{"gene":"SH3BP5","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1998,"finding":"SH3BP5 (Sab) was identified as a novel protein that binds the SH3 domain of Bruton's tyrosine kinase (Btk) through a non-proline-rich structure commonly conserved among SH3 domains, with high preference for Btk over other cytoplasmic tyrosine kinases.","method":"Protein interaction cloning, immunoprecipitation, SH3 domain binding assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation and binding assays in single study; selectivity for Btk shown by comparison with other kinases","pmids":["9571151"],"is_preprint":false},{"year":1999,"finding":"SH3BP5 (Sab) negatively regulates Bruton's tyrosine kinase (Btk) activity by inhibiting its auto- and transphosphorylation; forced overexpression of Sab in B cells reduced BCR-induced tyrosine phosphorylation of Btk, calcium mobilization, IP3 production, and apoptotic cell death.","method":"Overexpression in B cells, in vitro kinase assay, calcium mobilization assay, IP3 measurement, apoptosis assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (kinase activity, calcium, IP3, apoptosis) with consistent results showing negative regulation","pmids":["10339589"],"is_preprint":false},{"year":2002,"finding":"SH3BP5 (Sab) is a JNK-interacting protein that binds to and is phosphorylated by JNK in vitro; interaction requires the most N-terminal KIM (KIM1) motif, physical interaction is necessary for phosphorylation, and Sab localizes to mitochondria where it co-localizes with a fraction of active JNK after stress.","method":"Yeast two-hybrid, in vitro kinase assay, deletion/site-directed mutagenesis, confocal immunocytochemistry, cell fractionation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus independent localization by confocal microscopy and fractionation in single study","pmids":["12167088"],"is_preprint":false},{"year":2004,"finding":"SAPK3 (p38 MAPK subfamily member) localizes to mitochondria and phosphorylates Sab in vitro, primarily on Ser321, dependent on the KIM1 motif of Sab; this reveals a shared mitochondrial substrate between SAPK3 and JNK.","method":"In vitro kinase assay, site-directed mutagenesis, subcellular fractionation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay with mutagenesis, single lab, single study","pmids":["15158451"],"is_preprint":false},{"year":2004,"finding":"Sab is a mitochondria-associated JNK-interacting protein; the JNK-Sab interaction occurs via a KIM motif distinct from the Btk-binding domain, and Sab co-localizes with active JNK at mitochondria after stress treatment.","method":"Interacting protein screen, confocal microscopy, mitochondrial co-localization","journal":"Biochemical Society transactions","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — corroborates findings from PMID 12167088 with additional localization data, consistent across two publications from same lab","pmids":["15506969"],"is_preprint":false},{"year":2011,"finding":"JNK-Sab interaction at mitochondria is required for JNK mitochondrial translocation, Bcl-2 phosphorylation, loss of mitochondrial membrane potential, and superoxide generation; a cell-permeable peptide mimicking the KIM1 domain of Sab (Tat-Sab(KIM1)) selectively disrupted mitochondrial JNK signaling without affecting c-Jun phosphorylation or AP-1 transcription.","method":"siRNA knockdown, cell-permeable inhibitory peptide (Tat-SabKIM1), JNK translocation assay, Bcl-2 phosphorylation, mitochondrial membrane potential assay, superoxide measurement","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, peptide inhibitor, membrane potential, ROS) in single study demonstrating selective mitochondrial JNK signaling function","pmids":["21563797"],"is_preprint":false},{"year":2014,"finding":"Sab knockdown prevents ER stress-induced sustained JNK activation, impaired mitochondrial respiration, and apoptosis; p-JNK plus ATP added to isolated liver mitochondria promotes superoxide production amplified by calcium and blocked by a KIM1 blocking peptide, establishing that ER stress triggers JNK-Sab interaction at mitochondria leading to impaired respiration and ROS, which sustains JNK activation.","method":"siRNA knockdown, isolated mitochondria respiration assay, superoxide measurement, blocking peptide, cellular oxygen consumption rate (OCR) assay, apoptosis measurement","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution with isolated mitochondria plus cellular knockdown with multiple functional readouts","pmids":["24407242"],"is_preprint":false},{"year":2015,"finding":"In palmitic acid-induced hepatocyte lipotoxicity, Sab knockdown or a membrane-permeable Sab blocking peptide prevented palmitic acid-induced mitochondrial impairment (decreased OCR) and inhibited the late phase of JNK activation and cell death, placing the JNK-Sab interaction downstream of PERK but upstream of sustained JNK activation and mitochondrial dysfunction.","method":"siRNA knockdown (adeno-shSab), cell-permeable blocking peptide, oxygen consumption rate (OCR) measurement, cell death assay, PERK/CHOP activation measurement","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockdown and pharmacological inhibition with multiple readouts, pathway epistasis established by PERK inhibition experiments","pmids":["25666017"],"is_preprint":false},{"year":2016,"finding":"p-JNK interacts with Sab on the outer mitochondrial membrane and phosphorylates it (requiring ATP), leading to release and activation of intramitochondrial SHP1 (PTPN6) from Sab on the inner face of the outer membrane; activated SHP1 transfers to the inner membrane where it dephosphorylates P-Y419Src (inactivating mitochondrial Src) via a platform protein DOK4; inactivation of mitochondrial Src inhibits electron transport, increases ROS, sustains JNK activation, and promotes cell death. Sab liver-specific knockout abrogated sustained JNK activation and liver injury.","method":"Liver-specific Sab knockout (Cre-lox), Sab knockdown, isolated mitochondria respiration assay, p-JNK + ATP addition to mitochondria, SHP1/DOK4 knockdown, mitochondrial fractionation, in vivo APAP and TNF/galactosamine models","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic KO combined with biochemical reconstitution in isolated mitochondria, component knockdowns (SHP1, DOK4) with functional readouts, in vivo validation in multiple models","pmids":["26845758"],"is_preprint":false},{"year":2017,"finding":"Sab-mediated signaling is required for imatinib mesylate-induced mitochondrial dysfunction in cardiomyocyte-like H9c2 cells; Sab knockdown or KIM1 peptide inhibition prevented ROS production, lipid peroxidation, impaired mitochondrial respiration, ATP loss, and apoptosis; overexpression of Sab increased cardiotoxicity; Sab expression was induced by cardiovascular-like stress in an AP-1-dependent manner.","method":"siRNA knockdown, overexpression, KIM1 inhibitory peptide, ROS measurement, Seahorse respiration assay, ATP assay, lipid peroxidation, protein carbonylation, apoptosis assay, AP-1 reporter","journal":"Toxicology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, overexpression, peptide