N-BAR mutant rescue, and live-cell imaging of Atg9 trafficking","pmids":["21068542"],"confidence":"High","gaps":["How fission is spatially restricted to autophagy sites unclear","Partner fission machinery not yet defined at this stage"]},{"year":2012,"claim":"Implicated Bif-1 in EGFR endocytic degradation, showing its loss stalls cargo in Rab5 endosomes and sustains Erk signaling and migration.","evidence":"siRNA, EGFR degradation and Rab5/Rab7 colocalization assays, chemotaxis, and gefitinib rescue","pmids":["22785202"],"confidence":"Medium","gaps":["Direct molecular role in endosome maturation vs. indirect effect unclear","Whether N-BAR or SH3 mediates this is undefined"]},{"year":2013,"claim":"Established Bif-1 as indispensable for mitophagy and autophagosome maturation, linking its loss to mitochondrial accumulation, DNA damage, and lymphomagenesis.","evidence":"Eμ-Myc Bif-1 KO/haploinsufficient mice, CCCP-treated PARK2 MEFs, EM, and mitochondrial mass assays","pmids":["23287860","23680845"],"confidence":"High","gaps":["Mechanism by which Bif-1 promotes maturation step not defined","Selectivity for damaged mitochondria unexplained"]},{"year":2013,"claim":"Showed Bif-1 participates in selective autophagy of nicotinic acetylcholine receptors at the NMJ during muscle atrophy, extending its role to tissue-specific receptor turnover.","evidence":"In vivo denervation/fasting, ATG7 and TRIM63 KO mice, colocalization, and SQSTM1/LC3-II co-precipitation with CHRN","pmids":["24220501"],"confidence":"Medium","gaps":["Direct Bif-1 interaction with CHRN cargo not shown","Recruitment mechanism to these vesicles unknown"]},{"year":2016,"claim":"Identified Dynamin 2 as the fission partner that cooperates with Bif-1 to generate Atg9 vesicles from a Rab11-positive reservoir, completing the membrane-fission machinery model.","evidence":"Co-IP, DNM2 GTPase inhibitor, KO rescue, and live-cell imaging with Rab11 colocalization","pmids":["26980706"],"confidence":"Medium","gaps":["Stoichiometry/regulation of Bif-1–DNM2 complex unknown","How starvation enhances the interaction unresolved"]},{"year":2016,"claim":"Showed T145 phosphorylation tunes Bif-1's control of CHRN endocytic trafficking through RAB5 activity, adding a phosphoregulatory layer to its trafficking role.","evidence":"In vivo NMJ overexpression of T145E/T145A phosphomutants with vesicle tracking and RAB5 rescue","pmids":["27715385"],"confidence":"Medium","gaps":["Kinase responsible for T145 phosphorylation not identified","Generalizability beyond NMJ unclear"]},{"year":2016,"claim":"Revealed a metabolic role for Bif-1 in lipid catabolism, with its loss reducing lipolysis and lipid-droplet clearance and promoting obesity.","evidence":"Bif-1 KO mice (aging and high-fat diet), adipose histology, lipolysis and liver lipid-droplet clearance assays","pmids":["26857140"],"confidence":"Medium","gaps":["Whether lipid phenotype is autophagy-dependent not fully separated","Direct vs. systemic effects unresolved"]},{"year":2017,"claim":"Placed calpain (CAPNS1) upstream of Bif-1/Atg9 vesicle flux from Golgi, showing a calpain-cleavage-resistant Bif-1 mutant blocks autophagic flux.","evidence":"CAPNS1 siRNA, calpain-resistant Bif-1 point mutant, Atg9-Vps34 Co-IP, and Golgi/LC3 colocalization","pmids":["28302665"],"confidence":"Medium","gaps":["Whether Bif-1 is a direct calpain substrate not definitively shown","Cleavage product function undefined"]},{"year":2019,"claim":"Defined a distinct mitochondrial inner-membrane mechanism in which stress-induced Bif-1 binds prohibitin-2 via W344 to disrupt the prohibitin complex, drive OPA1 proteolysis, and cause fragmentation, validated in renal ischemia/reperfusion injury.","evidence":"Co-IP, domain-deletion and W344 point mutant, Bif-1 KO MEFs and KO mice in a renal I/R model with OPA1 proteolysis assays","pmids":["31126972"],"confidence":"High","gaps":["Trigger and machinery for Bif-1 mitochondrial translocation under stress not defined","How prohibitin disruption activates OPA1 protease unclear"]},{"year":2022,"claim":"Linked SUMO2 SUMOylation at K82 and ionizing radiation to Bif-1 association with mitochondrial proteins MFN1/2, TOM20, and Drp1, modulating radiation-induced mitophagy.","evidence":"Bioinformatic K82 prediction, Co-IP, confocal colocalization, and SH3GLB1 KO in cardiomyocytes and in vivo IR model","pmids":["35487252"],"confidence":"Medium","gaps":["SUMOylation site only predicted bioinformatically","Functional consequence of K82 modification on each interaction not dissected"]},{"year":2018,"claim":"Showed alternative splicing by SRRM4 generates neural-specific Bif-1 isoforms with opposite apoptotic functions, indicating isoform identity reverses its pro-apoptotic activity in neuroendocrine prostate cancer.","evidence":"Transcriptome comparison, SRRM4 gain/loss, and isoform-specific apoptosis assays under camptothecin/UV","pmids":["29759485"],"confidence":"Medium","gaps":["Molecular basis for anti-apoptotic switch in Bif-1b/c not defined","Domain differences between isoforms not mechanistically tested"]},{"year":2025,"claim":"Tentatively extended Bif-1 to NOTCH2 signaling, with its depletion