inhibition) with consistent results across multiple functional readouts","pmids":["28315715"],"is_preprint":false},{"year":2017,"finding":"Sab is expressed in the adult mouse brain, enriched in hippocampus, ventral midbrain, and cerebellum; it localizes to mitochondria in neuronal soma, dendrites, and axons (confirmed by electron microscopy in hippocampal sections); inhibiting Sab-mediated signaling with Tat-SabKIM1 peptide decreased firing frequency and spike amplitudes in cultured hippocampal neurons.","method":"Confocal microscopy, electron microscopy, synaptosome purification, neuronal culture, electrophysiology with peptide inhibitor","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by EM with functional consequence demonstrated by electrophysiology, single lab","pmids":["28606781"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of SH3BP5 bound to Rab11 revealed a coiled-coil architecture mediating guanine nucleotide exchange through a unique Rab-GEF interaction; Rab11 switch I adopts a constrained conformation distinct from other Rab-GEF complexes; SH3BP5 functions as a GEF for Rab11 with specificity over evolutionarily similar Rab GTPases; GEF-deficient mutants of SH3BP5 showed greatly decreased Rab11 activation in cellular assays.","method":"Crystal structure determination, in vitro GEF assay, mutagenesis, cellular Rab11 activation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro biochemical reconstitution, mutagenesis, and cellular functional validation in single study","pmids":["30217979"],"is_preprint":false},{"year":2016,"finding":"REI-1, the C. elegans ortholog of SH3BP5, functions as a GEF for RAB-11; loss of REI-1 impaired RAB-11 targeting to the late-Golgi compartment and recycling endosomes, reduced RAB-11 recruitment to the cleavage furrow, and delayed cytokinesis; human SH3BP5 also exhibits GEF activity toward human Rab11.","method":"GEF activity assay (C. elegans and human proteins), loss-of-function genetics, fluorescence co-localization, cytokinesis timing assay","journal":"Communicative & integrative biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GEF activity demonstrated biochemically for both C. elegans and human proteins, with genetic phenotypic validation in C. elegans","pmids":["28003861"],"is_preprint":false},{"year":2019,"finding":"SAB expression levels determine severity of JNK-dependent liver injury in a sex-dependent manner; female mice express low hepatic SAB protein due to an ERα→p53→miR34a-5p pathway where miR34a-5p targets the Sab mRNA coding region to repress SAB expression; fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB, enhancing injury, while ERα agonist increased miR34a-5p and decreased SAB and hepatotoxicity in males.","method":"Liver-specific Sab deletion, GalNAc-ASO knockdown of Sab, p53 knockdown, fulvestrant/ERα agonist treatment, miR34a-5p measurement, mRNA targeting assay, in vivo liver injury models (APAP, TNF/galactosamine)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion, ASO knockdown, multiple pharmacological interventions, and pathway epistasis across multiple models in single study","pmids":["31487267"],"is_preprint":false},{"year":2019,"finding":"In H9c2 cardiomyocyte-like cells, hypoxia/reoxygenation induces JNK activation, translocation to mitochondria via colocalization with Sab, and subsequent mitochondrial Src dephosphorylation; JNK inhibition or Sab siRNA reduced p-JNK/Sab colocalization, decreased Src dephosphorylation, and reduced mitochondrial ROS and oxidized cardiolipin, validating the JNK/Sab/Src/ROS pathway in cardiomyocyte ischemia/reperfusion injury.","method":"siRNA knockdown, JNK inhibitor, Src inhibitor PP2, confocal colocalization, ROS measurement, cardiolipin oxidation assay, mitochondrial membrane potential","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — corroborates established JNK/Sab/Src pathway in new cell context with siRNA and inhibitor validation, single lab","pmids":["31205589"],"is_preprint":false},{"year":2020,"finding":"Trans-fatty acids (elaidic acid) facilitate DNA damage-induced apoptosis by driving the mitochondrial JNK-Sab-ROS positive feedback loop; Sab knockdown blocked EA-enhanced mitochondrial ROS generation and JNK activation induced by doxorubicin; pharmacological inhibition of SHP1 (a Sab-associated protein) also suppressed this pathway.","method":"siRNA knockdown of Sab, pharmacological inhibitors of JNK/ROS/SHP1, mitochondrial ROS measurement, apoptosis assay, C. elegans UV-lethality assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Sab knockdown with multiple functional readouts plus pharmacological confirmation, consistent with established pathway in new context","pmids":["32066809"],"is_preprint":false},{"year":2021,"finding":"In HFHC diet-fed mice, SAB expression progressively increased through a sustained JNK/ATF2 activation loop; inducible hepatic Sab deletion or ASO knockdown markedly decreased sustained JNK activation, improved energy expenditure, reduced body fat, and prevented or reversed steatohepatitis and fibrosis; reversal of established NASH was achieved by GalNAc-Sab-ASO treatment.","method":"Inducible liver-specific Sab KO, antisense oligonucleotide knockdown (ASO, GalNAc-ASO), HFHC diet model, liver histology, p-JNK and p-ATF2 measurement, metabolic phenotyping","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus therapeutic ASO with in vivo NASH model, multiple timepoints and readouts; reversal experiment provides causal evidence","pmids":["34331779"],"is_preprint":false},{"year":2023,"finding":"METTL3-mediated m6A modification of SH3BP5 mRNA is read by YTHDF1, which maintains SH3BP5 mRNA stability; overexpression of SH3BP5 suppressed invasion of lung cancer cells in an m6A-dependent manner, and METTL3 suppresses lung cancer invasion through this SH3BP5 regulatory axis.","method":"METTL3/YTHDF1 overexpression and knockdown, SH3BP5 overexpression, m6A assay, invasion assay, mRNA stability assay","journal":"Archives of biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic link to m6A stability relies on overexpression/knockdown with limited direct reconstitution of the modification event","pmids":["38141906"],"is_preprint":false}],"current_model":"SH3BP5 (Sab) is a mitochondrial outer membrane scaffold/docking protein with two mechanistically distinct functions: (1) it serves as a substrate and docking site for activated JNK (via its KIM1 motif), enabling JNK to trigger an intramitochondrial signaling cascade—through SHP1 release/activation and DOK4—that inactivates Src on the inner membrane, impairs electron transport, and releases ROS, thereby sustaining a JNK-Sab-ROS positive feedback loop that drives apoptosis and organ injury; and (2) it acts as a guanine nucleotide exchange factor (GEF) for Rab11, adopting a coiled-coil architecture that activates Rab11 for roles in receptor recycling and membrane trafficking. Additionally, Sab negatively regulates Btk kinase activity in B cells."},"narrative":{"mechanistic_narrative":"SH3BP5 (Sab) is a mitochondrial outer-membrane scaffold protein that operates as the docking platform converting transient stress-kinase signaling into sustained mitochondrial dysfunction and cell death [PMID:12167088, PMID:26845758]. Stress-activated JNK binds Sab through its N-terminal KIM1 motif and is anchored on the outer mitochondrial membrane, where Sab serves as a JNK substrate; this interaction is required for JNK mitochondrial translocation, Bcl-2 phosphorylation, loss of membrane potential, and superoxide generation [PMID:12167088, PMID:21563797]. Phosphorylation of Sab by JNK (ATP-dependent) triggers release and activation of intramitochondrial SHP1 (PTPN6), which transfers via the platform protein DOK4 to the inner membrane and dephosphorylates/inactivates mitochondrial Src, impairing electron transport and elevating ROS; the resulting ROS sustains JNK activation, establishing a self-amplifying JNK–Sab–ROS feedback loop [PMID:26845758]. This loop is the effector arm of diverse injury settings: ER-stress and PERK-driven lipotoxicity, acetaminophen and TNF/galactosamine liver injury, ischemia/reperfusion and drug cardiotoxicity, and diet-induced steatohepatitis, where genetic deletion or KIM1-peptide/ASO blockade of Sab interrupts the sustained JNK phase and protects against organ injury [PMID:24407242, PMID:25666017, PMID:26845758, PMID:34331779]. Sab abundance is a rate-limiting determinant of injury severity, set transcriptionally through a JNK/ATF2 loop and AP-1, and repressed in females via an ERα→p53→miR34a-5p pathway targeting Sab mRNA [PMID:31487267, PMID:34331779]. Independently of its mitochondrial role, SH3BP5 functions as a guanine nucleotide exchange factor specific for Rab11, using a coiled-coil architecture to activate Rab11 for receptor recycling, endosomal trafficking, and cytokinesis [PMID:30217979, PMID:28003861]. Sab was originally identified as a selective binding partner and negative regulator of the SH3 domain of Bruton's tyrosine kinase (Btk), dampening BCR-induced signaling in B cells [PMID:9571151, PMID:10339589].","teleology":[{"year":1998,"claim":"Established the first molecular partner of Sab, defining it as an SH3-domain ligand with selectivity for Btk over other tyrosine kinases.","evidence":"Protein interaction cloning and SH3-domain binding/immunoprecipitation assays","pmids":["9571151"],"confidence":"Medium","gaps":["Binding mode to the SH3 domain not structurally resolved","Functional consequence of binding not yet shown"]},{"year":1999,"claim":"Showed the Btk interaction is functionally inhibitory, placing Sab as a negative regulator of BCR signaling and apoptosis in B cells.","evidence":"Overexpression in B cells with kinase, calcium, IP3, and apoptosis assays","pmids":["10339589"],"confidence":"High","gaps":["Based on overexpression rather than loss-of-function","Relationship between the Btk role and later mitochondrial role unexplained"]},{"year":2002,"claim":"Reframed Sab as a mitochondrial JNK-interacting protein, identifying the KIM1 motif as the docking determinant and a distinct functional axis from Btk binding.","evidence":"Yeast two-hybrid, in vitro kinase assay with mutagenesis, confocal microscopy and fractionation","pmids":["12167088"],"confidence":"High","gaps":["Downstream mitochondrial consequence of JNK docking not yet defined","Whether phosphorylation alters Sab activity unknown"]},{"year":2004,"claim":"Extended the kinase repertoire docking at Sab by showing SAPK3/p38 also phosphorylates it on Ser321 via KIM1, indicating shared mitochondrial substrate use.","evidence":"In vitro kinase assay, site-directed mutagenesis, subcellular fractionation","pmids":["15158451"],"confidence":"Medium","gaps":["Cellular significance of Ser321 phosphorylation not established","p38-driven outcome via Sab not demonstrated"]},{"year":2011,"claim":"Demonstrated that JNK–Sab docking is mechanistically required for mitochondrial JNK actions and that it can be selectively blocked, separating mitochondrial from nuclear (c-Jun/AP-1) JNK signaling.","evidence":"siRNA, Tat-SabKIM1 peptide, JNK translocation, Bcl-2 phosphorylation, membrane potential and superoxide assays","pmids":["21563797"],"confidence":"High","gaps":["Intramitochondrial relay from Sab to ROS not yet defined","Direct substrate of mitochondrial JNK unclear"]},{"year":2014,"claim":"Established the JNK–Sab–ROS feedback loop by reconstituting p-JNK/ATP-driven superoxide production in isolated mitochondria and linking it to sustained JNK activation in ER stress.","evidence":"siRNA, isolated-mitochondria respiration and superoxide assays, KIM1 blocking peptide, cellular OCR and apoptosis","pmids":["24407242"],"confidence":"High","gaps":["Molecular intermediates between Sab phosphorylation and respiratory impairment not yet identified"]},{"year":2016,"claim":"Resolved the intramitochondrial relay: JNK-phosphorylated Sab releases SHP1 which, via DOK4, inactivates inner-membrane Src to impair electron transport and amplify ROS, with in vivo liver-injury validation.","evidence":"Liver-specific Sab KO, isolated-mitochondria reconstitution, SHP1/DOK4 knockdown, APAP and TNF/galactosamine models","pmids":["26845758"],"confidence":"High","gaps":["Structural basis of SHP1 sequestration by Sab unknown","How Src inactivation impairs electron transport mechanistically not fully defined"]},{"year":2015,"claim":"Placed the Sab loop downstream of PERK in lipotoxicity, defining pathway epistasis for the sustained JNK phase in hepatocytes.","evidence":"adeno-shSab, blocking peptide, OCR, cell death, PERK/CHOP measurements","pmids":["25666017"],"confidence":"High","gaps":["Link between PERK output and JNK–Sab engagement not molecularly traced"]},{"year":2017,"claim":"Generalized the Sab loop beyond liver to cardiomyocyte drug toxicity and showed Sab expression is stress-inducible via AP-1.","evidence":"siRNA, overexpression, KIM1 peptide, Seahorse, ROS/ATP/lipid peroxidation assays, AP-1 reporter (H9c2)","pmids":["28315715"],"confidence":"High","gaps":["In vivo cardiac relevance not tested in this study"]},{"year":2017,"claim":"Showed Sab is expressed at neuronal mitochondria and that its signaling modulates neuronal excitability, extending its physiology beyond injury contexts.","evidence":"Confocal and electron microscopy, synaptosome purification, neuronal electrophysiology with Tat-SabKIM1","pmids":["28606781"],"confidence":"Medium","gaps":["Mechanism linking Sab signaling to firing properties unresolved","No in vivo neuronal phenotype"]},{"year":2016,"claim":"Identified a wholly distinct biochemical function: SH3BP5/REI-1 acts as a Rab11 GEF controlling endosomal recycling, Golgi targeting and cytokinesis, conserved from C. elegans to human.","evidence":"GEF assays for worm and human proteins, loss-of-function genetics, co-localization, cytokinesis timing","pmids":["28003861"],"confidence":"Medium","gaps":["Relationship between mitochondrial and GEF functions in the same cell unknown","Subcellular site of GEF activity not pinned to specific membranes"]},{"year":2018,"claim":"Provided the structural mechanism of the GEF function, showing a coiled-coil architecture that