impairing N2ICD nuclear localization and glioblastoma growth.","evidence":"SH3GLB1 genetic depletion with N2ICD nuclear localization and in vivo tumor assays","pmids":["40639082"],"confidence":"Low","gaps":["Mechanism of how SH3GLB1 controls N2ICD nuclear localization undefined","No direct interaction shown","Single lab, limited methodological detail"]},{"year":2025,"claim":"Identified SH3GLB1 as an in vitro fentanyl-binding protein, raising an unvalidated possible small-molecule interaction.","evidence":"Affinity-based protein profiling with a photoaffinity probe, click chemistry, and molecular docking (preprint)","pmids":["bio_10.1101_2025.02.20.634605"],"confidence":"Low","gaps":["No functional validation of the interaction","No mutagenesis or specificity controls","Physiological relevance unknown"]},{"year":null,"claim":"The signal and machinery that direct Bif-1 between its apoptotic, autophagic, mitophagic, and trafficking modes — and how its post-translational modifications (Y80, T145, K82, calpain cleavage) are coordinated — remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model for how Bif-1 partitions among competing functions","Structural basis for partner selection (Bax vs. UVRAG vs. prohibitin-2) undefined","Upstream kinases/regulators of most modification sites unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,11]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,3,16]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[7,14]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8,12]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7,11]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,7,9]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[16,7]}],"complexes":["UVRAG–Beclin1–VPS34 (PI3KC3) complex"],"partners":["BAX","UVRAG","BECN1","DNM2","PHB2","SRC","MFN1","DRP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y371","full_name":"Endophilin-B1","aliases":["Bax-interacting factor 1","Bif-1","SH3 domain-containing GRB2-like protein B1"],"length_aa":365,"mass_kda":40.8,"function":"May be required for normal outer mitochondrial membrane dynamics (PubMed:15452144). Required for coatomer-mediated retrograde transport in certain cells (By similarity). May recruit other proteins to membranes with high curvature. May promote membrane fusion (PubMed:11604418). Involved in activation of caspase-dependent apoptosis by promoting BAX/BAK1 activation (PubMed:16227588). Isoform 1 acts proapoptotic in fibroblasts (By similarity). Involved in caspase-independent apoptosis during nutrition starvation and involved in the regulation of autophagy. Activates lipid kinase activity of PIK3C3 during autophagy probably by associating with the PI3K complex II (PI3KC3-C2) (PubMed:17891140). Associated with PI3KC3-C2 during autophagy may regulate the trafficking of ATG9A from the Golgi complex to the peripheral cytoplasm for the formation of autophagosomes by inducing Golgi membrane tubulation and fragmentation (PubMed:21068542). Involved in regulation of degradative endocytic trafficking and cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20643123). Isoform 2 acts antiapoptotic in neuronal cells; involved in maintenance of mitochondrial morphology and promotes neuronal viability (By similarity)","subcellular_location":"Cytoplasm; Golgi apparatus membrane; Mitochondrion outer membrane; Cytoplasmic vesicle, autophagosome membrane; Midbody","url":"https://www.uniprot.org/uniprotkb/Q9Y371/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3GLB1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000097033","cell_line_id":"CID000670","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":2},{"compartment":"golgi","grade":1}],"interactors":[{"gene":"SH3GLB2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000670","total_profiled":1310},"omim":[{"mim_id":"609288","title":"SH3 DOMAIN, GRB2-LIKE, ENDOPHILIN B2; SH3GLB2","url":"https://www.omim.org/entry/609288"},{"mim_id":"609287","title":"SH3 DOMAIN, GRB2-LIKE, ENDOPHILIN B1; SH3GLB1","url":"https://www.omim.org/entry/609287"},{"mim_id":"300127","title":"OLIGOPHRENIN 1; OPHN1","url":"https://www.omim.org/entry/300127"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SH3GLB1"},"hgnc":{"alias_symbol":["CGI-61","KIAA0491","Bif-1","PPP1R70"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y371","domains":[{"cath_id":"1.20.1270.60","chopping":"33-252","consensus_level":"high","plddt":94.9022,"start":33,"end":252},{"cath_id":"2.30.30.40","chopping":"306-362","consensus_level":"high","plddt":91.1561,"start":306,"end":362}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y371","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y371-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y371-F1-predicted_aligned_error_v6.png","plddt_mean":83.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3GLB1","jax_strain_url":"https://www.jax.org/strain/search?query=SH3GLB1"},"sequence":{"accession":"Q9Y371","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y371.