catalyzes Rab11 nucleotide exchange with specificity over related Rabs.","evidence":"Crystal structure of SH3BP5–Rab11, in vitro GEF assay, mutagenesis, cellular Rab11 activation","pmids":["30217979"],"confidence":"High","gaps":["How the GEF and JNK-docking activities are spatially partitioned within the protein not addressed"]},{"year":2019,"claim":"Showed Sab abundance is rate-limiting for injury and is set sex-dependently through an ERα→p53→miR34a-5p axis repressing Sab mRNA.","evidence":"Liver-specific deletion, GalNAc-ASO, p53 knockdown, fulvestrant/ERα agonist, miR34a-5p targeting assays, in vivo injury models","pmids":["31487267"],"confidence":"High","gaps":["Whether this regulation operates in non-hepatic tissues untested"]},{"year":2019,"claim":"Validated the JNK/Sab/Src/ROS pathway in cardiomyocyte ischemia/reperfusion, confirming Src dephosphorylation and cardiolipin oxidation as downstream events.","evidence":"siRNA, JNK and Src inhibitors, confocal colocalization, ROS and cardiolipin oxidation assays (H9c2)","pmids":["31205589"],"confidence":"Medium","gaps":["Cell-line model only; no in vivo cardiac confirmation in this study"]},{"year":2020,"claim":"Connected dietary trans-fatty acids to potentiation of the Sab feedback loop during DNA-damage-induced apoptosis.","evidence":"Sab siRNA, JNK/ROS/SHP1 inhibitors, mitochondrial ROS and apoptosis assays, C. elegans UV-lethality","pmids":["32066809"],"confidence":"Medium","gaps":["How trans-fatty acids prime the loop mechanistically unclear"]},{"year":2021,"claim":"Demonstrated therapeutic tractability: inducible Sab deletion or ASO knockdown prevents and reverses diet-induced steatohepatitis and fibrosis via interruption of the JNK/ATF2 loop.","evidence":"Inducible liver-specific KO, GalNAc-Sab-ASO, HFHC diet model, histology, metabolic phenotyping","pmids":["34331779"],"confidence":"High","gaps":["Durability and off-target consequences of chronic Sab suppression not addressed"]},{"year":2023,"claim":"Linked SH3BP5 expression to an m6A regulatory axis (METTL3/YTHDF1) with a tumor-suppressive effect on lung cancer invasion.","evidence":"METTL3/YTHDF1 perturbation, SH3BP5 overexpression, m6A, invasion and mRNA stability assays","pmids":["38141906"],"confidence":"Low","gaps":["Single-lab, overexpression-based; direct m6A modification of SH3BP5 not reconstituted","Which SH3BP5 function mediates invasion suppression unknown"]},{"year":null,"claim":"How the mitochondrial JNK-docking/scaffold function and the cytosolic/endosomal Rab11-GEF function are reconciled within one protein — and whether they are co-active or context-switched in the same cell — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study tests both activities in the same system","Determinants partitioning Sab between mitochondria and recycling endosomes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,12]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,8,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[11,12]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,8,15]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,1]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11,12]}],"complexes":[],"partners":["JNK","BTK","SHP1","DOK4","RAB11","SAPK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60239","full_name":"SH3 domain-binding protein 5","aliases":["SH3 domain-binding protein that preferentially associates with BTK"],"length_aa":455,"mass_kda":50.4,"function":"Functions as a guanine nucleotide exchange factor (GEF) with specificity for RAB11A and RAB25 (PubMed:26506309, PubMed:30217979). Inhibits the auto- and transphosphorylation activity of BTK. Plays a negative regulatory role in BTK-related cytoplasmic signaling in B-cells. May be involved in BCR-induced apoptotic cell death","subcellular_location":"Cytoplasmic vesicle membrane; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/O60239/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3BP5","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":[],"url":"https://opencell.sf.czbiohub.org/search/SH3BP5","total_profiled":1310},"omim":[{"mim_id":"620652","title":"SH3 DOMAIN-BINDING PROTEIN 5-LIKE; SH3BP5L","url":"https://www.omim.org/entry/620652"},{"mim_id":"617807","title":"NEURODEVELOPMENTAL DISORDER WITH ATAXIC GAIT, ABSENT SPEECH, AND DECREASED CORTICAL WHITE MATTER; NDAGSCW","url":"https://www.omim.org/entry/617807"},{"mim_id":"605612","title":"SH3 DOMAIN-BINDING PROTEIN 5; SH3BP5","url":"https://www.omim.org/entry/605612"},{"mim_id":"604198","title":"RAS-ASSOCIATED PROTEIN RAB11B; RAB11B","url":"https://www.omim.org/entry/604198"},{"mim_id":"604028","title":"SEC22 HOMOLOG C, VESICLE TRAFFICKING PROTEIN; SEC22C","url":"https://www.omim.org/entry/604028"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nuclear bodies","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SH3BP5"},"hgnc":{"alias_symbol":["Sab"],"prev_symbol":[]},"alphafold":{"accession":"O60239","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60239","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60239-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60239-F1-predicted_aligned_error_v6.png","plddt_mean":70.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3BP5","jax_strain_url":"https://www.jax.org/strain/search?query=SH3BP5"},"sequence":{"accession":"O60239","fasta_url":"https://rest.uniprot.org/uniprotkb/O60239.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60239/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60239"}},"corpus_meta":[{"pmid":"26845758","id":"PMC_26845758","title":"c-Jun N-terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)-dependent pathway leading to inactivation of intramitochondrial Src.","date":"2016","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/26845758","citation_count":151,"is_preprint":false},{"pmid":"24407242","id":"PMC_24407242","title":"JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/24407242","citation_count":139,"is_preprint":false},{"pmid":"16641277","id":"PMC_16641277","title":"Simian immunodeficiency virus SIVagm.sab infection of Caribbean African green monkeys: a new model for the study of SIV pathogenesis in natural hosts.","date":"2006","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/16641277","citation_count":111,"is_preprint":false},{"pmid":"25666017","id":"PMC_25666017","title":"Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity.","date":"2015","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/25666017","citation_count":108,"is_preprint":false},{"pmid":"9152988","id":"PMC_9152988","title":"Association of polymorphisms of dopamine D2 receptor (DRD2), and dopamine transporter (DAT1) genes with schizoid/avoidant behaviors (SAB).","date":"1997","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/9152988","citation_count":92,"is_preprint":false},{"pmid":"12167088","id":"PMC_12167088","title":"A new c-Jun N-terminal kinase (JNK)-interacting protein, Sab (SH3BP5), associates with mitochondria.","date":"2002","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12167088","citation_count":84,"is_preprint":false},{"pmid":"30463289","id":"PMC_30463289","title":"The Regulation of JNK Signaling Pathways in Cell Death through the Interplay with Mitochondrial SAB and Upstream Post-Translational Effects.