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y371/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y371"}},"corpus_meta":[{"pmid":"17891140","id":"PMC_17891140","title":"Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis.","date":"2007","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17891140","citation_count":728,"is_preprint":false},{"pmid":"16227588","id":"PMC_16227588","title":"Loss of Bif-1 suppresses Bax/Bak conformational change and mitochondrial apoptosis.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16227588","citation_count":165,"is_preprint":false},{"pmid":"20643123","id":"PMC_20643123","title":"A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic.","date":"2010","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/20643123","citation_count":154,"is_preprint":false},{"pmid":"11259440","id":"PMC_11259440","title":"Molecular cloning and characterization of Bif-1. 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It contains an SH3 domain near its C-terminus and interacts with Bax as confirmed by coimmunoprecipitation and immunofluorescence. Overexpression of Bif-1 promotes Bax conformational change, caspase activation, and apoptotic cell death in FL5.12 cells following IL-3 deprivation.\",\n      \"method\": \"Yeast two-hybrid, coimmunoprecipitation, immunofluorescence, overexpression in FL5.12 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, immunofluorescence, functional overexpression assay) in a single rigorous study; foundational paper replicated by subsequent work\",\n      \"pmids\": [\"11259440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Endogenous Bif-1 is required for conformational change of both Bax and Bak, cytochrome c release, and caspase-3 activation during intrinsic apoptosis. Bif-1 heterodimerizes with Bax on mitochondria in intact cells, and this interaction is enhanced by apoptosis induction and precedes Bax conformational change. While Bif-1 did not directly interact with Bak, it plays a regulatory role in Bak activation.\",\n      \"method\": \"RNAi knockdown in HeLa cells, Bif-1 knockout MEFs, coimmunoprecipitation, apoptosis assays (cytochrome c release, caspase-3 activation), soft-agar and nude-mouse tumorigenesis assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi and genetic KO with defined apoptotic phenotype, multiple orthogonal methods, replicated across cell types\",\n      \"pmids\": [\"16227588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Bif-1 interacts with Beclin 1 through UVRAG and functions as a positive mediator of the class III PI3-kinase (PI3KC3/VPS34). Both the BAR and SH3 domains are required for Bif-1 to activate PI3KC3 and induce autophagosome formation, while the SH3 domain alone is sufficient for binding to UVRAG. Upon nutrient deprivation, Bif-1 localizes to autophagosomes co-localizing with Atg5 and LC3. Loss of Bif-1 suppresses autophagosome formation and promotes spontaneous tumor development in mice.\",\n      \"method\": \"Coimmunoprecipitation, domain-deletion mutants, siRNA knockdown, immunofluorescence colocalization, Bif-1 knockout mouse tumorigenesis assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, genetic KO with in vivo tumor phenotype, multiple orthogonal approaches in a single high-impact study\",\n      \"pmids\": [\"17891140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Bif-1 N-BAR domain stimulates BAX-driven mitochondrial outer membrane permeabilization (MOMP) and BAX conformational activation in a reconstituted system with purified proteins and MOM-like liposomes. This process requires physical interaction between Bif-1 N-BAR and BAX and the presence of cardiolipin. Large-scale membrane morphological rearrangements induced by Bif-1 N-BAR could be separated from functional BAX activation. DLP1/Drp1 caused global morphological changes in MOM-like liposomes but did not stimulate BAX-permeabilizing function.\",\n      \"method\": \"In vitro reconstitution with purified proteins and MOM-like liposomes, domain mutagenesis (N-BAR domain), cardiolipin-dependence assay, MOMP measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins plus mutagenesis, single lab but multiple orthogonal biochemical methods\",\n      \"pmids\": [\"19074440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"c-Src kinase binds to Bif-1 and directly phosphorylates it on tyrosine 80. Src phosphorylation of Bif-1 suppresses its interaction with Bax, inhibiting Bax activation during anoikis. Apoptotic stimuli repress this phosphorylation event.\",\n      \"method\": \"Kinase assay, site-directed mutagenesis (Y80), coimmunoprecipitation, anoikis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct kinase assay with mutagenesis identifying specific phosphorylation site, Co-IP confirmation of functional consequence, single lab with multiple methods\",\n      \"pmids\": [\"18474606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A specific PI3K-III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 (but not ATG14L) regulates both receptor degradation and cytokinesis. UVRAG and BIF-1 localize strongly to the midbody, supporting an unanticipated role of BIF-1 in cytokinesis.