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30463289","citation_count":69,"is_preprint":false},{"pmid":"19487483","id":"PMC_19487483","title":"Sab, a novel autotransporter of locus of enterocyte effacement-negative shiga-toxigenic Escherichia coli O113:H21, contributes to adherence and biofilm formation.","date":"2009","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/19487483","citation_count":66,"is_preprint":false},{"pmid":"10339589","id":"PMC_10339589","title":"Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10339589","citation_count":60,"is_preprint":false},{"pmid":"9571151","id":"PMC_9571151","title":"Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase 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PTPN4.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38761175","citation_count":7,"is_preprint":false},{"pmid":"38994477","id":"PMC_38994477","title":"SH3BP5-AS1/IGF2BP2/VDAC2 Axis Promotes the Apoptosis and Ferroptosis of Bladder Cancer Cells.","date":"2023","source":"Bladder cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/38994477","citation_count":5,"is_preprint":false},{"pmid":"28606781","id":"PMC_28606781","title":"Sab is differentially expressed in the brain and affects neuronal activity.","date":"2017","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/28606781","citation_count":5,"is_preprint":false},{"pmid":"40782448","id":"PMC_40782448","title":"A sprayable TQ/Ce6@SAB/F-gel for accelerating wound healing via hypoxia-tolerant photodynamic therapy and immune-metabolic 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oxidative stress-related biomarkers in gestational diabetes mellitus: SH3BP5, ITGAM, PRRG1, and MIS12.","date":"2026","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41787525","citation_count":0,"is_preprint":false},{"pmid":"41564701","id":"PMC_41564701","title":"Unraveling the mechanism of adventitious bud formation in sugarcane spontaneous adventitious bud (SAB) mutant.","date":"2026","source":"Plant physiology and biochemistry : PPB","url":"https://pubmed.ncbi.nlm.nih.gov/41564701","citation_count":0,"is_preprint":false},{"pmid":"40964322","id":"PMC_40964322","title":"Axon termination of the SAB motor neurons in C. elegans depends on pre- and postsynaptic activity.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40964322","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.28.25338947","title":"Respiratory virus co-infection is a risk factor for worse outcomes 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was identified as a novel protein that binds the SH3 domain of Bruton's tyrosine kinase (Btk) through a non-proline-rich structure commonly conserved among SH3 domains, with high preference for Btk over other cytoplasmic tyrosine kinases.\",\n      \"method\": \"Protein interaction cloning, immunoprecipitation, SH3 domain binding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation and binding assays in single study; selectivity for Btk shown by comparison with other kinases\",\n      \"pmids\": [\"9571151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SH3BP5 (Sab) negatively regulates Bruton's tyrosine kinase (Btk) activity by inhibiting its auto- and transphosphorylation; forced overexpression of Sab in B cells reduced BCR-induced tyrosine phosphorylation of Btk, calcium mobilization, IP3 production, and apoptotic cell death.\",\n      \"method\": \"Overexpression in B cells, in vitro kinase assay, calcium mobilization assay, IP3 measurement, apoptosis assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (kinase activity, calcium, IP3, apoptosis) with consistent results showing negative regulation\",\n      \"pmids\": [\"10339589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SH3BP5 (Sab) is a JNK-interacting protein that binds to and is phosphorylated by JNK in vitro; interaction requires the most N-terminal KIM (KIM1) motif, physical interaction is necessary for phosphorylation, and Sab localizes to mitochondria where it co-localizes with a fraction of active JNK after stress.\",\n      \"method\": \"Yeast two-hybrid, in vitro kinase assay, deletion/site-directed mutagenesis, confocal immunocytochemistry, cell fractionation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis plus independent localization by confocal microscopy and fractionation in single study\",\n      \"pmids\": [\"12167088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SAPK3 (p38 MAPK subfamily member) localizes to mitochondria and phosphorylates Sab in vitro, primarily on Ser321, dependent on the KIM1 motif of Sab; this reveals a shared mitochondrial substrate between SAPK3 and JNK.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, subcellular fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay with mutagenesis, single lab, single study\",\n      \"pmids\": [\"15158451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sab is a mitochondria-associated JNK-interacting protein; the JNK-Sab interaction occurs via a KIM motif distinct from the Btk-binding domain, and Sab co-localizes with active JNK at mitochondria after stress treatment.\",\n      \"method\": \"Interacting protein screen, confocal microscopy, mitochondrial co-localization\",\n      \"journal\": \"Biochemical Society transactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — corroborates findings from PMID 12167088 with additional localization data, consistent across two publications from same lab\",\n      \"pmids\": [\"15506969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JNK-Sab interaction at mitochondria is required for JNK mitochondrial translocation, Bcl-2 phosphorylation, loss of mitochondrial membrane potential, and superoxide generation; a cell-permeable peptide mimicking the KIM1 domain of Sab (Tat-Sab(KIM1)) selectively disrupted mitochondrial JNK signaling without affecting c-Jun phosphorylation or AP-1 transcription.\",\n      \"method\": \"siRNA knockdown, cell-permeable inhibitory peptide (Tat-SabKIM1), JNK translocation assay, Bcl-2 phosphorylation, mitochondrial membrane potential assay, superoxide measurement\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, peptide inhibitor, membrane potential, ROS) in single study demonstrating selective mitochondrial JNK signaling function\",\n      \"pmids\": [\"21563797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sab knockdown prevents ER stress-induced sustained JNK activation, impaired mitochondrial respiration, and apoptosis; p-JNK plus ATP added to isolated liver mitochondria promotes superoxide production amplified by calcium and blocked by a KIM1 blocking peptide, establishing that ER stress triggers JNK-Sab interaction at mitochondria leading to impaired respiration and ROS, which sustains JNK activation.