\",\n      \"method\": \"siRNA-mediated depletion of individual subunits, high-content microscopy-based assays for receptor degradation and cytokinesis, immunofluorescence localization to midbody\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific cellular phenotype readout and localization data; single lab, two orthogonal approaches\",\n      \"pmids\": [\"20643123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GSK-3β inhibition results in elevation of Bif-1 protein levels, and silencing Bif-1 abrogates the GSK-3β-inhibition-induced autophagic response and necrotic cell death under serum starvation. This places Bif-1 downstream of GSK-3β in regulating autophagy and cell survival.\",\n      \"method\": \"GSK-3β chemical inhibitors and siRNA, Bif-1 siRNA silencing, cell death assays (morphology and biochemical markers), western blotting\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via siRNA, two orthogonal GSK-3β inhibition methods, single lab\",\n      \"pmids\": [\"20159967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Bif-1 is required for Atg9 trafficking and fission of Golgi membranes during autophagy induction. Upon starvation, Atg9-positive membranes undergo tubulation and fragmentation to produce punctate structures positive for Rab5, Atg16L, and LC3. Loss of Bif-1 suppresses starvation-induced Golgi membrane fission and peripheral redistribution of Atg9. Bif-1 mutants lacking functional N-BAR domain regions (membrane binding/bending) fail to restore Golgi fission, Atg9 foci, and autophagosome formation in Bif-1-deficient cells.\",\n      \"method\": \"Loss-of-function (siRNA/KO), N-BAR domain mutants, live-cell fluorescence microscopy of Atg9 trafficking, Golgi morphology assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis combined with KO rescue and live imaging; multiple orthogonal approaches, builds on replicated biology\",\n      \"pmids\": [\"21068542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Bif-1 promotes EGFR endocytic degradation in breast cancer cells. Loss of Bif-1 delays EGFR degradation, sequesters internalized EGF in Rab5-positive endosomes, impairs Rab7 recruitment and activation, and alters intracellular pH and acidic vesicle localization. This results in sustained Erk1/2 activation and increased EGF-stimulated chemotactic cell migration.\",\n      \"method\": \"siRNA knockdown, EGFR degradation assay, Rab5/Rab7 colocalization by immunofluorescence, Erk1/2 activation by western blot, chemotaxis assay, EGFR inhibitor (gefitinib) rescue\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype, multiple pathway readouts, pharmacological rescue, single lab\",\n      \"pmids\": [\"22785202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Bif-1 is indispensable for autophagy-dependent clearance of damaged mitochondria (mitophagy). Loss of Bif-1 causes accumulation of ER-associated immature autophagosomes and suppresses autophagosome maturation. At the premalignant stage, allelic loss of Bif-1 increases mitochondrial mass, accumulation of DNA damage, and upregulation of Mcl-1, linking impaired mitophagy to chromosomal instability and apoptosis resistance during Myc-driven lymphomagenesis.\",\n      \"method\": \"Bif-1 KO/haploinsufficient mice with Eμ-Myc transgene, CCCP-treated PARK2-expressing MEFs, electron microscopy of autophagosome morphology, mitochondrial mass assays, immunoblotting for Mcl-1/Bcl-xl, caspase-3 activation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with in vivo phenotype, primary cell assays, multiple orthogonal methods across two papers from same group (PMID 23287860 and 23680845)\",\n      \"pmids\": [\"23287860\", \"23680845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SH3GLB1 (Bif-1) is present on endo/lysosomal carriers of nicotinic acetylcholine receptors (CHRN) at the neuromuscular junction during fasting-induced muscle atrophy, together with TRIM63 and SQSTM1, and these vesicles are surrounded by the autophagic marker MAP1LC3A in an ATG7-dependent fashion, indicating SH3GLB1 participates in selective autophagy-mediated CHRN turnover.\",\n      \"method\": \"In vivo mouse studies (denervation, fasting), ATG7 KO, TRIM63 KO, immunofluorescence colocalization, co-precipitation of SQSTM1/LC3-II with CHRN\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mice with defined phenotype, co-precipitation, in vivo imaging; single lab\",\n      \"pmids\": [\"24220501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bif-1 interacts with Dynamin 2 (DNM2) and this interaction is enhanced upon nutrient starvation. Bif-1 and DNM2 cooperatively induce the generation of Atg9-containing vesicles from a Rab11-positive reservoir. Inhibition of DNM2 GTPase activity causes accumulation of Atg9-positive tubular structures from this reservoir. Atg9 trafficking to the Rab11-positive reservoir is constitutive and independent of Bif-1, but membrane tubulation from the reservoir requires Bif-1.\",\n      \"method\": \"Coimmunoprecipitation, DNM2 GTPase inhibitor, live-cell fluorescence microscopy, Bif-1 KO rescue experiments, Rab11 colocalization\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, pharmacological inhibition, KO rescue, live imaging; single lab, multiple methods\",\n      \"pmids\": [\"26980706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Threonine-145 phosphorylation of SH3GLB1 regulates CHRN (nicotinic acetylcholine receptor) endocytic trafficking at neuromuscular junctions. Phosphomimetic T145E mutant slows processing of endocytic CHRN vesicles, while phosphodeficient T145A augments it. Co-expression of RAB5 largely rescued the slow processing induced by T145E. SH3GLB1 phosphomutants alter the expression of RAB5 activity regulators.\",\n      \"method\": \"Overexpression of T145E/T145A phosphomutants in vivo at mouse NMJs, CHRN vesicle tracking, RAB5 co-expression rescue experiments, immunofluorescence\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphomutant analysis in vivo with defined phenotypic readout and rescue experiment; single lab\",\n      \"pmids\": [\"27715385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bif-1 deficiency reduces the basal rate of adipose tissue lipolysis, causes adipocyte hypertrophy, and attenuates fasting/refeeding-induced lipid droplet clearance in the liver, demonstrating a role for Bif-1 in regulating lipid catabolism and preventing obesity. Bif-1 loss also downregulates Atg9a and Lamp1 in adipose tissue.\",\n      \"method\": \"Bif-1 KO mice (aging and high-fat diet challenge), adipose tissue histology, lipolysis assays, liver lipid droplet clearance assay, western blotting for autophagy-lysosomal proteins\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model with multiple metabolic phenotype readouts; single lab\",\n      \"pmids\": [\"26857140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Calpain (activated via CAPNS1) enables dynamic flux of Atg9/Bif-1-containing vesicles from Golgi stacks toward the budding autophagosome. CAPNS1 depletion causes Atg9 and Bif-1 to remain in GM130-positive Golgi stacks, prevents Atg9 interaction with Vps34 and transferrin receptor, and causes LC3 body/Rab5 early endosome accumulation. A calpain-cleavage-resistant Bif-1 point mutant causes accumulation of p62 and LC3-II.\",\n      \"method\": \"CAPNS1 siRNA depletion, calpain-resistant Bif-1 point mutant overexpression, coimmunoprecipitation (Atg9-Vps34), immunofluorescence colocalization of Atg9/Bif-1 with Golgi/LC3 markers\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion, point mutant, Co-IP, imaging; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28302665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The RNA splicing factor SRRM4 promotes alternative splicing of the Bif-1 gene, producing neural-specific isoforms Bif-1b and Bif-1c in treatment-induced neuroendocrine prostate cancer. The predominant variant Bif-1a is pro-apoptotic, whereas Bif-1b and Bif-1c are anti-apoptotic in PCa cells under camptothecin and UV treatment.\",\n      \"method\": \"Transcriptome comparison, SRRM4 overexpression and knockdown, isoform-specific apoptosis assays (camptothecin/UV treatment)\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional isoform-specific apoptosis assays with defined stimuli, splicing factor manipulation; single lab\",\n      \"pmids\": [\"29759485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Upon cell stress, Bif-1 translocates to mitochondria and binds prohibitin-2 via its C-terminus (specifically requiring tryptophan-344), resulting in disruption of the prohibitin complex and proteolytic inactivation/cleavage of the inner membrane fusion protein OPA1, promoting mitochondrial fragmentation and apoptosis. Bif-1 deficiency inhibits prohibitin complex disruption, OPA1 proteolysis, and mitochondrial fragmentation. In vivo, Bif-1 bound prohibitin-2 during renal ischemia/reperfusion injury, and Bif-1 KO protected against OPA1 proteolysis, fragmentation, and kidney injury.\",\n      \"method\": \"Coimmunoprecipitation, domain-deletion analysis, W344 point mutant, Bif-1 KO mice (renal ischemia/reperfusion model), MEFs, mitochondrial fractionation, OPA1 proteolysis assays\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — point mutagenesis identifying critical residue, Co-IP, in vitro and in vivo genetic KO with defined mechanistic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"31126972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SUMO2-mediated SUMOylation of SH3GLB1 at lysine 82 is promoted by ionizing radiation, as shown by co-IP and laser confocal colocalization of SUMO2 and SH3GLB1. IR promotes interactions between SH3GLB1 and mitochondrial membrane proteins MFN1/2, TOM20, and Drp1. SH3GLB1 deficiency inhibits mitophagy activation and restores mitochondrial cristae.\",\n      \"method\": \"Bioinformatics prediction of SUMOylation site (K82), coimmunoprecipitation, laser confocal microscopy colocalization, SH3GLB1 KO in cardiomyocytes and in vivo IR model\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and colocalization confirming interaction, KO functional phenotype, single lab; SUMOylation site predicted bioinformatically but Co-IP supports interaction\",\n      \"pmids\": [\"35487252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SH3GLB1 is required for the nuclear localization of the NOTCH2 intracellular domain (N2ICD) and NOTCH2 signaling activation in glioblastoma. Genetic depletion of SH3GLB1 impairs N2ICD nuclear localization, reduces tumorigenic potential, and impairs tumor growth in vivo.