\",\n      \"method\": \"siRNA knockdown, isolated mitochondria respiration assay, superoxide measurement, blocking peptide, cellular oxygen consumption rate (OCR) assay, apoptosis measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution with isolated mitochondria plus cellular knockdown with multiple functional readouts\",\n      \"pmids\": [\"24407242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In palmitic acid-induced hepatocyte lipotoxicity, Sab knockdown or a membrane-permeable Sab blocking peptide prevented palmitic acid-induced mitochondrial impairment (decreased OCR) and inhibited the late phase of JNK activation and cell death, placing the JNK-Sab interaction downstream of PERK but upstream of sustained JNK activation and mitochondrial dysfunction.\",\n      \"method\": \"siRNA knockdown (adeno-shSab), cell-permeable blocking peptide, oxygen consumption rate (OCR) measurement, cell death assay, PERK/CHOP activation measurement\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockdown and pharmacological inhibition with multiple readouts, pathway epistasis established by PERK inhibition experiments\",\n      \"pmids\": [\"25666017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"p-JNK interacts with Sab on the outer mitochondrial membrane and phosphorylates it (requiring ATP), leading to release and activation of intramitochondrial SHP1 (PTPN6) from Sab on the inner face of the outer membrane; activated SHP1 transfers to the inner membrane where it dephosphorylates P-Y419Src (inactivating mitochondrial Src) via a platform protein DOK4; inactivation of mitochondrial Src inhibits electron transport, increases ROS, sustains JNK activation, and promotes cell death. Sab liver-specific knockout abrogated sustained JNK activation and liver injury.\",\n      \"method\": \"Liver-specific Sab knockout (Cre-lox), Sab knockdown, isolated mitochondria respiration assay, p-JNK + ATP addition to mitochondria, SHP1/DOK4 knockdown, mitochondrial fractionation, in vivo APAP and TNF/galactosamine models\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic KO combined with biochemical reconstitution in isolated mitochondria, component knockdowns (SHP1, DOK4) with functional readouts, in vivo validation in multiple models\",\n      \"pmids\": [\"26845758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sab-mediated signaling is required for imatinib mesylate-induced mitochondrial dysfunction in cardiomyocyte-like H9c2 cells; Sab knockdown or KIM1 peptide inhibition prevented ROS production, lipid peroxidation, impaired mitochondrial respiration, ATP loss, and apoptosis; overexpression of Sab increased cardiotoxicity; Sab expression was induced by cardiovascular-like stress in an AP-1-dependent manner.\",\n      \"method\": \"siRNA knockdown, overexpression, KIM1 inhibitory peptide, ROS measurement, Seahorse respiration assay, ATP assay, lipid peroxidation, protein carbonylation, apoptosis assay, AP-1 reporter\",\n      \"journal\": \"Toxicology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, overexpression, peptide inhibition) with consistent results across multiple functional readouts\",\n      \"pmids\": [\"28315715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sab is expressed in the adult mouse brain, enriched in hippocampus, ventral midbrain, and cerebellum; it localizes to mitochondria in neuronal soma, dendrites, and axons (confirmed by electron microscopy in hippocampal sections); inhibiting Sab-mediated signaling with Tat-SabKIM1 peptide decreased firing frequency and spike amplitudes in cultured hippocampal neurons.\",\n      \"method\": \"Confocal microscopy, electron microscopy, synaptosome purification, neuronal culture, electrophysiology with peptide inhibitor\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by EM with functional consequence demonstrated by electrophysiology, single lab\",\n      \"pmids\": [\"28606781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of SH3BP5 bound to Rab11 revealed a coiled-coil architecture mediating guanine nucleotide exchange through a unique Rab-GEF interaction; Rab11 switch I adopts a constrained conformation distinct from other Rab-GEF complexes; SH3BP5 functions as a GEF for Rab11 with specificity over evolutionarily similar Rab GTPases; GEF-deficient mutants of SH3BP5 showed greatly decreased Rab11 activation in cellular assays.\",\n      \"method\": \"Crystal structure determination, in vitro GEF assay, mutagenesis, cellular Rab11 activation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro biochemical reconstitution, mutagenesis, and cellular functional validation in single study\",\n      \"pmids\": [\"30217979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"REI-1, the C. elegans ortholog of SH3BP5, functions as a GEF for RAB-11; loss of REI-1 impaired RAB-11 targeting to the late-Golgi compartment and recycling endosomes, reduced RAB-11 recruitment to the cleavage furrow, and delayed cytokinesis; human SH3BP5 also exhibits GEF activity toward human Rab11.\",\n      \"method\": \"GEF activity assay (C. elegans and human proteins), loss-of-function genetics, fluorescence co-localization, cytokinesis timing assay\",\n      \"journal\": \"Communicative & integrative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GEF activity demonstrated biochemically for both C. elegans and human proteins, with genetic phenotypic validation in C. elegans\",\n      \"pmids\": [\"28003861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SAB expression levels determine severity of JNK-dependent liver injury in a sex-dependent manner; female mice express low hepatic SAB protein due to an ERα→p53→miR34a-5p pathway where miR34a-5p targets the Sab mRNA coding region to repress SAB expression; fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB, enhancing injury, while ERα agonist increased miR34a-5p and decreased SAB and hepatotoxicity in males.\",\n      \"method\": \"Liver-specific Sab deletion, GalNAc-ASO knockdown of Sab, p53 knockdown, fulvestrant/ERα agonist treatment, miR34a-5p measurement, mRNA targeting assay, in vivo liver injury models (APAP, TNF/galactosamine)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion, ASO knockdown, multiple pharmacological interventions, and pathway epistasis across multiple models in single study\",\n      \"pmids\": [\"31487267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In H9c2 cardiomyocyte-like cells, hypoxia/reoxygenation induces JNK activation, translocation to mitochondria via colocalization with Sab, and subsequent mitochondrial Src dephosphorylation; JNK inhibition or Sab siRNA reduced p-JNK/Sab colocalization, decreased Src dephosphorylation, and reduced mitochondrial ROS and oxidized cardiolipin, validating the JNK/Sab/Src/ROS pathway in cardiomyocyte ischemia/reperfusion injury.\",\n      \"method\": \"siRNA knockdown, JNK inhibitor, Src inhibitor PP2, confocal colocalization, ROS measurement, cardiolipin oxidation assay, mitochondrial membrane potential\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — corroborates established JNK/Sab/Src pathway in new cell context with siRNA and inhibitor validation, single lab\",\n      \"pmids\": [\"31205589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Trans-fatty acids (elaidic acid) facilitate DNA damage-induced apoptosis by driving the mitochondrial JNK-Sab-ROS positive feedback loop; Sab knockdown blocked EA-enhanced mitochondrial ROS generation and JNK activation induced by doxorubicin; pharmacological inhibition of SHP1 (a Sab-associated protein) also suppressed this pathway.\",\n      \"method\": \"siRNA knockdown of Sab, pharmacological inhibitors of JNK/ROS/SHP1, mitochondrial ROS measurement, apoptosis assay, C. elegans UV-lethality assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Sab knockdown with multiple functional readouts plus pharmacological confirmation, consistent with established pathway in new context\",\n      \"pmids\": [\"32066809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In HFHC diet-fed mice, SAB expression progressively increased through a sustained JNK/ATF2 activation loop; inducible hepatic Sab deletion or ASO knockdown markedly decreased sustained JNK activation, improved energy expenditure, reduced body fat, and prevented or reversed steatohepatitis and fibrosis; reversal of established NASH was achieved by GalNAc-Sab-ASO treatment.\",\n      \"method\": \"Inducible liver-specific Sab KO, antisense oligonucleotide knockdown (ASO, GalNAc-ASO), HFHC diet model, liver histology, p-JNK and p-ATF2 measurement, metabolic phenotyping\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus therapeutic ASO with in vivo NASH model, multiple timepoints and readouts; reversal experiment provides causal evidence\",\n      \"pmids\": [\"34331779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3-mediated m6A modification of SH3BP5 mRNA is read by YTHDF1, which maintains SH3BP5 mRNA stability; overexpression of SH3BP5 suppressed invasion of lung cancer cells in an m6A-dependent manner, and METTL3 suppresses lung cancer invasion through this SH3BP5 regulatory axis.\",\n      \"method\": \"METTL3/YTHDF1 overexpression and knockdown, SH3BP5 overexpression, m6A assay, invasion assay, mRNA stability assay\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic link to m6A stability relies on overexpression/knockdown with limited direct reconstitution of the modification event\",\n      \"pmids\": [\"38141906\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3BP5 (Sab) is a mitochondrial outer membrane scaffold/docking protein with two mechanistically distinct functions: (1) it serves as a substrate and docking site for activated JNK (via its KIM1 motif), enabling JNK to trigger an intramitochondrial signaling cascade—through SHP1 release/activation and DOK4—that inactivates Src on the inner membrane, impairs electron transport, and releases ROS, thereby sustaining a JNK-Sab-ROS positive feedback loop that drives apoptosis and organ injury; and (2) it acts as a guanine nucleotide exchange factor (GEF) for Rab11, adopting a coiled-coil architecture that activates Rab11 for roles in receptor recycling and membrane trafficking. Additionally, Sab negatively regulates Btk kinase activity in B cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SH3BP5 (Sab) is a mitochondrial outer-membrane scaffold protein that operates as the docking platform converting transient stress-kinase signaling into sustained mitochondrial dysfunction and cell death [#2, #8]. Stress-activated JNK binds Sab through its N-terminal KIM1 motif and is anchored on the outer mitochondrial membrane, where Sab serves as a JNK substrate; this interaction is required for JNK mitochondrial translocation, Bcl-2 phosphorylation, loss of membrane potential, and superoxide generation [#2, #5]. Phosphorylation of Sab by JNK (ATP-dependent) triggers release and activation of intramitochondrial SHP1 (PTPN6), which transfers via the platform protein DOK4 to the inner membrane and dephosphorylates/inactivates mitochondrial Src, impairing electron transport and elevating ROS; the resulting ROS sustains JNK activation, establishing a self-amplifying JNK–Sab–ROS feedback loop [#8]. This loop is the effector arm of diverse injury settings: ER-stress and PERK-driven lipotoxicity, acetaminophen and TNF/galactosamine liver injury, ischemia/reperfusion and drug cardiotoxicity, and diet-induced steatohepatitis, where genetic deletion or KIM1-peptide/ASO blockade of Sab interrupts the sustained JNK phase and protects against organ injury [#6, #7, #8, #16]. Sab abundance is a rate-limiting determinant of injury severity, set transcriptionally through a JNK/ATF2 loop and AP-1, and repressed in females via an ERα→p53→miR34a-5p pathway targeting Sab mRNA [#13, #16]. Independently of its mitochondrial role, SH3BP5 functions as a guanine nucleotide exchange factor specific for Rab11, using a coiled-coil architecture to activate Rab11 for receptor recycling, endosomal trafficking, and cytokinesis [#11, #12]. Sab was originally identified as a selective binding partner and negative regulator of the SH3 domain of Bruton's tyrosine kinase (Btk), dampening BCR-induced signaling in B cells [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the first molecular partner of Sab, defining it as an SH3-domain ligand with selectivity for Btk over other tyrosine kinases.\",\n      \"evidence\": \"Protein interaction cloning and SH3-domain binding/immunoprecipitation assays\",\n      \"pmids\": [\"9571151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding mode to the SH3 domain not structurally resolved\", \"Functional consequence of binding not yet shown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed the Btk interaction is functionally inhibitory, placing Sab as a negative regulator of BCR signaling and apoptosis in B cells.\",\n      \"evidence\": \"Overexpression in B cells with kinase, calcium, IP3, and apoptosis assays\",\n      \"pmids\": [\"10339589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Based on overexpression rather than loss-of-function\", \"Relationship between the Btk role and later mitochondrial role unexplained\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Reframed Sab as a mitochondrial JNK-interacting protein, identifying the KIM1 motif as the docking determinant and a distinct functional axis from Btk binding.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro kinase assay with mutagenesis, confocal microscopy and fractionation\",\n      \"pmids\": [\"12167088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream mitochondrial consequence of JNK docking not yet defined\", \"Whether phosphorylation alters Sab activity unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the kinase repertoire docking at Sab by showing SAPK3/p38 also phosphorylates it on Ser321 via KIM1, indicating shared mitochondrial substrate use.\",\n      \"evidence\": \"In vitro kinase assay, site-directed mutagenesis, subcellular fractionation\",\n      \"pmids\": [\"15158451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular significance of Ser321 phosphorylation not established\", \"p38-driven outcome via Sab not demonstrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that JNK–Sab docking is mechanistically required for mitochondrial JNK actions and that it can be selectively blocked, separating mitochondrial from nuclear (c-Jun/AP-1) JNK signaling.