\",\n      \"method\": \"SH3GLB1 genetic depletion, N2ICD nuclear localization assay, in vivo tumor growth assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited methodological detail in abstract, mechanism of N2ICD nuclear localization not fully defined\",\n      \"pmids\": [\"40639082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Affinity-based protein profiling using a fentanyl-derived probe identified SH3GLB1 (endophilin-B1) as a protein that physically binds fentanyl in vitro across multiple species and tissue types, with molecular docking identifying putative binding sites.\",\n      \"method\": \"Affinity-based protein profiling with photoaffinity probe, click chemistry, molecular docking\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (affinity probe capture), preprint, no functional validation of the interaction, no mutagenesis or specificity controls described in abstract\",\n      \"pmids\": [\"bio_10.1101_2025.02.20.634605\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SH3GLB1/Bif-1 is a dual-domain (N-BAR + SH3) membrane-curvature protein that: (1) promotes intrinsic apoptosis by heterodimerizing with Bax on mitochondria (requiring its N-BAR domain and cardiolipin) to drive BAX/BAK conformational change and MOMP, an interaction negatively regulated by c-Src phosphorylation at Y80; (2) activates autophagy by joining the UVRAG–Beclin1–VPS34 PI3K-III complex (via SH3–UVRAG interaction) and driving Golgi membrane fission and Atg9-vesicle generation through a Bif-1–Dynamin2 fission machinery at a Rab11-positive reservoir, with its membrane-binding/bending N-BAR domain essential for this function; (3) regulates mitophagy and mitochondrial inner membrane dynamics by translocating to mitochondria under stress to bind prohibitin-2 (via C-terminal W344), disrupting the prohibitin complex and inducing OPA1 proteolysis and mitochondrial fragmentation; and (4) participates in EGFR endocytic trafficking, lipid catabolism, and selective autophagy of nicotinic acetylcholine receptors at neuromuscular junctions, with T145 phosphorylation modulating the latter process.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SH3GLB1/Bif-1 (endophilin-B1) is a dual-domain membrane-remodeling protein that couples membrane curvature generation to the control of apoptosis, autophagy, and mitochondrial dynamics [#1, #2]. Through its N-BAR domain it directly stimulates BAX-driven mitochondrial outer membrane permeabilization in a cardiolipin-dependent manner, heterodimerizing with Bax on mitochondria to promote BAX/BAK conformational activation, cytochrome c release, and caspase activation during intrinsic apoptosis [#0, #1, #3]; this pro-apoptotic interaction is suppressed by c-Src-mediated phosphorylation at tyrosine 80 [#4]. In autophagy, Bif-1 binds Beclin 1 via UVRAG (through its SH3 domain) to positively regulate the class III PI3-kinase VPS34 complex, while its membrane-binding/bending N-BAR domain drives Golgi membrane fission and the generation of Atg9-containing vesicles from a Rab11-positive reservoir together with Dynamin 2, supporting autophagosome formation [#2, #7, #11]. Bif-1 is required for mitophagy and autophagosome maturation [#9], and under stress it translocates to mitochondria and binds prohibitin-2 via a C-terminal tryptophan-344, disrupting the prohibitin complex to induce OPA1 proteolysis and mitochondrial fragmentation [#16]. Beyond these core roles, Bif-1 mediates EGFR endocytic degradation [#8], lipid catabolism and lipid-droplet clearance [#13], and selective autophagic turnover of nicotinic acetylcholine receptors at the neuromuscular junction, the latter modulated by threonine-145 phosphorylation [#10, #12]. Its loss promotes tumor development, linking impaired autophagy/mitophagy to genomic instability [#2, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established Bif-1's first molecular identity by showing it is a Bax-binding protein that can drive apoptosis, framing it as a pro-death regulator.\",\n      \"evidence\": \"Yeast two-hybrid cloning, Co-IP, immunofluorescence, and overexpression in IL-3-deprived FL5.12 cells\",\n      \"pmids\": [\"11259440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show endogenous requirement\", \"Mechanism of how Bif-1 promotes Bax conformational change unresolved\", \"Domain requirements not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that endogenous Bif-1 is genetically required for Bax/Bak activation and MOMP, moving it from a sufficient overexpression effect to a necessary apoptotic mediator with tumor-suppressor implications.\",\n      \"evidence\": \"RNAi knockdown, Bif-1 KO MEFs, reciprocal Co-IP, apoptosis assays, and tumorigenesis assays\",\n      \"pmids\": [\"16227588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Indirect mechanism for Bak activation (no direct binding)\", \"Biochemical mechanism of MOMP stimulation not reconstituted\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected Bif-1 to autophagy by placing it in the UVRAG–Beclin1–VPS34 PI3KC3 complex and assigning distinct domain functions, defining its second major cellular role.