\",\n      \"evidence\": \"siRNA, Tat-SabKIM1 peptide, JNK translocation, Bcl-2 phosphorylation, membrane potential and superoxide assays\",\n      \"pmids\": [\"21563797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intramitochondrial relay from Sab to ROS not yet defined\", \"Direct substrate of mitochondrial JNK unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the JNK–Sab–ROS feedback loop by reconstituting p-JNK/ATP-driven superoxide production in isolated mitochondria and linking it to sustained JNK activation in ER stress.\",\n      \"evidence\": \"siRNA, isolated-mitochondria respiration and superoxide assays, KIM1 blocking peptide, cellular OCR and apoptosis\",\n      \"pmids\": [\"24407242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular intermediates between Sab phosphorylation and respiratory impairment not yet identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the intramitochondrial relay: JNK-phosphorylated Sab releases SHP1 which, via DOK4, inactivates inner-membrane Src to impair electron transport and amplify ROS, with in vivo liver-injury validation.\",\n      \"evidence\": \"Liver-specific Sab KO, isolated-mitochondria reconstitution, SHP1/DOK4 knockdown, APAP and TNF/galactosamine models\",\n      \"pmids\": [\"26845758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SHP1 sequestration by Sab unknown\", \"How Src inactivation impairs electron transport mechanistically not fully defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed the Sab loop downstream of PERK in lipotoxicity, defining pathway epistasis for the sustained JNK phase in hepatocytes.\",\n      \"evidence\": \"adeno-shSab, blocking peptide, OCR, cell death, PERK/CHOP measurements\",\n      \"pmids\": [\"25666017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between PERK output and JNK–Sab engagement not molecularly traced\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Generalized the Sab loop beyond liver to cardiomyocyte drug toxicity and showed Sab expression is stress-inducible via AP-1.\",\n      \"evidence\": \"siRNA, overexpression, KIM1 peptide, Seahorse, ROS/ATP/lipid peroxidation assays, AP-1 reporter (H9c2)\",\n      \"pmids\": [\"28315715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo cardiac relevance not tested in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed Sab is expressed at neuronal mitochondria and that its signaling modulates neuronal excitability, extending its physiology beyond injury contexts.\",\n      \"evidence\": \"Confocal and electron microscopy, synaptosome purification, neuronal electrophysiology with Tat-SabKIM1\",\n      \"pmids\": [\"28606781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking Sab signaling to firing properties unresolved\", \"No in vivo neuronal phenotype\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a wholly distinct biochemical function: SH3BP5/REI-1 acts as a Rab11 GEF controlling endosomal recycling, Golgi targeting and cytokinesis, conserved from C. elegans to human.\",\n      \"evidence\": \"GEF assays for worm and human proteins, loss-of-function genetics, co-localization, cytokinesis timing\",\n      \"pmids\": [\"28003861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between mitochondrial and GEF functions in the same cell unknown\", \"Subcellular site of GEF activity not pinned to specific membranes\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the structural mechanism of the GEF function, showing a coiled-coil architecture that catalyzes Rab11 nucleotide exchange with specificity over related Rabs.\",\n      \"evidence\": \"Crystal structure of SH3BP5–Rab11, in vitro GEF assay, mutagenesis, cellular Rab11 activation\",\n      \"pmids\": [\"30217979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the GEF and JNK-docking activities are spatially partitioned within the protein not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed Sab abundance is rate-limiting for injury and is set sex-dependently through an ERα→p53→miR34a-5p axis repressing Sab mRNA.\",\n      \"evidence\": \"Liver-specific deletion, GalNAc-ASO, p53 knockdown, fulvestrant/ERα agonist, miR34a-5p targeting assays, in vivo injury models\",\n      \"pmids\": [\"31487267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this regulation operates in non-hepatic tissues untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Validated the JNK/Sab/Src/ROS pathway in cardiomyocyte ischemia/reperfusion, confirming Src dephosphorylation and cardiolipin oxidation as downstream events.\",\n      \"evidence\": \"siRNA, JNK and Src inhibitors, confocal colocalization, ROS and cardiolipin oxidation assays (H9c2)\",\n      \"pmids\": [\"31205589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-line model only; no in vivo cardiac confirmation in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected dietary trans-fatty acids to potentiation of the Sab feedback loop during DNA-damage-induced apoptosis.\",\n      \"evidence\": \"Sab siRNA, JNK/ROS/SHP1 inhibitors, mitochondrial ROS and apoptosis assays, C. elegans UV-lethality\",\n      \"pmids\": [\"32066809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How trans-fatty acids prime the loop mechanistically unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated therapeutic tractability: inducible Sab deletion or ASO knockdown prevents and reverses diet-induced steatohepatitis and fibrosis via interruption of the JNK/ATF2 loop.\",\n      \"evidence\": \"Inducible liver-specific KO, GalNAc-Sab-ASO, HFHC diet model, histology, metabolic phenotyping\",\n      \"pmids\": [\"34331779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability and off-target consequences of chronic Sab suppression not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked SH3BP5 expression to an m6A regulatory axis (METTL3/YTHDF1) with a tumor-suppressive effect on lung cancer invasion.\",\n      \"evidence\": \"METTL3/YTHDF1 perturbation, SH3BP5 overexpression, m6A, invasion and mRNA stability assays\",\n      \"pmids\": [\"38141906\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab, overexpression-based; direct m6A modification of SH3BP5 not reconstituted\", \"Which SH3BP5 function mediates invasion suppression unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the mitochondrial JNK-docking/scaffold function and the cytosolic/endosomal Rab11-GEF function are reconciled within one protein — and whether they are co-active or context-switched in the same cell — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No study tests both activities in the same system\", \"Determinants partitioning Sab between mitochondria and recycling endosomes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 8, 10]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 8, 15]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 1]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JNK\", \"BTK\", \"SHP1\", \"DOK4\", \"RAB11\", \"SAPK3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}