\",\n      \"evidence\": \"Co-IP, domain-deletion mutants, siRNA, colocalization with Atg5/LC3, and KO mouse tumorigenesis\",\n      \"pmids\": [\"17891140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How N-BAR membrane activity feeds into PI3KC3 activation not mechanistically resolved\", \"Site of autophagosome nucleation undefined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the biochemistry of Bif-1's pro-apoptotic action, proving the N-BAR domain directly stimulates BAX-mediated MOMP in a cardiolipin-dependent fashion separable from gross membrane remodeling.\",\n      \"evidence\": \"In vitro reconstitution with purified proteins and MOM-like liposomes plus N-BAR mutagenesis\",\n      \"pmids\": [\"19074440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of N-BAR–BAX contact not defined\", \"How cardiolipin requirement integrates with curvature generation unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a phosphoregulatory switch by which c-Src phosphorylation at Y80 disrupts Bif-1–Bax binding, explaining how the apoptotic interaction is gated by survival signaling.\",\n      \"evidence\": \"Direct kinase assay, Y80 site-directed mutagenesis, Co-IP, and anoikis assay\",\n      \"pmids\": [\"18474606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling c-Src activity on Bif-1 not mapped\", \"Structural effect of Y80 phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the Bif-1/UVRAG/VPS34 sub-complex to receptor degradation and cytokinesis, broadening its membrane-trafficking roles beyond autophagosome formation.\",\n      \"evidence\": \"siRNA depletion of individual subunits with high-content microscopy and midbody localization\",\n      \"pmids\": [\"20643123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role at midbody vs. indirect effect unresolved\", \"Single lab, two approaches\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed Bif-1 downstream of GSK-3β in an autophagy/cell-survival axis, identifying an upstream regulatory input to Bif-1 levels.\",\n      \"evidence\": \"GSK-3β chemical and siRNA inhibition with Bif-1 silencing and cell death assays\",\n      \"pmids\": [\"20159967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GSK-3β to Bif-1 protein stabilization unknown\", \"Whether regulation is transcriptional or post-translational unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the membrane-fission mechanism of Bif-1 in autophagy, showing the N-BAR domain is required for starvation-induced Golgi fission and Atg9 vesicle generation.\",\n      \"evidence\": \"siRNA/KO loss-of-function, N-BAR mutant rescue, and live-cell imaging of Atg9 trafficking\",\n      \"pmids\": [\"21068542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fission is spatially restricted to autophagy sites unclear\", \"Partner fission machinery not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Implicated Bif-1 in EGFR endocytic degradation, showing its loss stalls cargo in Rab5 endosomes and sustains Erk signaling and migration.\",\n      \"evidence\": \"siRNA, EGFR degradation and Rab5/Rab7 colocalization assays, chemotaxis, and gefitinib rescue\",\n      \"pmids\": [\"22785202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular role in endosome maturation vs. indirect effect unclear\", \"Whether N-BAR or SH3 mediates this is undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established Bif-1 as indispensable for mitophagy and autophagosome maturation, linking its loss to mitochondrial accumulation, DNA damage, and lymphomagenesis.\",\n      \"evidence\": \"Eμ-Myc Bif-1 KO/haploinsufficient mice, CCCP-treated PARK2 MEFs, EM, and mitochondrial mass assays\",\n      \"pmids\": [\"23287860\", \"23680845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Bif-1 promotes maturation step not defined\", \"Selectivity for damaged mitochondria unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed Bif-1 participates in selective autophagy of nicotinic acetylcholine receptors at the NMJ during muscle atrophy, extending its role to tissue-specific receptor turnover.\",\n      \"evidence\": \"In vivo denervation/fasting, ATG7 and TRIM63 KO mice, colocalization, and SQSTM1/LC3-II co-precipitation with CHRN\",\n      \"pmids\": [\"24220501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Bif-1 interaction with CHRN cargo not shown\", \"Recruitment mechanism to these vesicles unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified Dynamin 2 as the fission partner that cooperates with Bif-1 to generate Atg9 vesicles from a Rab11-positive reservoir, completing the membrane-fission machinery model.\",\n      \"evidence\": \"Co-IP, DNM2 GTPase inhibitor, KO rescue, and live-cell imaging with Rab11 colocalization\",\n      \"pmids\": [\"26980706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry/regulation of Bif-1–DNM2 complex unknown\", \"How starvation enhances the interaction unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed T145 phosphorylation tunes Bif-1's control of CHRN endocytic trafficking through RAB5 activity, adding a phosphoregulatory layer to its trafficking role.\",\n      \"evidence\": \"In vivo NMJ overexpression of T145E/T145A phosphomutants with vesicle tracking and RAB5 rescue\",\n      \"pmids\": [\"27715385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for T145 phosphorylation not identified\", \"Generalizability beyond NMJ unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a metabolic role for Bif-1 in lipid catabolism, with its loss reducing lipolysis and lipid-droplet clearance and promoting obesity.\",\n      \"evidence\": \"Bif-1 KO mice (aging and high-fat diet), adipose histology, lipolysis and liver lipid-droplet clearance assays\",\n      \"pmids\": [\"26857140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether lipid phenotype is autophagy-dependent not fully separated\", \"Direct vs. systemic effects unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed calpain (CAPNS1) upstream of Bif-1/Atg9 vesicle flux from Golgi, showing a calpain-cleavage-resistant Bif-1 mutant blocks autophagic flux.\",\n      \"evidence\": \"CAPNS1 siRNA, calpain-resistant Bif-1 point mutant, Atg9-Vps34 Co-IP, and Golgi/LC3 colocalization\",\n      \"pmids\": [\"28302665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Bif-1 is a direct calpain substrate not definitively shown\", \"Cleavage product function undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a distinct mitochondrial inner-membrane mechanism in which stress-induced Bif-1 binds prohibitin-2 via W344 to disrupt the prohibitin complex, drive OPA1 proteolysis, and cause fragmentation, validated in renal ischemia/reperfusion injury.\",\n      \"evidence\": \"Co-IP, domain-deletion and W344 point mutant, Bif-1 KO MEFs and KO mice in a renal I/R model with OPA1 proteolysis assays\",\n      \"pmids\": [\"31126972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger and machinery for Bif-1 mitochondrial translocation under stress not defined\", \"How prohibitin disruption activates OPA1 protease unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked SUMO2 SUMOylation at K82 and ionizing radiation to Bif-1 association with mitochondrial proteins MFN1/2, TOM20, and Drp1, modulating radiation-induced mitophagy.\",\n      \"evidence\": \"Bioinformatic K82 prediction, Co-IP, confocal colocalization, and SH3GLB1 KO in cardiomyocytes and in vivo IR model\",\n      \"pmids\": [\"35487252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMOylation site only predicted bioinformatically\", \"Functional consequence of K82 modification on each interaction not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed alternative splicing by SRRM4 generates neural-specific Bif-1 isoforms with opposite apoptotic functions, indicating isoform identity reverses its pro-apoptotic activity in neuroendocrine prostate cancer.\",\n      \"evidence\": \"Transcriptome comparison, SRRM4 gain/loss, and isoform-specific apoptosis assays under camptothecin/UV\",\n      \"pmids\": [\"29759485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for anti-apoptotic switch in Bif-1b/c not defined\", \"Domain differences between isoforms not mechanistically tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tentatively extended Bif-1 to NOTCH2 signaling, with its depletion impairing N2ICD nuclear localization and glioblastoma growth.\",\n      \"evidence\": \"SH3GLB1 genetic depletion with N2ICD nuclear localization and in vivo tumor assays\",\n      \"pmids\": [\"40639082\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism of how SH3GLB1 controls N2ICD nuclear localization undefined\", \"No direct interaction shown\", \"Single lab, limited methodological detail\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified SH3GLB1 as an in vitro fentanyl-binding protein, raising an unvalidated possible small-molecule interaction.\",\n      \"evidence\": \"Affinity-based protein profiling with a photoaffinity probe, click chemistry, and molecular docking (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.02.20.634605\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation of the interaction\", \"No mutagenesis or specificity controls\", \"Physiological relevance unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The signal and machinery that direct Bif-1 between its apoptotic, autophagic, mitophagic, and trafficking modes — and how its post-translational modifications (Y80, T145, K82, calpain cleavage) are coordinated — remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model for how Bif-1 partitions among competing functions\", \"Structural basis for partner selection (Bax vs. UVRAG vs. prohibitin-2) undefined\", \"Upstream kinases/regulators of most modification sites unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 3, 16]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 7, 9]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [16, 7]}\n    ],\n    \"complexes\": [\n      \"UVRAG–Beclin1–VPS34 (PI3KC3) complex\"\n    ],\n    \"partners\": [\n      \"BAX\",\n      \"UVRAG\",\n      \"BECN1\",\n      \"DNM2\",\n      \"PHB2\",\n      \"SRC\",\n      \"MFN1\",\n      \"DRP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}